Candidate metabolite markers of peripheral neuropathy in Chinese patients with type 2 diabetes.

OBJECTIVES: To analyze the serum and urine metabolites present in type 2 diabetes mellitus (T2DM) patients and T2DM patients with diabetic peripheral neuropathy (DPN) and to select differentially expressed biomarkers for early diagnosis of DPN. METHODS: Serum and urine metabolites from 74 T2DM patients with peripheral neuropathy and 41 without peripheral neuropathy were analyzed using gas chromatograph system with time-of-flight mass spectrometer metabolomics to detect biomarkers of peripheral neuropathy in T2DM. RESULTS: There were increased serum triglycerides, alanine aminotransferase, and decreased C-peptide, and total cholesterol levels in T2DM patients with DPN compared to those without peripheral neuropathy. Metabolomic analysis revealed visible differences in metabolic characteristics between two groups, and overall 53 serum differential metabolites and 56 urine differential metabolites were identified with variable influence on projection (VIP) >1 and P<0.05. To further analyze the correlation between the identified metabolites and DPN, four serum metabolites and six urine metabolites were selected with VIP>2, and fold change (FC) >1, including serum ß-alanine, caproic acid, ß-alanine/L-aspartic acid, and L-arabinose/L-arabitol, and urine gluconic acid, erythritol, galactonic acid, guanidoacetic acid, cytidine, and aminoadipic acid. Furthermore, five serum biomarkers and six urine biomarkers were found to show significant changes (P<0.05, VIP>1, and FC>1) respectively in patients with mild, moderate, and severe DPN. In addition, we found that glyoxylate and dicarboxylate metabolism was a differential metabolic pathway not only between T2DM and DPN, but also among different degrees of DPN. The differential metabolites such as ß-alanine and caproic acid are expected to be biomarkers for DPN patients, and the significant changes in glyoxylate and dicarboxylate metabolism may be related to the pathogenesis of DPN. CONCLUSION: There were serum and urine spectrum metabolomic differences in patients with DPN, which could serve as biomarkers for T2DM and DPN patients.

Apatinib Inhibits Angiogenesis in Intrahepatic Cholangiocarcinoma by Regulating the Vascular Endothelial Growth Factor Receptor-2/Signal Transducer and Activator of Transcription Factor 3/Hypoxia Inducible Factor 1 Subunit Alpha Signaling Axis.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC), which is difficult to diagnose and is usually fatal due to its late clinical presentation and a lack of effective treatment, has risen over the past decades but without much improvement in prognosis. OBJECTIVE: The study aimed to investigate the role of apatinib that targets vascular endothelial growth factor receptor-2 (VEGFR2) in ICC. METHODS: MTT assays, cell scratch assays, and tube formation assays were used to assess the effect of apatinib on human ICC cell line (HuCCT-1) and RBE cells proliferation, migration, and angiogenic capacity, respectively. Expression of vascular endothelial growth factor (VEGF), VEGFR2, signal transducer and activator of transcription factor 3 (STAT3), pSTAT3, and hypoxia inducible factor 1 subunit alpha (HIF-1α) pathway proteins was assessed using Western blotting and mRNA expression analysis in HuCCT-1 was performed using RT-qPCR assays. The pcDNA 3.1(-)-VEGFR2 and pcDNA 3.1(-)-HIF-1α were transfected into HuCCT-1 and RBE cells using Lipofectamine 2,000 to obtain overexpressed HuCCT-1 and RBE cells. RESULTS: We found that apatinib-inhibited proliferation, migration, and angiogenesis of HuCCT-1 and RBE cells in vitro in a dose-dependent manner. We also proved that apatinib effectively inhibits angiogenesis in tumor cells by blocking the expression of VEGF and VEGFR2 in these cells. In addition, we demonstrated that apatinib regulates the expression of STAT3 phosphorylation by inhibiting VEGFR2. Finally, we showed that apatinib regulates ICC angiogenesis and HIF-1α/VEGF expression via STAT3. CONCLUSIONS: Based on the above findings, we conclude that apatinib inhibits HuCCT-1 and RBE cell proliferation, migration, and tumor angiogenesis by inhibiting the VEGFR2/STAT3/HIF-1α axis signaling pathway. Apatinib can be a promising drug for ICC-targeted molecular therapy.

[Regulatory effects of glabridin and quercetin on energy metabolism of breast cancer cells].

It is reported that energy metabolism is the core feature of tumor cells. This study is aimed to investigate the regulatory effect of two flavonoids( glabridin and quercetin) on energy supply and glycolysis of breast cancer cells,and provide reference for developing some anticancer herbal drugs with the function of regulating tumor energy metabolism. Based on the characteristics of each pathway during energy metabolism,in the present study,the triple negative breast cancer tumor cells( MDA-MB-231) were selected to investigate the effects of glabridin and quercetin on the energy metabolism of breast cancer cells and discuss the possible mechanisms from the following five potential targets: glucose uptake,protein expression of glucose transporter 1( GLUT1),adenosine triphosphate( ATP) level,lactate dehydrogenase( LDH) activity,and lactic acid( LD) concentration. The results showed that both quercetin and glabridin could decrease the glucose uptake capacity of breast cancer cells by down-regulating the protein expression of GLUT1. Quercetin had no significant effect on LDH activity and LD concentration; it did not affect the glycolysis process,but increased the intracellular ATP level. Glabridin decreased the activity of LDH and reduced LD concentration,thereby inhibiting the glycolysis metabolism of breast cancer cells. Therefore,both quercetin and glabridin can regulate the energy metabolism of breast cancer cells and can be used as potential anticancer agents or anti-cancer adjuvants.

Relation Between Cellular Senescence and Liver Diseases.

Cellular senescence refers to a process that cellular proliferation and differentiation modulated by the multiple stimulating factors gradually decline. Aging cells present the irreversible stop of proliferation and differentiation and change in secretory function because the cell cycle of aging cells is steadily blocked at some point. It has have been shown that cellular senescence plays an important role in the occurrence and development of liver diseases. In this paper, we review the advances in relations between cellular senescence and liver diseases.

Acorus tatarinowii Schott extract protects PC12 cells from amyloid-beta induced neurotoxicity.

Amyloid-beta induced neurotoxicity has been identified as a major cause of Alzheimer's disease. Acorus tatarinowii Schott is one of the most frequently used Chinese herbs for Alzheimer's disease treatment. However, the effects of Acorus tatarinowii Schott on amyloid-beta mediated nerve cell damage remains unknown. In the present study, neuronal differentiated PC12 cells were used as a model to evaluate the effects of A. tatarinowii Schott extract (ATSE) against Abeta25-35 induced neurotoxicity. The results showed pretreatment with ATSE significantly protected PC12 cells from Abeta25-35 induced cell death, lactate dehydrogenase release, DNA damage, mitochondrial dysfunction and cytochrome c release from mitochondria. In addition, pretreatment with ATSE also significantly inhibited Abeta25-35 induced caspase-3 activation and reactive oxygen species generation in PC12 cells. These observations suggested that ATSE protects PC12 cells from amyloid-beta induced neurotoxicity.

Effect of the Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia.

OBJECTIVE: To investigate the effect of Chinese medicine prescription-Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia and its influence on the immune function. METHODS: A total of 48 Wistar rats were randomly divided into the normal control group, the damp-heat syndrome model group, the Haoqinqingdan decoction group (high, medium and low dose group) and the ribavirin group. The body temperature and weight of rats in each group were recorded after modeling. After treatment for 6 d, the concentration of T lymphocyte subgroup (CD3(+)CD4(+), CD3(+)CD8(+)) was determined by flow cytometry. The OD value of IFN-γ/IL-4 was detected by double-antibody sandwich ELISA method, and its concentration was acquired through conversion. RESULTS: After modeling, the temperature and weight of rats in each modeling group showed the increasing trend (P<0.01). From the second day of treatment, there was significant difference in the body mass between groups, and the rat weight of the control group was higher than in the modeling group (P<0.05 or 0.01). With the advances of treatment, only the temperature in the medium and high dose Haoqinqingdan decoction groups declined significantly (P<0.05). After treatment, the CD4(+)/CD8(+) ratio of the damp-heat syndrome model group decreased more significantly compared with the control group. Elevated CD3(+) CD8(+) percentages and declined CD4(+)/CD8(+) ratios can be observed in the low dose group and ribavirin group (P<0.05). Moreover, the CD3(+) CD4(+) percentage of ribavirin group was lower than in the control group (P<0.05). After treatment, the IFN-γ and IFN-γ/ IL-4 levels in the peripheral blood of rats in the damp-heat syndrome group were obviously higher than in the control group (P<0.05). CONCLUSIONS: Compared with ribavirin, the high dose Haoqinqingdan decoction can improve the ratio of T lymphocyte subgroup and Th1/Th2 cell balance more effectively.

Clinical evaluation of oral Fructus bruceae oil combined with radiotherapy for the treatment of esophageal cancer.

OBJECTIVE: To evaluate the therapeutic efficacy and side effects of oral Fructus bruceae oil combined with radiotherapy in the treatment of esophageal cancer. METHODS: A total of 80 patients with esophageal cancer were equally and randomly divided into two groups. The patients in Group A were treated with radiotherapy (60-65 Gy, 6-7 weeks) and oral Fructus bruceae oil (20 mL, 3 times per day for 12 weeks), while the patients in Group B were treated with radiotherapy alone. The short-term effect was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) and quality of life (QOL) was evaluated by the Karnofsky scoring (KFS). The outcome measures included complete remission (CR) rate, partial remission (PR) rate, effective rate as CR+PR, patients' QOL and adverse effects. RESULTS: After 12-week treatment, the CR and CR+PR were significantly higher in Group A than those in Group B (P <0.05). There was an improvement in esophageal obstruction of 87.5% and 60.0%, respectively, and in KFS of 84.6% and 43.9%, respectively, in Groups A and B. CONCLUSION: Oral medication with oral Fructus bruceae oil could effectively improve the efficacy of radiotherapy in esophageal cancer, including a reduction in esophageal obstruction, and also reduce the side effects of radiotherapy; thus it would be very promising for clinical application.

[Application study of the 2008 staging system of nasopharyngeal carcinoma].

BACKGROUND AND OBJECTIVE: The 2008 staging system of nasopharyngeal carcinoma (NPC) was generated based on the NPC 92 and AJCC staging system. It remains open to be consummated. This study was to evaluate its rationality as well as compare the stage distribution among the 3 staging systems, by using of MRI imaging. METHODS: MRI data was collected from a cohort of 177 cases of untreated NPC for retrospective review. We accepted the nasal involvement criteria of 2008 staging system, in which the borderline between the nasal cavity and nasopharynx was a line linked between both posterior walls of the maxillary sinus, for all of the 3 systems. RESULTS: Involvement of oropharynx, nasopharynx, soft palatine, prevertebral muscles, post-styloid space, intracranial, orbit, 1st and/or 2nd cervical body are 100% accompanied with other same or more advanced T-stage classifications. The same situations happened in more than 95% of involvement of the medial pterygoid muscle or masticator space beyond it. Cervical lymph node metastasis (LNM) accounted for 76.3%. Proportion of metastatic lymph node extracapsular extension (ECE) and/or bilateral neck LNM elevated as maximum diameter of the node increased, no matter transverse or longitudinal. There were 11 cases of parotid LNM in this group. Advanced stage accounted for 81.4%, 78.5% and 75.7% in 2008, UICC and NPC 92 staging system, respectively, without statistic difference. CONCLUSION: Nasal involvement criteria and T-stage classification of the medial pterygoid muscle defined by NPC 2008 staging system seems reasonable. Stage distribution is also similar to the other 2 systems. However, diameter of the LNM might not be a prognostic factor. Parameters such as how to classify a parotid LNM, or a node which occupies more than one region, require further clarify.

[Influence of patient setup error on planning risk volumes for nasopharyngeal carcinoma patients receiving intensity-modulated radiation therapy].

BACKGROUND & OBJECTIVE: Determination of planning risk volumes (PRVs) for an organ at risk greatly affects dose optimization in designing the intensity-modulated radiation therapy (IMRT) regimen. Patient setup errors have been found to closely correlate to the definition of PRVs. This study was to investigate the safety margin for the organ at risk during IMRT planning for nasopharyngeal carcinoma (NPC) patients. METHODS: Nineteen NPC patients (stage T1-2N0M0) who received IMRT for the first time were studied. Repeated computed tomography (CT) scans were performed for the patients once a week during the whole treatment course. A total of 85 CT scan reports were obtained. Differences between patient positioning of each time and first treatment setup were caluculated by comparing the anatomical landmarks (that is, optical nerve, pituitary, spine, and parotid) on each CT scan image using Osiris software. RESULTS: The displacement of optical nerve and pituitary in X, Y, and Z directions were, in absolute values, (0.86+/-0.53) mm, (0.84+/-0.68) mm, and (0.93+/-1.02)mm, respectively. The standard deviations (SDs) of systematic errors for the axial vector displacement were 0.83 mm, 1.08 mm, and 1.21 mm, while the SDs of random errors were 0.85 mm, 0.83 mm and 1.14 mm. The displacement of spine and parotid in X, Y, and Z directions were, in absolute values, (0.98+/-0.74) mm, (1.25+/-0.88) mm, and (1.43+/-1.02) mm, respectively. The SDs of systematic errors for axial vector displacement were 0.98 mm, 1.35 mm, and 1.87 mm, while the SDs of random errors were 1.02 mm, 1.46 mm, and 1.54 mm. CONCLUSION: It is feasible to determine the size of a safety margin of IMRT for organs at risk using repeated CT scans for NPC patients.

[Design planning target volumes (PTVs) in intensity-modulated radiotherapy for nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Intensity-modulated radiotherapy (IMRT) may help to diminish radiation-induced normal tissue damage and improve quality of life of nasopharyngeal carcinoma (NPC) patients. However, highly conformal treatment techniques commonly establish steep dose gradients between tumor and normal tissues, therefore, daily setup variations can significantly compromise the ultimate precision of idealized IMRT delivery. This study was to investigate the setup accuracy of thermoplastic masks used for immobilizing NPC patients treated by simultaneous integrated boost IMRT, and to determine adequate margins to account for those uncertainties. METHODS: Nineteen patients with early stage (T1-2N0M0) NPC received CT scan weekly during their 6-week treatment course of fractionated IMRT. A total of 85 scanning parameters were obtained. The differences in anatomic landmark coordinates in 3-dimensional directions between daily setup and the first day setup were calculated through comparing the CT images with Osiris software. RESULTS: Mean target isocenter translation was (0.89+/-0.69) mm in x-direction, (0.82+/-0.79) mm in y-direction, and (0.95+/-1.24) mm in z-direction. The systematic errors were 0.94 mm, 1.00 mm, and 1.32 mm. The random errors were 0.87 mm, 0.80 mm, and 1.04 mm. The mean total magnitude vector of isocenter motion was 1.87 mm; the 95% confidence interval (CI) was 2.03-7.24 mm. CONCLUSION: During IMRT for early stage nasopharyngeal carcinoma, setting appropriate margin of planning target volume (PTV) by widening 3 mm from clinical target volume (CTV) in x, y, z directions will be sufficient to compensate for the dosimetric uncertainty of target areas due to patient setup error. The measured data in the present study should enable the user of this kind of thermoplastic mask to assign appropriate margins for the generation of planning target volumes (PTVs).

Study on photocatalytic degradation of several volatile organic compounds.

The gas-phase photolytic and photocatalytic reactions of several aromatics and chlorohydrocarbons were investigated. The experimental results revealed that chlorohydrocarbons like trichloroethylene, dichloromethane and chloroform could be degraded through either photolysis or photocatalysis under irradiation of germicidal lamp, and the elimination rate of chlorohydrocarbons through photolysis was quicker than that through photocatalysis. UV light from a germicidal lamp could directly lead to degradation of toluene but could hardly act on benzene. The photodegradation rate for these volatile organic compounds (VOCs) through photolysis followed an order: trichloroethylene>chloroform>dichloromethane>toluene>benzene>carbon tetrachloride, and through photocatalysis followed: trichloroethylene>chloroform>toluene>dichloromethane>benzene>carbon tetrachloride. Besides, a series of modified TiO2 photocatalysts were prepared by depositing noble metal, doping with transition metal ion, recombining with metal oxides and modifying with super strong acid. Activity of these catalysts was examined upon photocatalytic degradation of benzene as a typical compound that was hard to be degraded. It indicated that these modification methods could promote the activity of TiO2 catalyst to different extent. The apparent zero-order reaction rate constant for degrading benzene over SnO2/TiO2 catalyst had the highest value, which was nearly three times as that over P25 TiO2. But it simultaneously had the lowest rate for mineralizing the objective compound. In spite that Fe3+/TiO2 catalyst behaved slightly less active than SnO2/TiO2 for degradation of benzene, the mineralization rate over Fe3+/TiO2 was the highest one among the prepared catalysts.

Photoassisted reaction of sulfur mustard under UV light irradiation.

The photoassisted reaction of sulfur mustard (HD) in both the vapor and droplet states under UV light irradiation was investigated. It was found that HD molecules in either the gas or the condensed phase could be easily converted into other chemicals under the irradiation of a germicidal lamp. The products detected upon reaction suggested that the photoassisted reaction of HD molecules in the gas phase produced a kind of nontoxic heavy polymer, and this method seemed to be applicable for decontamination of air. Nevertheless, the photoassisted reaction of HD droplets would produce a series of products containing -SCH2CH2Cl or -OCH2CH2CI groups, some of which were proven to be even more toxic than HD. Therefore, it was not an effective method forthe decontamination of HD droplets. The obtained experimental results would indicate that two possible pathways might be involved in the destruction of HD molecules: (1) HD molecules may undergo a photochemical reaction upon absorbing photons of sufficient energy, which leads to cleavage the C-S bond in HD molecules at the primary step, or (2) HD molecules could be oxidized by the photogenerated ozone.

Photoassisted reaction of chemical warfare agent VX droplets under UV light irradiation.

A photoassisted reaction of O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) droplets in air was carried out. The experimental results indicated that VX droplets could be easily and chemically transformed into other compounds under irradiation of a germicidal lamp over sufficient time. Quantum chemical calculation results demonstrated that UV light less than 278 nm wavelength could possibly initiate photoreaction of VX and that both P-S and P=O bonds in the VX molecule were lengthened. The identification of reaction products by gas and liquid chromatography mass spectroscopy and NMR revealed that the VX molecule in air under UV light irradiation could undergo isomerization of S-esters to O-esters, cleavage of P-S, S-C, and C-N bonds, and ozonation of tertiary amines.