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Background: The ultrasound-guided transversus abdominis plane (TAP) block is generally used for analgesia but not for anesthesia. A TAP block has a partial analgesic effect on the parietal peritoneum in abdominal surgeries. We hypothesized that an ultrasound-guided oblique subcostal TAP block, used as the principal anesthesia technique, could provide a better anesthetic effect on peritoneum stimulation in peritoneal dialysis catheter (PDC) implantation in end-stage renal diseases (ESRD) patients than local anesthetic infiltration (LAI)., Methods: End-stage renal disease patients undergoing PDC implantation were randomized into 3 groups: LAI Group, unilateral TAP group (Uni-TAP Group) and bilateral TAP group (Bi-TAP Group). A 40-mL dose of 0.25% ropivacaine was used for the regional block (LAI or TAP). The quality of anesthesia, visual analogue scale (VAS) of pain, cumulative rescuing sufentanil consumption, and venous plasma ropivacaine concentrations were compared among the 3 groups., Results: Sixty-nine patients were enrolled, and higher 'Satisfied' anesthesia rates from nephrologists and patients were recorded in the 2 TAP groups, compared with the LAI Group. Significantly lower VAS scores were observed in the Uni-TAP Group at a majority of time points compared with the LAI Group. Less cumulative rescuing sufentanil was used in the 2 TAP groups (2.5 ± 2.7 and 3.0 ± 2.8 μg, respectively) compared with the LAI Group (5.8 ± 2.6 μg, p < 0.05). The median peak venous plasma ropivacaine concentrations were below the reported toxic threshold in all 3 groups., Conclusions: As the principal anesthesia technique, an ultrasound-guided unilateral oblique subcostal TAP block with 40 mL of 0.25% ropivacaine provided better anesthetic effect in PDC implantations in ESRD patients than LAI., (Copyright © 2018 International Society for Peritoneal Dialysis.)

A new ent-abietane diterpernoid, named ebracteolata D (1), along with 11 known analogues, was isolated from the roots of Euphorbia ebracteolata Hayata. The structure of 1 was elucidated on the basis of spectroscopic analysis and molecular modeling. Cytotoxicity of compounds 1-12 was evaluated as well as the effect on the NF-κB pathway. Among them, compound 12, jolkinolide B, displayed broad inhibitory effects against proliferation of tumor cell lines. Mechanistic studies indicated that the compound 12 can inhibit TNF-α induced NF-κB activation, thereby inducing tumor cell apoptosis.

Background: Autophagy exists widely in various physiological and pathological conditions. Lots of investigations have verified that the autophagic activity is always related to the occurrence and the development of cancer. Endometriosis (EMs) is a disease that endometrium-like tissues abnormally grow outside the uterus and also considered to possess the characters of tumor because of its malignant biological behavior., Introduction: Recently, several studies have already revealed that autophagy may play a potential role in proliferative-phase EMs. However, the function of autophagic activity in secretory-phase EMs is still unclear., Methods: In our work, we explored autophagic activity between normal endometrium and EMs lesion endometrium during different menstrual phases and EMs stages. The clinical endometrium samples from 73 women were selected in this study, including 30 healthy individuals and 43 patients with EMs (endometrium samples include eutopic and its matched ectopic endometrium). All the participants were divided into two groups according to the menstrual cycle, namely proliferative-phase and secretive- phase group. Among the patients with EMs, 22 individuals in proliferative phase and the other 21 individuals in secretory phase were further classified into the groups of Stage I-II and Stage III-IV according to revised-American Fertility Society (r-AFS). Two autophagy-related proteins microtubuleassociated protein 1 light chain 3 beta-II (LC3B-II) and sequestosome protein (P62), which are believed to be the indicators of autophagy activity, were chosen in the study. Immunohistochemical (IHC) staining, Western blot assay and Real-Time quantitative Polymerase Chain Reaction (RTqPCR) were used to examine the expression of LC3B-II and P62 in protein and mRNA level accordingly., Result: It showed that the expression of LC3B-II both in protein and mRNA level decreased and that of P62 increased in secretory phase of the healthy group (P<0.05), but showed no significant difference in ectopic and its eutopic endometrium group during proliferative and secretory phase (P>0.05). In addition, the expression of LC3B-II in ectopic endometrium group was significantly lower than that of its eutopic endometrium group (P<0.05), and the expression of P62 was significantly higher accordingly (P<0.05). At the same time, both LC3B-II and P62 levels remained same between eutopic endometrium group and control group (P>0.05). Furthermore, compared to Stage I-II EMs group, the expression of LC3B-II was significantly lower (P<0.05) and P62 was significantly higher (P<0.05) in Stage III-IV EMs during secretory phase., Conclusion: Taken together, the periodicity-losing in EMs and the decreased autophagic activity in ectopic endometrium may exert a potential role in the pathogenesis of EMs. Down-regulated autophagy of ectopic endometrium in secretory phase may be related to the progression of EMs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Carbon nanoparticles suspension injection (CNSI) has been widely used in tumor drainage lymph node mapping, and its new applications in drug delivery, photothermal therapy, and so on have been extensively investigated. To develop new clinical applications, the toxicity of CNSI after intravenous exposure should be thoroughly investigated to ensure its safe use. Herein, we studied the bioaccumulation of CNSI in reticuloendothelial system (RES) organs and the corresponding toxicity to mice. After the intravenous injection of CNSI, no abnormal behavior of mice was observed during the 28-day observation period. The body weight increases were similar among the exposed groups and the control group. The parameters of hematology and serum biochemistry remained nearly unchanged, with very few of them showing significant changes. The low toxicity of CNSI was also reflected by the unchanged histopathological characteristics of these organs. The injection of CNSI did not induce higher apoptosis levels either. The slight oxidative stress was observed in RES organs at high dosages at day 7 post-exposure. The implication to the clinical applications and toxicological evaluations of carbon nanomaterials is discussed., Competing Interests: Tiantian He and Xiao-Hai Tang are employees of Chongqing Lummy Pharmaceutical Co., Ltd. The authors report no other conflicts of interest in this work. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Objective: Ischemic stroke risk rises with the increasing cardiovascular risk factors in patients with and without AF. How atrial fibrillation (AF) incrementally contributes to the risk for ischemic stroke with increasing age and multiple cardiovascular risk factors is unclear. Von Willebrand factor (vWF) is a biomarker of endothelial dysfunction., Patients and Methods: We suggested that in older patients with high CHA2DS2-VASc Score, the vWF and ADAMTS13 would be comparable between patients with and without AF. Consecutive 196 old patients (≥ 60 years, 45.9% with concomitant AF) with and without non-valve atrial fibrillation were recruited from April 2014 to April 2016. Data on baseline clinical characteristics were recorded at study entry. Plasma ADAMTS13 levels and plasma vWF levels were determined. Statistical analyses were performed using SPSS19.0 statistical software package., Results: There were significant correlations between plasma vWf levels, ADMATS13 and CHA2DS2- VASc Score in older patients with and without AF (with AF: Spearman, r = 0.215, p < 0.05; without AF: Spearman, r = 0.197, p < 0.05). Results of research indices in our older patients were as follows: vWf 180. 79 ± 28.27 IU/dL in AF and 153.5 ± 35.54 in non AF with p < 0.001, ADAMTS13 431.5 ± 160.33 IU/dL in AF and 536.7 ± 169.96 in non AF with p < 0.05. Results of research indices in our older patients (≥ 75 year) were as follows: vWf 181.4 ± 22.04 in AF and 174.1 ± 29.45 in non AF, and ADMATS-13 412.9 ± 130.76 IU/dL in AF and 451.7 ± 153.18 in non AF. There were no differences (p > 0.05). CHA2DS2-VASc Score can predict stroke risk in old patients without atrial fibrillation. At high CHA2DS2-VASc Score, the levels of vWF and ADAMTS13 have difference in old patients (60-74) with and without AF, but in such older patients, age (≥ 75 year), there were no differences. In elderly patients, atrial fibrillation has a limited effect on VWF, and the age is an important factor affecting the endothelial function., Conclusions: For elderly patients with a high incidence rate of stroke and thrombosis, we should pay more attention to the thrombotic events, and atrial fibrillation can be used as one of the risk factors involved and improving the risk scoring system of stroke.

A novel fluorescent sensor, 1-((2-hydroxynaphthalen-1-yl)methylene)urea (ocn) has been designed and applied as a highly selective and sensitive fluorescent probe for recognition of Al 3 + in Tris-HCl (pH = 7.20) solution. The probe ocn exhibits an excellent selectivity to Al 3 + over other examined metal ions, anions and amino acids with a prominent fluorescence 'turn-on' at 438 nm. ocn binds to Al 3 + with a 2:1 binding stoichiometry and the detection limit was 0.3 μM. Furthermore, its capability of biological application was evaluated and the results showed that the sensor could be used to detect Al 3 + in living cells., (Copyright © 2016 John Wiley & Sons, Ltd.)

Although pain is frequently accompanied with depression, little is known about the risk factors contributing to individual differences to the comorbidity of pain and depression. In this study, we examined whether cytokines and brain-derived neurotrophic factor (BDNF) might contribute to the individual differences in the development of neuropathic pain-induced depression. Rats were randomly subjected to spared nerved ligation (SNI) or sham surgery. The SNI rats were divided into two groups by the data from depression-related behavioral tests. Rats with depression-like phenotype displayed higher levels of pro-inflammatory cytokines (e.g., interleukin (IL)-1β, IL-6) as well as imbalance of pro/anti-inflammatory cytokines compared with rats without depression-like phenotype and sham-operated rats. Levels of BDNF in the prefrontal cortex of rats with depression-like phenotype were lower than those of rats without depression-like phenotype and sham-operated rats. A single dose of ketamine ameliorated depression-like behaviors in the rats with depression-like phenotype. Interestingly, higher serum levels of IL-1β and IL-6 in the rat with depression-like phenotype were normalized after a single dose of ketamine. These findings suggest that alterations in the inflammatory cytokines and BDNF might contribute to neuropathic pain-induced depression, and that serum cytokines may be predictable biomarkers for ketamine's antidepressant actions.

Human's application of safflower (Carthamus tinctorius) has a long history, but the origin remains unclear. Safflower was introduced into China for traditional Chinese medicine, and Sichuan was major producing area. However, in recent years, the main producing area is in Xinjiang province, in contrast Sichuan safflower is difficult to find. By reading relevant document literature and the production and marketing information of safflower, and having field investigation in the main producing areas, the origin of safflower and the reasons of producing areas' changes were explored. The origin of safflower is considered as the Fertile Crescent in reasonably. The change of producing areas in China is effected by the factors of natural environment and society. The suitability of producing areas and quality of safflower still need to study further., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1β, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.

Objectives: To explore the genetic variation sites of caveolin （CAV） and their correlation with sudden unexplained death （SUD）., Methods: The blood samples were collected from SUD group （71 cases）, coronary artery disease （CAD） group （62 cases） and control group （60 cases）, respectively. The genome DNA were extracted and sequencing was performed directly by amplifying gene coding region and exon-intron splicing region of CAV1 and CAV3 using PCR. The type of heritable variation of CVA was confirmed and statistical analysis was performed., Results: A total of 4 variation sites that maybe significative were identified in SUD group, and two were newfound which were CAV1 ： c.45C>T （T15T） and CAV1 ：c.512G>A （R171H）, and two were SNP loci which were CAV1 ：c.246C>T （rs35242077） and CAV3 ：c.99C>T （rs1008642） and had significant difference （ P <0.05） in allele and genotype frequencies between SUD and control groups. Forementioned variation sites were not found in CAD group., Conclusions: The variants of CAV1 and CAV3 may be correlated with a part of SUD group., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Forensic Medicine)

Rationale: Ecthyma gangrenosum (EG) is an aggressive cutaneous disease caused by local or systemic infection with Pseudomonas aeruginosa. EG is characterized by cutaneous manifestations ranging from nodule and papule, to necrotic ulceration with surrounding erythema, especially with black eschar or central crust. EG presents with characteristic skin lesions which is important to establish diagnosis of sepsis caused by P aeruginosa, a serious condition that can be treated efficiently if diagnosed early., Patient Concerns: A 3-month-old female infant was presented with characteristic skin lesions of EG and developed sepsis 3 days later., Diagnoses: Ecthyma gangrenosum and sepsis caused by Pseudomonas aeruginosa., Interventions: Meropenem was used in combination with ceftazidime at first and excision of necrotic skin lesions was performed later., Outcomes: Cure., Lessons: Early recognition of EG plays an important role in providing appropriate empiric antibiotic treatment at early stage of sepsis, and improves the prognosis. Surgical excision may be helpful if no improvement was achieved via antibiotic treatment.

Objective: To investigate the effect and mechanism of CRM197, the heparin binding-epidermal growth factor-like growth factor (HB-EGF) inhibitor, on the reverse of the resistance of ovarian cancer to paclitaxel. Methods: (1)The effect of CRM197 on the 50% inhibitory concentrations (IC(50)) of human ovarian carcinoma cell line A2780 and paclitaxel-resistant ovarian carcinoma cell line A2780/Taxol was tested by methyl thiazolyl tetrazolium (MTT) assay. Western blot was used to detect the effect of CRM197 on the expression of HB-EGF, epidermal growth factor receptor (EGFR) and plasma membrane glycoprotein (P-gp) protein in A2780 and A2780/Taxol cells. Real-time PCR was used to examine the MDR1 mRNA expression in these cells. (2) A2780/Taxol cells were divided into 4 groups, including the cells transfected with empty vector and saline treatment (empty vector group), MDR1 small interference RNA (siRNA) vector and saline treatment (MDR1 siRNA group), empty vector and CRM197 treatment (empty vector+CRM197 group) and MDR1 siRNA vector and CRM197 treatment (MDR1 siRNA+CRM197 group), respectively. Flow cytometry was used to detecte the effect of intracellular rhodomine 123 (Rh123) accumulation, and caspase-3 activity assay was used to test the effect of apoptosis in four groups of A2780/Taxol cells. (3) In experiments in vivo, A2780/Taxol cells were inoculated to nude mouse subcutaneously to determine the EGFR and P-gp protein expression following CRM197 treatment by immunohistochemistry. Results: (1) In vitro, MTT examination showed that the IC(50) of A2780/Taxol cells to paclitaxel in A2780/Taxol+CRM197 group [(6.4±0.3) μmol/L] was significantly lower than the IC(50) in A2780/Taxol group [ (34.1±0.5) μmol/L, P< 0.01], and the reveral fold of CRM197 was 5.3. The expression level of HB-EGF protein in A2780/Taxol+CRM197 group (1.44±0.29) was significantly lower than HB-EGF protein in A2780/Taxol group (2.72±0.32), respectively ( P< 0.05). The expression level of EGFR protein (0.71±0.25) and P-gp protein (0.82±0.19) in A2780/Taxol+CRM197 group was significantly lower than EGFR protein (1.87±0.31) and P-gp protein (1.84±0.27) of A2780/Taxol group ( P< 0.05). Compared with A2780/Taxol group (1.78±0.27) , MDR1 mRNA was significantly down-regulated in A2780/Taxol+CRM197 group (0.79±0.13, P< 0.05). (2) The fluorescence intensity of Rh123 of the A2780/Taxol cells in empty vector group, MDR1 siRNA group,empty vector+CRM197 group, MDR1 siRNA+CRM197 group was 33.4±1.6, 56.3±3.3, 43.5±3.1,100.4±7.4, and the pNA of the A2780/Taxol cells was (11.4±1.2) , (52.8±0.9) , (71.2±3.6) , (82.7±3.8) μmol/L. The expression levels in MDR1 siRNA+CRM197 group were both higher than the expression levels in empty vector+CRM197 group, and the expression levels in empty vector+CRM197 group, MDR1 siRNA group were both higher than the expression levels in empty vector group ( P< 0.05). (3) In vivo, the expression scores of EGFR protein in A2780/Taxol+CRM197 tumors (4.4±1.4) were lower than that in A2780/Taxol tumors (10.2±3.1, P< 0.05). The expression scores of P-gp protein in A2780/Taxol+CRM197 tumors (3.8±1.1) were lower than that in A2780/Taxol tumors (8.8±2.7, P< 0.05). Conclusion: CRM197 reverses the resistance of ovarian cancer to paclitaxel by increasing caspase-3 activity to advance apoptosis via EGFR/MDR1/P-gp pathway.

Hierarchical morphology-dependent gas-sensing performances have been demonstrated for three-dimensional SnO 2 nanostructures. First, hierarchical SnO 2 nanostructures assembled with ultrathin shuttle-shaped nanosheets have been synthesized via a facile and one-step hydrothermal approach. Due to thermal instability of hierarchical nanosheets, they are gradually shrunk into cone-shaped nanostructures and finally deduced into rod-shaped ones under a thermal treatment. Given the intrinsic advantages of three-dimensional hierarchical nanostructures, their gas-sensing properties have been further explored. The results indicate that their sensing behaviors are greatly related with their hierarchical morphologies. Among the achieved hierarchical morphologies, three-dimensional cone-shaped hierarchical SnO 2 nanostructures display the highest relative response up to about 175 toward 100 ppm of acetone as an example. Furthermore, they also exhibit good sensing responses toward other typical volatile organic compounds (VOCs). Microstructured analyses suggest that these results are mainly ascribed to the formation of more active surface defects and mismatches for the cone-shaped hierarchical nanostructures during the process of thermal recrystallization. Promisingly, this surface-engineering strategy can be extended to prepare other three-dimensional metal oxide hierarchical nanostructures with good gas-sensing performances.

Epidermolytic palmoplantar keratoderma (EPPK) is a rare autosomal dominant skin disorder characterized by diffuse hyperkeratosis on the palms and soles. Whole-exome sequencing (WES) has become a powerful tool for the detection of rare causal variants of Mendelian disorders. However, no causal gene for EPPK in the Uygur population has been identified until now, and no treatment exists than can address the underlying pathology.WES analysis was undertaken on two individuals from a large Uygur EPPK pedigree whose disease locus mapped to 17q21.2 (chr:38994621-39893408) following previous linkage analysis. KRT9 (NM&#95;000226.3:c.487C>T, p.Arg163Trp), and KRT15 (XM&#95;005257346.1:c.212G>T, XP&#95;005257403.1:p.Gly71Val) located in this region, have been identified as two candidate causative genes for EPPK in the Uygur family. Sanger sequencing was conducted on this region in other affected individuals (n = 38) from this family, non-affected individuals (n = 56) from this family and 100 unrelated controls. The missense mutation KRT9 c.487C>T, identified in this large Uygur population, is a potential causative mutation. To date, EPPK has no effective therapy, and siRNA is a potential avenue for EPPK therapy. To investigate this, full-length wild-type Keratin9 (KRT9; pKRT9-WT) and p.Arg163Trp (pKRT9-R163W) were then transfected into HaCaT cells. The small interfering RNAs targeting the KRT9 R163W mutant and wildtype KRT9 were transfected into HaCaT cells, and total RNA isolated at 72 h post-transfection. Quantitative polymerase chain reaction and western blotting were used to analyse the effects of knock-down on KRT9 mRNA and protein levels, respectively. siRNA was shown to specifically inhibit mutant KRT9 mRNA and protein expression (p < 0.01, with 95% confidence limits). Our study suggests that KRT9 is a causal gene for EPPK. This information is helpful for understanding the pathogenesis of EPPK in the Uygur population and raises the possibility of designing a novel siRNA treatment strategy for this population of EPPK patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To compare the clinical effects of Shang Ring scissor circumcision (SC) and electrotome circumcision (EC) in the treatment of redundant prepuce or phimosis.Methods: Results: Conclusion., Methods: This retrospective study included 524 patients with redundant prepuce or phimosis, 422 treated by SC and 120 by EC. We made comparisons between the two groups of patients in the operation time, intra- and post-operative pain scores, pain scores before, at and after ring removal, wound healing time, and incidence rates of postoperative edema and incision dehiscence., Results: The operation time was longer in the SC than in the EC group (［59.99±5.39］ vs ［39.94±4.94］ sec, P<0.05), but there were no significant differences between the two groups in the intraoperative pain scores (1.02±0.74 vs 1.08±0.59, P>0.05) or the pain scores within 24 h after operation (6.74±1.01 vs 6.56±1.06, P>0.05), 24 h prior to ring removal (1.14±0.69 vs 1.10±0.64, P>0.05), and after ring removal (2.73±0.74 vs 2.85±0.75, P>0.05) except at ring removal, which was remarkably lower in the SC than in the EC group (3.56±0.47 vs 4.77±0.58, P<0.05). The wound healing time was markedly shorter in the former than in the latter (［14.11±1.26］ vs ［39.78±7.55］ d, P<0.05), but the incidence rate of incision dehiscence showed no significant difference between the two groups (4.03% ［17/422］ vs 9.17% ［11/120］, P>0.05). The rate of postoperative satisfaction with the external penile appearance was 100% in both of the two groups., Conclusions: Shang Ring scissor circumcision is preferred to electrotome circumcision for its advantages of less pain at ring removal and shorter healing time despite its longer operation time.

Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies., Key Messages: • Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD., Competing Interests: Weill Cornell has filed a patent application on some of the intellectual property (IP) in this manuscript and this IP was licensed to Sveikatal, Inc. LJG and XHT are founders and have financial interests in Sveikatal, Inc.

This study was conducted to produce pectin-doxorubicin conjugate（PDC） nanosuspensions by high-pressure homogenization, and investigating the physico-chemical properties, the cumulative release rate in vitro and in vivo, and the anti-tumor activity. The major production parameters such as pressure, cycle numbers and types of stabilizers on the mean particle size and polydispersity index（PI） of PDC nanosuspensions were investigated. The cumulative release rate in phosphate buffer saline（PBS） at pH 5.1 or 7.0 were studied. The concentration of doxorubicin（DOX） in plasma of rabbit were recorded after intraperitoneal injection of PDC nanosuspensions(DOX was equivalent to 10 mg·kg-1) or DOX (10 mg·kg-1). We established an animal model of the nude mice with SKOV3 cell, and injected the PDC nanosuspensions(DOX was equivalent to 10, 5, 2.5 mg·kg-1) in the first day, and observed the growth state of nude mice. The particle size of PDC nanosuspensions was 118.8 ± 6.93 nm, PI was 0.14 ± 0.03, as well as the zeta potential was -27.2 ± 0.36 m V. It shows that no drug release was found in PBS at p H 7.4. About 40% cumulative release was determined in PBS at 5.1 after 30 h. The concentration of DOX in plasma of PDC group was 60 ng·mL-1, and was lower than that of DOX group. Compared with control group, high-dose-group decreased the weight of nude mice’s ascites tumor and burrknot. PDC nanosuspensions can inhibit the growth of SKOV3 cell line in nude mice.In summary, PDC nanosuspensions are target-specific drugs with high efficiency and low toxicity in the ascites cancer model.

Cyclooxygenase-2 (COX-2) serves an important role in the carcinogenesis and progression of gastric cancer. Harmine (HM) and paclitaxel (PTX) are reported as promising drug candidates for cancer therapy, but whether a synergistic anti-tumor effect of HM combined with PTX exists in human gastric cancer remains unknown. The present study evaluated the effects of HM and/or PTX on cell proliferation and apoptosis in a gastric cancer cell line, SGC-7901. HM and PTX inhibited cell proliferation in a dose-dependent manner. Both HM and PTX alone induced apoptosis in gastric cancer cells. The combination of HM and PTX exerted synergistic effects on proliferation inhibition and apoptosis induction in SGC-7901 cells, with down-regulation of COX-2, PCNA and Bcl-2 and up-regulation of Bax expression. The results indicated that combination chemotherapy using HM with PTX exerts an anti-tumor effect for treating gastric cancer. The combination of the two drugs inhibits gastric cancer development more effectively than each drug alone through down-regulation of COX-2 expression.

Objective To investigate the changes of regulatory T cells (Tregs) and whether Tregs can modulate the distribution of macrophage subtypes in visceral adipose tissue in the early stage of obesity.Methods After C57BL/6 mice obesity models were successfully established,metabolic parameters and numbers of Tregs and M1/M2 macrophage were measured at 4,10,and 20 weeks.The changes of metabolic parameters and adipose tissue inflammation in obesity mice after rapamycin intervention were evaluated. Results The early-stage obesity models were successfully established.Compared with normal diet mice,high fat diet mice had significantly higher epididymal adipose tissue mass and serum leptin levels(P<0.05).However,there was no statistical difference in blood glucose and insulin levels between these two groups(All P>0.05). Macrophages infiltration in adipose tissue in high fat diet mice gradually increased with time,coincident with decrease in Treg numbers. Increased numbers of Treg,improved metabolic parameters,and decreased ratio of M1/M2 can be seen after rapamycin intervention in mice.Conclusion The decrease of Tregs in the early stage of obesity may contribute to abnormal distribution of macrophage subtypes in visceral adipose.

Hypoxia has been a research focus in cancer because of its important role in maintaining tumor microenvironments. Previous studies have demonstrated that the expression of several miRNAs was altered under hypoxic conditions, suggesting their crucial roles in the development of cancer. In the present study, the expression of 22 miRNAs reported to be significantly upregulated in cervical cancer tissues was examined. We found that four of these miRNAs were upregulated in response to hypoxia in HeLa cervical cancer cells. MiR-152 was upregulated to the greatest extent and was also found to be upregulated by hypoxia in C33A cells and tumor, but not in non-tumor cervical tissues. Moreover, we found that hypoxia-inducible factor-1α regulated the expression of miR-152 in HeLa cells through a hypoxia-responsive element. A bioinformatic tool predicted that WNT1 and ERBB3 were target genes of miR-152. This was confirmed by dual luciferase assays and Western blots. Overexpression of miR-152 repressed WNT1 and ERBB3 expression and decreased proliferation of HeLa cells. Collectively, these data indicate an important role for miR-152 in regulating the hypoxic response of tumor cells., (© 2015 by the Society for Experimental Biology and Medicine.)

In the past 10 years, several publications have highlighted the role of the regulator of G protein signalling (RGS) family in multiple diseases, including cardiovascular diseases. As one of the multifunctional family members, RGS14 is involved in various biological processes, such as synaptic plasticity, cell division, and phagocytosis. However, the role of RGS14 in cardiovascular diseases remains unclear. In the present study, we used a genetic approach to examine the role of RGS14 in pathological cardiac remodelling in vivo and in vitro. We observed that RGS14 was down-regulated in human failing hearts, murine hypertrophic hearts, and isolated hypertrophic cardiomyocytes. Moreover, the extent of aortic banding-induced cardiac hypertrophy and fibrosis was exacerbated in RGS14 knockout mice, whereas RGS14 transgenic mice exhibited a significantly alleviated response to pressure overload. Furthermore, research of the underlying mechanism revealed that the RGS14-dependent rescue of cardiac remodelling was attributed to the abrogation of mitogen-activated protein kinase (MEK)-extracellular signal-regulated protein kinase (ERK) 1/2 signalling. The results showed that constitutive activation of MEK1 nullified the cardiac protection in RGS14 transgenic mice, and inhibition of MEK-ERK1/2 by U0126 reversed RGS14 deletion-related hypertrophic aggravation. These results demonstrated that RGS14 attenuated the development of cardiac remodelling through MEK-ERK1/2 signalling. RGS14 exhibited great potential as a target for the treatment of pathological cardiac remodelling.

Objective: This retrospective study was aimed to investigate the characteristics of hearing recovery in the complete deafness type of SSNHL(≥81 dBHL) in patients with different ages. Method: Clinical outcomes of 179 total deafness type of idiopathic sudden deafness were compared.Patients were divided into 5 groups according to age,they were,pediatric group(13 years or less),youthful group(14-44 years),middle-aged group(45-59 years),presenium group(60-74 years),senectitude group(75 years or higher).Patients were divided into 3 groups according to the initial degree of hearing loss: 81 dB group (81-89 dBHL),90 dB group(90- 99 dBHL),100 dB group(100 dBHL or higher).Routine comprehensive treatment including corticosteroids,the inner ear microcirculation improvement drugs,neurotrophic drugs,saturationoxygen and hyperbaric oxygen therapy,etc.was applied.Patients were treated in accordance with the age and body weight. Result: The percentage of youthful group(83/179,46.4%) was highest( P <0.05),middle-aged group(57/179,31.8%)followed( P <0.05),presenium group(26/179,14.5%)was lower( P <0.05),pediatric group(8/179,4.5%) and senectitude group(5/179,2.8%)were the lowest.No a complete recovery in either pediatric group or senectitude group.A complete recovery was rare in the other groups.Recovery rate of the different aged groups was similar( P >0.05).The percentage of 100 dB group(108/179,60.3%) was highest( P <0.05).The percentage of 81 dB group(39/179,21.8%)was similar to 90 dB group(32/179,17.9%)( P >0.05).Recovery rate was similar in 81 dB group(25/39,64.1%)and 90 dB group(18/32,56.2%)( P >0.05).Recovery rate of both 81 dB group and 90 dB group were greater than 100 dB group(24/108,22.2%)( P <0.05).The 100 dB group reduced the satisfactory recovery effects.There were no differences in the proportion of the patients with dizziness(95/179,53.1%)and without dizziness(84/179,46.9%)( P >0.05).Recovery rate of patients without dizziness(43/84,51.2%) was greater than with dizziness(24/95,25.3%)( P <0.05).The percentage of the patients without dizziness(31/39,79.5%)in 81 dB group was the highest( P <0.05),90 dB group(18/32,56.2%)followed( P <0.05).The percentage of the patients with dizziness in 100 dB group(73/108,67.6%)was highest( P <0.05).Recovery rate was similar in the patients without dizziness of 81 dB group(21/31,67.7%)and 90 dB group(11/18,61.1%)( P >0.05).Recovery rate of the above two groups was greater than that of 100 dB group(11/35,31.4%)( P <0.05). Conclusion: Recovery rate of the different aged groups was similar.The percentage of the patients with dizziness in 100 dB group was highest.Initial hearing threshold in excess of 100 dB reduced the satisfactory recovery in patients with total deafness type of SSNHL.Our results provided a good reference for other clinicians., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objective: To evaluate a new prenatal diagnosis model of chromosomal abnormalities and nine microdeletion syndromes by using both traditional karyotyping and a newly-developed rapid prenatal diagnosis technology, BACs-on-Beads (BoBs) technique., Methods: From June 2012 to December 2014, 807 pregnant women with high risk after screening or with other indicators, were performed amniocentesis. Traditional karyotyping and BoBs were employed simultaneously for prenatal diagnosis., Results: Thirty-two cases with chromosome aneupoidies were successfully detected both by BoBs and karyotyping, including 18 cases of trisomy 21, 6 cases of trisomy 18, 1 case of trisomy 13, and 7 cases with sex chromosome abnormality. All 8 fetuses with chromosome structural abnormalities detected by karyotyping were missed by BoBs; while BoBs contributed more in detection of five microdeletion syndrome cases, including 3 cases of DiGeorge syndromes (two with microduplication and one with microdeletion), one case of Miller-Dieker syndrome, and one case of Wolf-Hirschhorn syndrome., Conclusion: Combined use of traditional karyotyping and BoBs, is a rapid and effective prenatal diagnosis model that may enlarge our horizon on chromosomal diseases and should be widely used in future clinical service.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been proven to be a promising chemotherapeutic target for ovarian cancer. Our previous studies have demonstrated that inhibition of HB-EGF by the special inhibitor, cross-reacting material 197 (CRM197), potently inhibits the anti-tumor activity in paclitaxel-resistant ovarian cancer. Here, we found that inhibition of HB-EGF by CRM197 significantly reverses the resistance to paclitaxel in paclitaxel-resistant ovarian carcinoma cell line (A2780/Taxol). A2780/Taxol cells over-expressed HB-EGF and epidermal growth factor receptor (EGFR) and CRM197 notably suppressed the expression of HB-EGF and EGFR. Experiments performed in vitro and in vivo further suggested that CRM197 markedly down-regulated the ATP-binding cassette sub-family B member 1 (ABCB1/MDR1) messenger RNA (mRNA) expression (P = 0.01), plasma membrane glycoprotein (P-gp) protein (P = 0.009), and P-gp-mediated efflux (P = 0.007) through inhibition of nuclear factor-κB (NF-κB) expression, which were classical chemoresistance-related targets with respect to paclitaxel therapy. Meanwhile, inhibition of HB-EGF enhanced caspase-3 activity to induce apoptosis via MDR1 inhibition in A2780/Taxol cells (P = 0.038). Collectively, HB-EGF is a molecular target for the resistance of ovarian cancer to paclitaxel and CRM197 as a HB-EGF-targeted agent might be a chemosensitizing agent for paclitaxel-resistant ovarian carcinoma. Our findings provide novel possible mechanisms for HB-EGF to be a target to restore the chemosensitivity to paclitaxel.

Aims: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease., Methods: Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D)., Results: We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle., Conclusions: Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis., (© 2015 John Wiley & Sons Ltd.)

Unlabelled: Deacetylation of 7-aminocephalosporanic acid (7-ACA) at position C-3 provides valuable starting material for producing semisynthetic β-lactam antibiotics. However, few enzymes have been characterized in this process before now. Comparative analysis of the genome of the thermophilic bacterium Alicyclobacillus tengchongensis revealed a hypothetical protein (EstD1) with typical esterase features. The EstD1 protein was functionally cloned, expressed, and purified from Escherichia coli BL21(DE3). It indeed displayed esterase activity, with optimal activity at around 65°C and pH 8.5, with a preference for esters with short-chain acyl esters (C2 to C4). Sequence alignment revealed that EstD1 is an SGNH hydrolase with the putative catalytic triad Ser15, Asp191, and His194, which belongs to carbohydrate esterase family 12. EstD1 can hydrolyze acetate at the C-3 position of 7-aminocephalosporanic acid (7-ACA) to form deacetyl-7-ACA, which is an important starting material for producing semisynthetic β-lactam antibiotics. EstD1 retained more than 50% of its initial activity when incubated at pH values ranging from 4 to 11 at 65°C for 1 h. To the best of our knowledge, this enzyme is a new SGNH hydrolase identified from thermophiles that is able to hydrolyze 7-ACA., Importance: Deacetyl cephalosporins are highly valuable building blocks for the industrial production of various kinds of semisynthetic β-lactam antibiotics. These compounds are derived mainly from 7-ACA, which is obtained by chemical or enzymatic processes from cephalosporin C. Enzymatic transformation of 7-ACA is the main method because of the adverse effects chemical deacylation brought to the environment. SGNH hydrolases are widely distributed in plants. However, the tools for identifying and characterizing SGNH hydrolases from bacteria, especially from thermophiles, are rather limited. Here, our work demonstrates that EstD1 belongs to the SGNH family and can hydrolyze acetate at the C-3 position of 7-ACA. Moreover, this study can enrich our understanding of the functions of these enzymes from this family., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARβ2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a "silent" VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA.

We compared the changes in global gene expression between an early stage (the termination of the carcinogen treatment and prior to the appearance of frank tumors) and a late stage (frank squamous cell carcinoma (SCC)) of tongue carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral cavity and esophageal squamous cell carcinoma. Gene ontology and pathway analyses show that increases in "cell cycle progression" and "degradation of basement membrane and ECM pathways" are early events during SCC carcinogenesis and that changes in these pathways are even greater in the actual tumors. Myc, NFκB complex (NFKB1/RELA), and FOS transcription networks are the major transcriptional networks induced in early stage tongue carcinogenesis. Decreases in metabolism pathways, such as in "tricarboxylic acid cycle" and "oxidative phosphorylation", occurred only in the squamous cell carcinomas and not in the early stages of carcinogenesis. We detected increases in ALDH1A3, PTGS2, and KRT1 transcripts in both the early and late stages of carcinogenesis. The identification of the transcripts and pathways that change at an early stage of carcinogenesis provides potentially useful information for early diagnosis and for prevention strategies for human tongue squamous cell carcinomas.

Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM. The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression.

Background: Head and neck squamous cell carcinoma (HNSCC) is a cancer that is characterized by its high morbidity and mortality rates. While tobacco use and alcohol consumption are 2 major contributing factors for HNSCC carcinogenesis, how the combination of tobacco and alcohol increases HNSCC risk is not understood., Methods: We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis and Meadows-Cook alcohol mouse models to elucidate the molecular events and to identify the novel biomarkers associated with oral cancer development., Results: By genome-wide RNA-seq of tongue samples (3 mice per group), we identified changes in transcripts that mediate alcohol metabolism and oxidative stress (Aldh2, Aldh1a3, Adh1, Adh7, and Cyp2a5) in mice treated with 4-NQO followed by ethanol (4-NQO/EtOH) as compared to the vehicle control/untreated (V.C./Untr.) samples. We measured major, global increases in specific histone acetylation and methylation epigenetic marks (H3K27ac, H3K9/14ac, H3K27me3, and H3K9me3) in the oral cavities of V.C./EtOH, 4-NQO/Untr., and 4-NQO/EtOH treatment groups compared to the V.C./Untr. group. We detected changes in histone epigenetic marks near regulatory regions of genes involved in ethanol metabolism by chromatin immunoprecipitation. For instance, the Aldh2 promoter showed increased H3K27me3 marks, and Aldh2 mRNA levels were reduced by 10-fold in 4NQO/EtOH versus V.C./Untr. tongue samples. 4-NQO/EtOH treatment also caused increases in markers of oxidative stress, including 4-HNE, MCT4/SLC16a3, and TOM20, as measured by immunohistochemistry., Conclusions: We delineate a mechanism by which 4-NQO and ethanol can regulate gene expression during the development of HNSCC and suggest that histone epigenetic marks and oxidative stress markers could be the novel biomarkers and targets for the prevention of HNSCC., (Copyright © 2015 by the Research Society on Alcoholism.)

Objective: We investigated whether glutamate, NMDA receptors, and eukaryote elongation factor-2 kinase (eEF-2K)/eEF-2 regulate P-glycoprotein expression, and the effects of the eEF-2K inhibitor NH125 on the expression of P-glycoprotein in rat brain microvessel endothelial cells (RBMECs)., Methods: Cortex was obtained from newborn Wistar rat brains. After surface vessels and meninges were removed, the pellet containing microvessels was resuspended and incubated at 37°C in culture medium. Cell viability was assessed by the MTT assay. RBMECs were identified by immunohistochemistry with anti-vWF. P-glycoprotein, phospho-eEF-2, and eEF-2 expression were determined by western blot analysis. Mdr1a gene expression was analyzed by RT-PCR., Results: Mdr1a mRNA, P-glycoprotein and phospho-eEF-2 expression increased in L-glutamate stimulated RBMECs. P-glycoprotein and phospho-eEF-2 expression were down-regulated after NH125 treatment in L-glutamate stimulated RBMECs., Conclusions: eEF-2K/eEF-2 should have played an important role in the regulation of P-glycoprotein expression in RBMECs. eEF-2K inhibitor NH125 could serve as an efficacious anti-multidrug resistant agent.

The aim of this randomized controlled study was to investigate the effects of a novel external catheter fixation method for chemotherapy using inferior epigastric arterial catheterization for cervical cancer.Patients diagnosed with cervical cancer were randomly divided into a control group (n = 32) and a treatment group (n = 33). Patients in the control group underwent a traditional fixation method using a haemostat, elastic band and abdominal bandage. Patients in the treatment group underwent an improved fixation method using an indwelling needle and membrane cover. We used a visual analogue scale (VAS) to evaluate each patient's comfort score and also recorded the incidence of needlestick injury and the length of injection time in each group. The VAS scores measured before and after chemotherapy in the treatment group were lower than in the control group. The incidence of needlestick injury in the treatment group was significantly lower than in the control group. The length of injection time in treatment group was significantly lower than in the control group. Compared with the traditional fixation method, the improved fixation method not only increased patient comfort but also reduced both the risk of needlestick injury and the length of injection time. This improved technique deserves increased clinical use., (© 2014 Wiley Publishing Asia Pty Ltd.)

Esophageal squamous cell carcinomas (ESCCs) are very common, aggressive tumors, and are often associated with alcohol and tobacco abuse. Because ESCCs exhibit high recurrence rates and are diagnosed at late stages, identification of prognostic and drug targets for prevention and treatment is critical. We used the 4-nitroquinoline-1-oxide (4-NQO) murine model of oral carcinogenesis and the Meadows-Cook model of alcohol abuse to assess changes in the expression of molecular markers during the initial stages of ESCC. Combining these two models, which mimic chronic alcohol and tobacco abuse in humans, we detected increased cellular proliferation (EGFR and Ki67 expression), increased canonical Wnt signaling and downstream elements (β-catenin, FoxM1, and S100a4 protein levels), changes in cellular adhesive properties (reduced E-cadherin in the basal layer of the esophageal epithelium), and increased levels of phosphorylated ERK1/2 and p38. Additionally, we found that treatment with ethanol alone increased the numbers of epithelial cells expressing solute carrier family 2 (facilitated glucose transporter, member 1) (SLC2A1) and carbonic anhydrase IX (CAIX), and increased the phosphorylation of p38. Thus, we identified both 4-NQO- and ethanol-specific targets in the initial stages of esophageal carcinogenesis, which should lead to the development of potential markers and therapeutic targets for human ESCC.

Objective: To investigate the effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in C57BL/6 mice., Methods: Four-week-old C57BL/6 mice were allocated into normal diet group,high-fat diet group,and high-glucose diet group according to the random number table until 20 weeks old. Body weight,epididymal adipose tissue weight,blood leptin,fat infiltration in liver,M1/M2 macrophage subtypes,and monocyte chemoattractant protein-1 mRNA in epididymal adipose tissues were measured., Results: Compared with normal diet group,body weight,epididymal adipose tissue weight,and leptin concentration in high fat diet group at 20 weeks were significantly increased (P < 0.05),and oil red O staining showed more prominent adipocyte infiltration in liver in high-fat diet group than those in normal diet and high-glucose diet group. However,no apparent differences were seen in high-glucose diet group at 20 weeks in terms of body weight,epididymal adipose tissue weight and leptin concentration. In high-fat diet group,the macrophages infiltration in epididymal adipose tissue increased with time and the percentage of M2 macrophage decreased in high-fat diet group than that in high-glucose diet group(P<0.05). Compared with normal diet group,monocyte chemoattractant protein-1 mRNA expression increased significantly in high-fat diet group(P<0.05). In high-glucose group,however,no significant differences were discerned (P > 0.05)., Conclusion: High-fat diet,rather than 60% high glucose diet,will lead to obesity and macrophage infiltration in adipose tissues.

Cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, has been proven to be a promising antitumor agent for ovarian cancer therapy. Our previous studies have shown that CRM197 has potent antitumor activity in human cisplatin-resistant ovarian cancer. However, the relationship between CRM197 and the resistance to cisplatin remains unclear. Here, we report that CRM197 significantly reverses the resistance to cisplatin in cisplatin-resistant ovarian carcinoma cell line (A2780/CDDP). We established xenograft nude mice models with A2780 and A2780/CDDP cells. Notably, we observed that CRM197 suppresses the expression of HB-EGF and epidermal growth factor receptor in A2780/CDDP cells and xenografts harboring the overexpression of HB-EGF and epidermal growth factor receptor. Experiments conducted in vitro and in vivo suggest that CRM197 markedly downregulates the expression of excision repair cross-complementing group 1 (P = 0.002) and DNA repair capacity in A2780/CDDP tumor (P < 0.001) by inactivation of extracellular signal-regulated kinase signaling, providing novel possible mechanisms for the ability of CRM197 to restore drug sensitivity. These results suggest that CRM197 as an HB-EGF inhibitor might be a cisplatin-chemosensitizing agent for the treatment of ovarian carcinoma with resistance to cisplatin.

Background: Many studies have confirmed that brief remifentanil exposure can enhance pain sensitivity. We previously reported that activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia via regulating N-methyl-D-aspartate receptor plasticity in the spinal dorsal horn. In this study, we demonstrated that GSK-3β inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and function in the spinal dorsal horn., Methods: Using a rat model of remifentanil-induced incision hyperalgesia, mechanical and thermal pain was tested 1 day before infusion and 2 hours, 6 hours, 1 day, 2 days, 3 days, 5 days, and 7 days after infusion. Western blot analysis was used to detect AMPAR subunit (GluR1 and GluR2) trafficking, AMPAR phosphorylation status, and GSK-3β activity in the spinal dorsal horn. Furthermore, whole-cell patch-clamp recording was used to analyze the effect of GSK-3β inhibition on AMPAR-induced current in the spinal dorsal horn., Results: Membrane AMPAR subunit GluR1 was upregulated in the spinal cord in remifentanil-induced postoperative hyperalgesia rats (275 ± 36.54 [mean ± SD] vs 100 ± 9.53, P = 0.0009). Selective GSK-3β inhibitors, LiCl and TDZD, treatment ameliorates remifentanil-induced postoperative hyperalgesia, and this was associated with the downregulated GluR1 subunit in the membrane fraction (254 ± 23.51 vs 119 ± 14.74, P = 0.0027; 254 ± 23.51 vs 124 ± 9.35, P = 0.0032). Moreover, remifentanil incubation increased the amplitude and the frequency of AMPAR-induced current in dorsal horn neurons (61.09 ± 9.34 pA vs 32.56 ± 6.44 pA, P = 0.0009; 118.32 ± 20.33 milliseconds vs 643.67 ± 43.29 milliseconds, P = 0.0002), which was prevented with the application of LiCl and TDZD, respectively. Remifentanil-induced postoperative pain induced an increase in pGluR1 Ser845 and Rab5, which was prevented with the application of LiCl and TDZD., Conclusions: These results indicate that amelioration of remifentanil-induced postoperative hyperalgesia by GSK-3β inhibition is attributed to downregulated AMPAR GluR1 expression in the membrane fraction and inhibition of AMPAR function via altering pGluR1 and Rab5 expression in the spinal dorsal horn.

Limonium sinense (Girard) Kuntze is a traditional Chinese folk medicine used for the treatment of fever, hemorrhage, hepatitis and other disorders. Recently, it was found that the crude polysaccharides from L. sinense (LSP) has significant anti-tumor activity. However, research on the isolation and identification of anti-tumor polysaccharide fractions from LSP has not yet been reported. In this study, three polysaccharides LSP11, LSP21, LSP31 were isolated and purified from LSP by using DEAE-52 cellulose column and Sephadex G-100 column chromatography. It was found that LSP21 exhibited the most significant inhibitory effect on the growth of HepG2 cells in vitro. Further research showed that LSP21 inhibited the growth of HepG2 cells in a dose-dependent manner and could induce cell body shrinkage, chromatin condensation, and reduction in the number of tumor cells with normal morphology which suggested that its cytotoxicity on tumor cell might be related to both inhibition on cell proliferation and inducement of cell death. Finally, the structural characteristics of LSP21 were analyzed by high performance liquid chromatography (HPLC) and gas chromatography (GC). The results showed that LSP21 is a heteropolysaccharide with an average molecular weight of 1.31×10(6) Da and consists of glucose, galactose and mannose in the ratio of 1.77:1:2.38., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Renal tubular epithelial cell injury is a major pathological event that contributes to the development of diabetic kidney disease (DKD). Uncoupling protein-2 (UCP2), a mitochondrial membrane protein, has been reported to participate in the regulation of reactive oxygen species (ROS) generation, which contributes to tubular cell apoptosis induced by hyperglycemia. In this study, we found that genipin, a UCP2 inhibitor, dramatically boosted oxidative stress, attenuated antioxidative capacity, and exacerbated cell apoptosis accompanied with caspase-3 activation in rat renal proximal tubular cells (NRK-52E) incubated with high glucose. The present study results suggest that manipulation of UCP2 could be important in the prevention of oxidative stress damage in renal tubular epithelial cells induced by hyperglycemia in vitro.

We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.

Angiotensin II type 2 receptor (AT2R) is thought as an important regulatory target during antihypertensive treatment but its role in vasomotor regulation remains controversial. The interactional relationship between the sympathetic nervous systems and the renin-angiotensin-aldosterone system (RAS) has been revealed but poorly investigated. This work was designed to explore the effect of metoprolol (MET) treatment on the RAS, especially the expression and vasomotor function of AT2R, in spontaneously hypertensive rats (SHR). The results showed that upregulated renin activity and Ang II concentration of plasma in SHR were inhibited by MET treatment. In isolated superior mesenteric arteries from both Wistar-Kyoto rats and SHR, Ang II perfusion induced vasodilatation after AT1R inhibition by telmisartan, although the vasodilatation was harmed in SHR. Furthermore, AT2R inhibitor PD123319 arrested the vasodilatation induced by Ang II. SHR received MET exerted improved vasodilatation mediated by AT2R (47.29% ± 5.16% vs. 24.99% ± 4.93% for MET and SHR, respectively; P < 0.05). Western blot analysis showed that MET restored expression of AT2R in SHR, which may contribute to MET's antihypertensive effect. These results suggested an impact of β-adrenergic blocker on RAS and supported an important role of AT2R in antihypertensive treatment.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer affecting humans worldwide. To determine the potential mechanisms by which chronic tobacco and alcohol abuse lead to HNSCC of the oral cavity, we have used both the 4-nitroquinoline-1-oxide (4-NQO) murine oral carcinogenesis and the Meadows-Cook alcohol models. In this study, we treated mice with 4-NQO in drinking water for 10 weeks and then administered 20% (w:v) ethanol (EtOH) for another 10 weeks. We observed increased levels and/or activation of signaling proteins [p38 mitogen-activated protein kinase (MAPK), β-catenin and Erk 1/2] that are typically altered during HNSCC initiation in humans. We found that EtOH administration alone increased the expression of p38 MAPK but not Erk 1/2 MAPK. Total β-catenin levels in the tongues increased by 2- to 3-fold after 4-NQO treatment, with or without EtOH. However, EtOH combined with 4-NQO reduced phosphorylated β-catenin levels, whereas 4-NQO treatment alone did not. These data implicate EtOH as a regulator of β-catenin signaling in this HNSCC model. We also utilized K14-CreER(TAM); ROSA26 mice to mark permanently stem/progenitor cells in the tongue epithelia. We found that 4-NQO alone and 4-NQO plus EtOH treatment resulted in massive, horizontal expansion of stem/progenitor cell populations arising from single stem cells in the basal layer of the epithelia. This expansion is consistent with carcinogen-associated, symmetric division of stem/progenitor cells. Our data suggest that specific therapeutic targets for prevention of HNSCC of the oral cavity associated with both alcohol and tobacco use are p38 MAPK and β-catenin.

Objective: To investigate the prevalence and related risk factors of prehypertension in Hangzhou, Shaoxing,Jiaxing city, Zhejiang province., Methods: 3200 people were selected by stratified cluster random sampling method, and statistical methods including chi-square test, and logistic regression through SAS 9.0 were used., Results: The prevalence of pre- hypertension was 45.9%, higher for males and urban population, with significant differences seen between males and female(49.0% vs. 48.0%, P < 0.05), urban and rural areas(59.31% vs. 44.15%, P < 0.05). Data from the multiple factor logistic analysis showed that risk factors of prehypertension would include: older age, types of profession, under low education level, being urban residents, overweight and obesity, hyper triglyceride, and family history of hypertension, with ORs and 95% CI as 0.99 (0.98-0.99), 1.28(1.07-1.28), 1.31(1.10-1.56), 1.50(1.11-2.02), 1.33(0.98-1.81), 1.60 (1.19-2.16)and 1.18(1.00-1.39), respectively., Conclusion: Prehypertension prevalence was found high in the studied district, especially in urban residents with low education level. Strategies including reduction on risk factors as obesity and hyper triglyceride through health education as well as lifestyle modification should be taken to hold back the increasing trend on prehypertension in Zhejiang.