Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice.

Diabetic kidney disease is one of the most serious complications of diabetes. Although diabetic kidney disease can be effectively controlled through strict blood glucose management and corresponding symptomatic treatment, these therapies cannot reduce its incidence in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2) inhibitors and the traditional Chinese herb "Gegen" have been widely used in diabetes-related therapy. However, it remains unclear whether the combined use of these two kinds of medicines contributes to an increased curative effect on diabetic kidney disease. In this study, we examined this issue by evaluating the efficacy of the combination of puerarin, an active ingredient of Gegen, and canagliflozin, an SGLT2 inhibitor for a 12-week intervention using a mouse model of diabetes. The results indicated that the combination of puerarin and canagliflozin was superior to canagliflozin alone in improving the metabolic and renal function parameters of diabetic mice. Our findings suggested that the renoprotective effect of combined puerarin and canagliflozin in diabetic mice was achieved by reducing renal lipid accumulation. This study provides a new strategy for the clinical prevention and treatment of diabetic kidney disease. The puerarin and SGLT2 inhibitor combination therapy at the initial stage of diabetes may effectively delay the occurrence of diabetic kidney injury, and significantly alleviate the burden of renal lipotoxicity.

Affective Computing Based on Morphological Features of Photoplethysmography for Patients with Hypertension.

Negative and positive emotions are the risk and protective factors for the cause and prognosis of hypertension. This study aimed to use five photoplethysmography (PPG) waveform indices and affective computing (AC) to discriminate the emotional states in patients with hypertension. Forty-three patients with essential hypertension were measured for blood pressure and PPG signals under baseline and four emotional conditions (neutral, anger, happiness, and sadness), and the PPG signals were transformed into the mean standard deviation of five PPG waveform indices. A support vector machine was used as a classifier. The performance of the classifier was verified by using resubstitution and six-fold cross-validation (CV) methods. Feature selectors, including full search and genetic algorithm (GA), were used to select effective feature combinations. Traditional statistical analyses only differentiated between the emotional states and baseline, whereas AC achieved 100% accuracy in distinguishing between the emotional states and baseline by using the resubstitution method. AC showed high accuracy rates when used with 10 waveform features in distinguishing the records into two, three, and four classes by applying a six-fold CV. The GA feature selector further boosted the accuracy to 78.97%, 74.22%, and 67.35% in two-, three-, and four-class differentiation, respectively. The proposed AC achieved high accuracy in categorizing PPG records into distinct emotional states with features extracted from only five waveform indices. The results demonstrated the effectiveness of the five indices and the proposed AC in patients with hypertension.

[Effects of heterogeneous habitats on the coexistence of aquatic ecotype Alternanthera philoxeroides and Paspalum paspaloides]. / 异质生境对水生型空心莲子草-åŒç©—é›€ç¨—å ±å­˜çš„å½±å“.

Species coexistence depends on the comprehensive effects of biological properties and habitat heterogeneity. Based on a large-scale field survey (21°-35° N), we compared the differences on morphological and stoichiometric characteristics between the invasive aquatic species Alternanthera philoxeroides and the native co-occurring species Paspalum paspaloides, and examined the effects of environmental factors on such differences. The results showed that the coverage and importance value (IV) of A. philoxeroides were all significantly greater than P. paspa-loides (34.3% and 104.0%, respectively), whereas the height of P. paspaloides was significantly greater than A. philoxeroides (13.8%). Moreover, the total nitrogen concentration (TN) and N:P of A. philoxeroides were significantly greater than those of P. paspaloides (55.1% and 55.8%, respectively), whereas the total carbon concentration (TC) and C:N of P. paspaloides were significantly greater than those of A. philoxeroides (4.1% and 83.8%, respectively). A. philoxeroides coverage increased with the increases of longitude, and its abundance increased with the increases of water nitrate concentration and longitude, while its IV increased with the increases of water ammonium concentration. However, the coverage, abundance, and IV of P. paspaloides decreased with the increases of ammonium concentration. C:N of A. philoxeroides decreased with the increase of ammonium concentration. Increased mean annual temperature and mean annual precipitation increased C:N but decreased N:P of P. paspa-loides. The C:P of both species decreased with the increases of ammonium concentration and electrical conductivity. N:P of A. philoxeroides was little affected by environment. These results indicated that A. philoxeroides had greater coverage and N absorption capacity than P. paspaloides, and that enriched water nitrogen would aggravate the invasion of A. philoxeroides. Meanwhile, P. paspaloides improved its C-assimilate reserves and chose the growth competition strategy for resisting A. philoxeroides invasion under the superior hydrothermal conditions. Different responses to environmental changes contributed to their coexistence in aquatic ecosystem.

Response of carbon, nitrogen and phosphorus concentration and stoichiometry of plants and soils during a soybean growth season to O3 stress and straw return in Northeast China.

Carbon (C), nitrogen (N) and phosphorus (P) concentrations and stoichiometry play important roles in biogeochemical cycles of the ecosystems, yet it is still unclear how the allocations of C, N and P concentrations and stoichiometry among plant organs and soils related to O3 stress and straw return. Here, a pot experiment was conducted in open top chambers to monitor the response of C, N and P concentrations and stoichiometry of leaves, stems, roots and soils during a growing season (branching, flowering and podding stages) of soybean (Glycine max; a species highly sensitive to O3) to background O3 concentration (44.8 ± 5.6 ppb), O3 stress (79.7 ± 5.4 ppb) and straw treatment (no straw return and straw return). O3 stress significantly decreased root biomass. Straw return significantly increased root biomass under O3 stress at branching and flowering stages. Generally, O3 stress and straw return showed significant effects on the C, N and P concentrations of leaves and soils, and stoichiometric ratios of leaves, stems and microbial biomass. The C, N and P concentrations and stoichiometry of leaves, stems, roots and soils in response to O3 stress and straw return at the branching stage were inconsistent with the changes observed at the flowering and podding stages. The P conversion efficiency showed significant relationship with root P concentration under the combined effects of O3 stress and straw return. Altogether, the present study indicated that C, N and P concentrations of soybean might be more important than stoichiometric ratios as a driver of root defence against O3 stress in the case of straw return.

Electroencephalogram patterns in patients comorbid with major depressive disorder and anxiety symptoms: Proposing a hypothesis based on hypercortical arousal and not frontal or parietal alpha asymmetry.

BACKGROUND: Major depressive disorder (MDD) is often comorbid with anxiety disorders or symptoms. Brain hyperactivity, frontal alpha asymmetry (FAA), and parietal alpha asymmetry (PAA) have been considered as trait markers in patients with MDD. This study investigated the electroencephalogram (EEG) patterns among patients with MDD comorbid with anxiety symptoms. METHODS: One hundred and thirty-five patients with MDD comorbid with anxiety (MDD group) and 135 healthy controls (HC group) were analyzed. The Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) were completed, and 19 EEG channels were measured during the resting state, depressive recall and recovery tasks, and happiness recall and recovery tasks. FAA and PAA were computed by log (F4 alpha)-log (F3 alpha) and log (P4 alpha)-log (P3 alpha). RESULTS: The FAA and PAA indices between the two groups showed no significant differences; however, compared with the HC group, the MDD group had lower total delta and theta values, and higher total beta, low beta, and high beta values in the resting state. The total beta value positively correlated with the BDI-II and BAI scores in the MDD group. LIMITATIONS: Most patients had anxious MDD and taking prescriptions, antidepressants or benzodiazepine may affect EEG patterns. CONCLUSION: Compared with HCs, patients with MDD comorbid with anxiety had a higher beta activity in the entire brain region, supporting the role of brain hyperactivity, instead of FAA or PAA, as a trait marker in these patients. A neurofeedback protocol could be developed in future based on the brain hyperactivity findings.

A Single Session of Heart Rate Variability Biofeedback Produced Greater Increases in Heart Rate Variability Than Autogenic Training.

Heart rate variability biofeedback (HRV-BF) has been confirmed to increase heart rate variability (HRV) and cardiac outflows by baroreflex in healthy populations and clinical patients. Autogenic training (AT) is common used in the psychological intervention. This study integrates a single-session of HRV-BF and AT into a high-technology mobile application (app), and examines the effects on HRV indices, breathing rates, and subjective relaxation scores. Healthy college students were recruited and assigned to the single-session HRV-BF group or AT group. Participants in the HRV-BF group received HRV-BF combined with paced breathing training, which gradually stepped down their breathing rates from 12, to 8, to 6 breaths/per min; and received feedback of HRV indices from the app. Participants in the AT group received autogenic training and feedback of heart rate from the app. A chest belt Zephyr BioHarness was connected through Bluetooth to a Zenfone5 mobile phone, it collected the signals of interbeat intervals and breathing rates at pre-training, mid-training, and post-training stages. The Kubios HRV software was used to analyze HRV indices. The results reveal higher HRV indices and lower breathing rates during mid-training and post-training in the HRV-BF group compared to the AT group. There were higher high-frequency of HRV at post-training than pre-training in the AT group. Participants of both groups increased their subjective relaxation scores after training. The HRV-BF protocol increased cardiac outflows by baroreflex and decreased breathing rates, and the AT protocol increased high-frequency of HRV. These high-technology wearable devices combined with psychological interventions will apply to various populations in the future.

Serial measurements of cardiac troponin I in heart failure secondary to canine mitral valve disease.

Serial measurements of cardiac troponin I (cTnI) levels are considered to be better predictors of cardiac death than single-time-point analyses in human medicine. We hypothesised that cTnI levels could reflect the severity of myxomatous mitral valve disease (MMVD), and that serial changes in the cTnI level had a prognostic value in dogs with congestive heart failure (CHF) secondary to MMVD. Seventy-six dogs were initially enrolled and classified by the American College of Veterinary Internal Medicine (ACVIM) staging system. The single-timepoint cTnI concentration in these dogs significantly increased with the ACVIM stage. Twenty-seven dogs with CHF subsequently underwent serial measurement of cTnI levels, and the results showed that those who demonstrated a decrease in cTnI levels from the first to the third visit exhibited a higher risk of cardiac death than did those without such changes (P=0.012). We suspect that the downward trend in cTnI levels may be affected by medical treatment for CHF. In conclusion, although cTnI levels could reflect the severity of MMVD to a certain extent, the serial changes may be affected by medical treatment. Therefore, caution should be exercised when cTnI is used for assessment of the prognosis of CHF secondary to MMVD in dogs.

The effects of alpha asymmetry and high-beta down-training neurofeedback for patients with the major depressive disorder and anxiety symptoms.

BACKGROUND: Alpha-asymmetry neurofeedback (ALAY) was applied to patients with major depressive disorder (MDD) based on the theory of frontal alpha asymmetry. Neurophysiological studies have found a higher high-beta activity of electroencephalography (EEG) at the posterior cortex among patients with comorbid MDD and anxiety symptoms. The present study examined the effects of ALAY and high-beta down-training (Beta) neurofeedback in symptoms of depression and anxiety and EEG parameters. METHOD: Eighty-seven patients with comorbid MDD and anxiety symptoms were allocated to the ALAY, Beta, or control groups. Both neurofeedback groups received ten-session neurofeedback. All participants completed the Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), and five minutes resting EEG recording at pre-test and post-test. EEG raw signals were transformed into an A1 score [log (F4 alpha) - log (F3 alpha)], P3 and P4 high-beta power. RESULTS: BDI-II and BAI scores decreased at post-test in both ALAY and Beta groups, but no significant difference between the two groups. No significant interaction effect in A1 score at pre-test and post-test between the ALAY, Beta, and control groups. The P3 high-beta was significantly decreased in the Beta group, an increase in the control group, and no change in the ALAY group at post-test compared to the pre-test. CONCLUSIONS: Both neurofeedback groups decreased symptoms of depression and anxiety. The Beta group was more effective in decreasing high-beta power at the parietal cortex compared to other groups. This non-invasive psychological intervention can be used in the future for patients with comorbid MDD and anxiety symptoms.

[Therapeutic effects of Bianyanning decoction on acute pharyngitis in rats and its mechanism].

OBJECTIVE: To investigate the therapeutic effects and mechanisms of Bianyanning on acute pharyngitis in rats, and to provide evidence and experimental data for its clinical application. METHODS: The acute pharyngitis of rats was induced by spraying ammonia directly to their throat. The model rats were randomly divided into model control group, the high-, medium- and low-dose group of Bianyanning, while normal rats were used as control group, 10 in each group. After the corresponding drug treatment, the symptoms and manifestations of each group were observed and recorded; 24 hours after last gavaging, blood samples of each group were collected from the abdominal aorta. The serum contents of interleukin 1-beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE method was used to observe the characteristic of the lung tissues and the transmission electron microscopy method was used to observe the trachea cilia. RESULTS: After the treatment, compared with the model control group, the high-, medium- and low-dose group of Bianyanning, the symptoms of acute pharyngitis such as inflamed and congestive throat were relieved obviously. The morphological changes of lung and bronchus tissues were apparently improved. The contents of IL-1ß and TNF-α in serum were decreased significantly. CONCLUSION: Compound Bianyanning can promote the recovering process of acute pharyngitis, improve the morphology of lungs and bronchus, which may be related to inhibiting the releasing of the IL-1ß and TNF-α in serum.

Therapeutic effects of Bianyanning decoction on acute pharyngitis in rats and its mechanism / 中国应用生理学杂志

OBJECTIVE@#To investigate the therapeutic effects and mechanisms of Bianyanning on acute pharyngitis in rats, and to provide evidence and experimental data for its clinical application.@*METHODS@#The acute pharyngitis of rats was induced by spraying ammonia directly to their throat. The model rats were randomly divided into model control group, the high-, medium- and low-dose group of Bianyanning, while normal rats were used as control group, 10 in each group. After the corresponding drug treatment, the symptoms and manifestations of each group were observed and recorded; 24 hours after last gavaging, blood samples of each group were collected from the abdominal aorta. The serum contents of interleukin 1-beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE method was used to observe the characteristic of the lung tissues and the transmission electron microscopy method was used to observe the trachea cilia.@*RESULTS@#After the treatment, compared with the model control group, the high-, medium- and low-dose group of Bianyanning, the symptoms of acute pharyngitis such as inflamed and congestive throat were relieved obviously. The morphological changes of lung and bronchus tissues were apparently improved. The contents of IL-1β and TNF-α in serum were decreased significantly.@*CONCLUSION@#Compound Bianyanning can promote the recovering process of acute pharyngitis, improve the morphology of lungs and bronchus, which may be related to inhibiting the releasing of the IL-1β and TNF-α in serum.

Analysis on health cooperation intentions, demands, advantages and disadvantages among "Belt and Road" countries / 中国卫生政策研究

Objective: To understand the health cooperation intentions, demands, advantages and obstacles that are being experienced by countries along the Belt and Road,and to provide reference for China to deepen health cooperation with those countries in regard. Methods : A seminar was held at the High Level Symposium to find out about the health cooperation status among the "Belt and Road" countries, whereby the theme was: "Belt and Road for Health Cooperation towards a Health Silk Road". Therefore, a survey was conducted among 217 Chinese and foreign guests who were invited to attend the seminar. 209 questionnaires were valid and the effective rate was 96. 3％ after the questionnaire analysis carried out using SPSS22. 0. Results : Research results showed that among the respondents, 91. 7％ of the surveyed foreign partners are willing to cooperate in health, while only 73. 2％ of the Chinese respondents desired the cooperation. The demands for health cooperation between both countries was mainly about health industry,medical and health services, and infectious disease prevention and control. Both China and foreign countries confirmed that cooperation convenience and long-term partnership were the advantages of health cooperation among Belt and Road countries, while differences were highlighted in preferential policies. The biggest challenge was found to be the cultural differences. Among other disadvantages are the lack of communication platforms, the pressure of laws and regulations, unstable policies, etc. Conclusions : The willingness and broad space to cooperate in health are strong and large forboth China and foreign countries,and they are intending to put much of emphasis on health institutions,medical and health services and prevention and control of infectious diseases in the future. It is hence suggested that health cooperation should make good use of existing advantages of partnership and convenience,and overcome found obstacles in orderto deepen cooperation in the health industry.

The effects and possible mechanism of ß2AR gene expression in cardiocytes of canines with heart failure.

The objective of the present study was to observe the changes of ß2-adrenergic receptor (ß2AR) protein expression in a canine model of heart failure (HF), and the function of cardiocytes after transfection with Adv-ß2AR. The canine model of chronic HF was induced by rapid right ventricular pacing and cardiocytes were isolated with collagenase II. Cardiocytes were transfected with Adv-ß2AR to observe contractile function with a motion edge-detection system of single cells. Expression of ß2AR protein in cardiocytes was measured by immunoblotting and the levels of intracellular cAMP were measured by ELISA. Compared with the control group (the sham group), the expression of ß2AR protein in HF cardiocytes did not change, but the basal (1 mM Ca2+) contraction amplitude percentage (1.809±0.922 vs. 1.120±0.432%, P<0.05), the maximum contraction amplitude percentage (14.855±2.377 vs. 10.784±2.675%, P<0.01) and the basal levels of intracellular cAMP (9.39±2.54 vs. 5.26±0.95 pmol/ml, n=6, P<0.05) of HF cardiocytes were significantly decreased. However, when HF cardiocytes were transfected with Adv-ß2AR and cultured for 48 h, compared with the non-transfected group, the basal contraction amplitude percentage (0.851±0.324 vs. 1.629±0.522%, P<0.05), the maximum contraction amplitude percentage (9.260±2.208% vs. 12.205±1.437%, P<0.01) and the basal levels of intracellular cAMP (5.26±0.95 vs. 9.03±1.03 pmol/ml, n=6, P<0.05) of cardiocytes in the transfected group were significantly increased. In conclusion, the expression of ß2AR protein in HF cardiocytes did not change, but contraction function was impaired. The moderate overexpression of ß2AR gene in the HF cardiocytes increased the levels of intracellular cAMP and improved contraction function.

The Association of Type D personality with Heart Rate Variability and Lipid Profiles Among Patients with Coronary Artery Disease.

PURPOSE: Characteristics of the distressed (Type D) personality include negative affectivity (NA) and social inhibition (SI), which are associated with an increased risk of major adverse cardiac events and mortality among patients with coronary artery disease (CAD). The aims of this study were to examine: (1) the correlation of NA and SI with psychological characteristics, heart rate variability (HRV) indices, and lipids profiles and (2) the differences in psychological characteristics, HRV indices, and lipid profiles between patients with CAD with Type D personality and those with non-Type D personality. METHOD: A cross-sectional study was conducted on 168 patients with CAD. The Taiwanese 14-item Type D Scale, Chinese Hostility Inventory-Short Form, Beck Depression Inventory-II, Beck Anxiety Inventory, and Anger Rumination Scale were administered to all of the participants. The raw signals of electrocardiograms were recorded over a 5-min baseline resting period and then transformed to HRV indices representing short-term cardiac autonomic activations. Lipid profiles were acquired from patients' medical records. RESULTS: NA was positively correlated with hostility, depression, anxiety, and anger rumination. With respect to pathophysiological mechanisms for CAD with Type D personality, NA was negatively correlated with standard deviation of all normal-to-normal intervals (SDNN) and total power of HRV and positively correlated with total cholesterol. SI was positively correlated with suppressive hostility behavior and anger rumination; however, SI was not significantly correlated with expressive hostility behavior, or HRV indices and lipid profiles. CONCLUSION: Pathophysiological mechanisms leading to higher rates of adverse outcomes in CAD in individuals with Type D personalities may involve cardiac autonomic imbalance and lipid dysregulation.

Refractive index profiling of an optical waveguide from the determination of the effective index with measured differential fields.

The evanescent tails of a guiding mode as well as its first and second derivatives were measured by a modified end-fire coupling method. The effective index of the waveguide can be obtained by simultaneously fitting these three fields using single parameter. Combined with an inverse calculation algorithm, the fields with fitted evanescent tails showed great improvement in the refractive index profiling of the optical waveguide, especially at the substrate region. Single-mode optical fibers and planar waveguides of proton-exchanged (PE) and titanium-indiffusion (Ti:LiNbO3) on lithium niobate substrates with different refractive index profiles were measured for the demonstration.

Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition.

Polyomavirus enhancer activator 3 protein (Pea3), also known as ETV4, is a member of the Ets-transcription factor family, which promotes metastatic progression in various types of solid cancer. Pea3-driven epithelial-mesenchymal transition (EMT) has been described in lung and ovarian cancers. The mechanisms of Pea3-induced EMT, however, are largely unknown. Here we show that Pea3 overexpression promotes EMT in human breast epithelial cells through transactivation of Snail (SNAI1), an activator of EMT. Pea3 binds to the human Snail promoter through the two proximal Pea3 binding sites and enhances Snail expression. In addition, knockdown of Pea3 in invasive breast cancer cells results in down-regulation of Snail, partial reversal of EMT, and reduced invasiveness in vitro. Moreover, knockdown of Snail partially rescues the phenotype induced by Pea3 overexpression, suggesting that Snail is one of the mediators bridging Pea3 and EMT, and thereby metastatic progression of the cancer cells. In four breast cancer patient cohorts whose microarray and survival data were obtained from the Gene Expression Omnibus database, Pea3 and Snail expression are significantly correlated with each other and with overall survival of breast cancer patients. We further demonstrate that nuclear localization of Pea3 is associated with Snail expression in breast cancer cell lines and is an independent predictor of overall survival in a Chinese breast cancer patient cohort. In conclusion, our results suggest that Pea3 may be an important prognostic marker and a therapeutic target for metastatic progression of human breast cancer.

Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer.

BACKGROUND: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. METHODOLOGY/PRINCIPAL FINDINGS: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models.

Proteomic analysis of clear cell renal cell carcinoma. Identification of potential tumor markers.

OBJECTIVE: To identify new tumor specific proteins of renal cell carcinoma (RCC) using proteomic analysis. METHODS: Nine renal cell carcinomas were resected and these surgical operations were carried out from June 2007 to September 2008 in the Urology Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. The cancer tissues and para-cancer normal tissues were preserved in liquid nitrogen. We analyzed the RCC tissues and para-cancer normal tissues by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The 16 differentially expressed protein spots (p<0.05 by Student t-test) were identified by matrix assisted laser desorption ionization/time of flight mass spectrometry and tandem mass spectrometry. RESULTS: Six proteins were down regulated and 10 proteins were up regulated in clear cell RCC compared with corresponding normal kidney tissue. The down regulated proteins were calbindin, ester hydrolase C11orf54, alcohol dehydrogenase, ammecr1-like protein, adenosine diphosphate (ADP)/adenosine-5'-triphosphate (ATP) translocase 3 and leucine-tyrosine-arginine (LYR) motif-containing protein 5. The up regulated proteins were hypoxia inducible domain family member 1A, glutathione S-transferase P, thioredoxin-dependent peroxide reductase, peroxiredoxin-6, CD2-associated protein, annexin A5, gamma-enolase, retinal dehydrogenase 1, vimentin, and protein-glutamine gamma-glutamyltransferase 2. CONCLUSION: The data provide potential tumor markers for diagnosis of RCC.

Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma.

UNLABELLED: Primary liver cancer, hepatocellular carcinoma (HCC), is the fifth most common cancer and the third leading cancer killer in the world. There is no effective therapeutic option for most HCC patients. A new therapeutic strategy is essential. Granulin-epithelin precursor (GEP, also called progranulin, acrogranin, or PC-derived growth factor) was identified as a potential therapeutic target for HCC from our earlier genome-wide expression profiles. We aimed to conduct a detailed investigation with in vitro and animal experiments. We developed the anti-GEP monoclonal antibody (mAb), and examined its effect on hepatoma cells and normal liver cells in vitro. A nude mice model transplanted with human HCC was used to investigate if anti-GEP mAb can inhibit tumor growth in vivo. We demonstrated that anti-GEP mAb inhibited the growth of hepatoma cells but revealed no significant effect on normal liver cells. In the nude mice model transplanted with human HCC, anti-GEP mAb decreased the serum GEP level and inhibited the growth of established tumors in a dose-dependent manner. The anti-GEP mAb reduced tumor cell proliferation via the p44/42 MAPK and Akt pathways, and reduced tumor angiogenesis to deprive the nutrient supply with reduced microvessel density and tumor vascular endothelial growth factor level. CONCLUSION: We have shown that anti-GEP antibody can inhibit HCC growth, providing evidence that GEP is a therapeutic target for HCC treatment.

GEP associates with wild-type p53 in hepatocellular carcinoma.

Granulin-epithelin precursor (GEP) is a novel growth factor whose up-regulation we previously reported in 72% of hepatocellular carcinoma (HCC). GEP expression has been reported to be associated with p53 protein accumulation in a breast cancer study, though the p53 mutation status was not revealed. We aim to investigate whether p53 protein and mutation status correlates with GEP expression in HCC. The statistical comparison of p53 and GEP data revealed an overall positive association between the two protein expression patterns (P<0.001). Upon detailed analysis, the association of p53 and GEP protein expression was found to be highly significant only in HCCs with wild-type p53 (P=0.001); there was no association in HCCs with p53 mutation (P=0.669). The GEP levels in the HepG2 hepatoma cell line with a wild-type p53 background were modulated by transfection experiments. Overexpression of the GEP protein resulted in an increased p53 protein level and suppression of the GEP protein resulted in a decreased p53 protein level in HepG2 cells. In summary, we demonstrated that p53 wild-type protein nuclei accumulation is associated with GEP protein expression in human HCC specimens, and GEP modulates p53 wild-type protein levels in vitro.