Search

Objective To investigate the immunomodulatory activity of polysaccharides from the roots of Brassica rapa. Methods The crude polysaccharide from roots of B. rapa (BRP) was extracted and purified to further investigate the active fraction of BRT for inducing macrophage phagocytosis. Results Effects on RAW264.7 cells demonstrated that BRP behaved better phagocytic capacity and had potent immunomodulatory activity, including increasing production of nitric oxide (NO), tumor necrosis factor α (TNFα) and upregulating mRNA levels of inducible NO synthase (iNOS) and TNFα. Furthermore, modulation of macrophage by BRP was indicated to be mediated via the activation of Akt and nuclear factor-kappa B (NF-κB). Conclusion The beneficial effects of BRP could be used as an immunotherapeutic adjuvant in treatment of inflammatory diseases.

AIM: To investigate the relationship of matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta 2 (TGF-β2) levels in human vitreous with axial length (AL) of patients with high myopia. METHODS: The concentrations of MMP-2 and TGF-β2 levels were tested by enzyme-linked immunosorbnent assay (ELISA). Fifty-five human vitreous samples of 55 patients were collected during vitrectomy surgery, and were divided into two groups according to their spherical equivalent (SE) and AL. High myopia group (25 cases): AL≥26.00 mm, and control group or non-high myopia group (30 cases): AL

LOXL1-AS1, a recently characterized long non-coding RNA (lncRNA), has been reported to modulate tumor progression in several types of cancer. However, the expression and role of LOXL1-AS1 in breast cancer remain unclear. In this study, we sought to identify novel lncRNA regulators engaged in breast cancer metastasis. To this end, we examined 42 cancer-related lncRNAs between MCF7 (with low metastatic potential) and MDA-MB-231 (with high metastatic potential) cells. These lncRNAs have been found to affect the invasiveness of several cancer types, but they are still undefined in breast cancer. Among the 42 candidates, LOXL1-AS1 is significantly increased in MDA-MB-231 cells relative to MCF7 cells. We also show that LOXL1-AS1 is upregulated in breast cancer tissues and cells compared to noncancerous counterparts. Increased LOXL1-AS1 expression is correlated with tumor stage and lymph node metastasis in breast cancer patients. Biologically, overexpression of LOXL1-AS1 enhances and knockdown of LOXL1-AS1 suppresses breast cancer cell migration and invasion. In vivo studies demonstrate that depletion of LOXL1-AS1 inhibits breast cancer metastasis. Mechanistically, LOXL1-AS1 sponges miR-708-5p to increase nuclear factor κB (NF-κB) activity. LOXL1-AS1 can also interact with EZH2 protein to enhance EZH2-mediated transcriptional repression of miR-708-5p. Rescue experiments indicate that co-expression of miR-708-5p attenuates LOXL1-AS1-induced invasiveness in breast cancer. In addition, there is a negative correlation between LOXL1-AS1 and miR-708-5p expression in breast cancer specimens. Overall, LOXL1-AS1 upregulation facilitates breast cancer invasion and metastasis by blocking miR-708-5p expression and activity. LOXL1-AS1 serves as a potential therapeutic target for breast cancer treatment.

The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month-old C57BL/6 male mice (“young” mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment (“age-associated memory impairment” mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cognitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dysfunction in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017.

Objective: High-intensity focused ultrasound (HIFU) is an innovative non-invasive technology used for adenomyosis. Gonadotropin-releasing hormone agonist (GnRH-a) is a hormone commonly used for adenomyosis. We investigated and assessed the efficacy of HIFU combined with GnRH-a for adenomyosis.Methods: For this systematic review and meta-analysis, we searched Pubmed, Cochrane Library, Web of Science, Embase, CNKI, WanFang, and VIP databases for relevant articles published in Chinese or English that compared HIFU combined with GnRH-a vs. HIFU alone in patients with adenomyosis. The last literature search was completed on January 31, 2021. Two reviewers independently assessed study eligibility and assessed risk of bias. Another two reviewers extracted the data. The RevMan5.3 software was used for the data analysis. Changes in volume of the uterine and adenomyotic lesion were defined as the primary outcomes. The secondary outcomes were visual analog scale (VAS) scores for dysmenorrhea, menstrual volume scores, serum CA125 levels, and recurrence rate. This study is registered with PROSPERO (CRD42021234301).Results: Three hundred and ninety potentially relevant articles were screened. Nine studies with data for 766 patients were finally included. Compared with the HIFU alone group, the HIFU combined with GnRH-a group had a higher rate of uterine volume reduction (MD 7.51, 95% CI 5.84–9.17, p < 0.00001), smaller adenomyotic lesion volume (MD 4.11, 95% CI 2.93–5.30, p < 0.00001), lower VAS score for dysmenorrhea (MD 1.27, 95% CI 0.54–2.01, p = 0.0007) and menstrual volume score (MD 0.88, 95% CI 0.73–1.04, p < 0.00001), and lower CA125 level (SMD 0.31, 95% CI 0.05–0.56, p = 0.02) after the procedure. The recurrence rate in the HIFU combined with GnRH-a group was lower than that in the HIFU alone group (RR 0.28, 95% CI 0.10–0.82, p = 0.02).Conclusions: Compared with HIFU treatment alone, HIFU combined with GnRH-a for the treatment of adenomyosis has greater efficacy in decreasing the volumes of the uterine and adenomyotic lesions and alleviating symptoms. However, since the number of the included studies was too small and most of them were written in Chinese, this conclusion needs to be referenced with caution. And the long-term evidence of its efficacy is still insufficient.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/ identifier [CRD42021234].

The D1 dopamine receptor agonist, SKF-38393, induces cytotoxicity in striatal dopaminergic neurons via an extracellular signal-regulated kinase (ERK) signaling cascade. However, the underlying mechanism remains unclear. We hypothesized that repeated activation of dopaminergic receptors by agonists could lead to neuronal cell death. This study investigated the effects of SKF-38393 on dopaminergic neuronal cell death in a 6-hydroxydopamine-lesioned rat model of Parkinson’s disease (PD) and PC12 cells. In the PD model, SKF-38393 administration (3 and 10 mg/kg per day, s.c.) for 8 weeks significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells in nigrostriatal regions. SKF-38393 administration for 8 weeks induced phosphorylation of sustained ERK1/2 and Bad (Bcl-2-associated death promoter) at Ser155 (BadSer155), and augmented Bax (Bcl-2-associated X protein) expression. However, SKF-38393 only increased Bad phosphorylation at Ser112 (BadSer112) when administered for 4 weeks. In PC12 cells, toxic levels of SKF-38393 (20 and 50 μM) rapidly induced formation of neurite-like processes, but not in the presence of an adenylyl cyclase inhibitor (MDL-12330 A). SKF-38393 (20 and 50 μM) induced sustained ERK1/2 and BadSer155 phosphorylation as well as caspase-3 activation. At a non-toxic level (5 μM), SKF-38393 produced only transient ERK1/2 and BadSer112 phosphorylation. Repeated treatments with SKF-38393 (5 μM) for 1–3 days activated BadSer112. Repeated treatments for 4–7 days induced sustained ERK1/2 and BadSer155 phosphorylation as well as Bax and caspase-3 activation. These results suggest that SKF-38393 induces neurotoxicity by activation of the sustained ERK–Bad–Bax system. These findings contribute to an understanding of the adverse effects of D1 dopamine receptor agonists in patients with PD.

Glycyrrhizic acid (GA), a triterpene isolated from the roots and rhizomes of licorice, named Glycyrrhiza glabra, is the principal bioactive ingredient of anti-viral, anti-inflammatory and hepatoprotective effects. GA has been used in the clinical treatment of hepatitis, bronchitis, gastric ulcer, AIDS (acquired immunodeficiency syndrome), certain cancers and skin diseases. It has a direct effect on anti-HBV (hepatitis B virus) via affecting the HBsAg (hepatitis B surface antigen) to extracellular secretion, improving liver dysfunction in patients with chronic hepatitis B, and ultimately improving the immune status of HBV. GA can significantly inhibit the proliferation of HIV, showing an immune activation. The clinical application of GA on the prevention and treatments of various diseases may derive from its numerous pharmacological properties. This review provides the summary of the antiviral effects of GA on research progress and mechanism in recent years.

Summary Background & aims Previous studies implied that dietary isoflavone intake may reduce the risk of developing breast cancer, but some have shown ambiguous results. This study aimed to systematically evaluate and summarize available evidence on the effect dietary isoflavone intake has on the risk of developing breast cancer. Methods PubMed, Embase, and the Cochrane Library were searched for prospective cohort studies published through April 2017 that evaluated the effect of dietary isoflavone intake on the development of breast cancer. Results Sixteen prospective cohort studies, involving 11,169 breast cancer cases and 648,913 participants, were identified and included in our data analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high versus low intake of isoflavones (95% confidence interval [CI], 0.91–1.09; P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI, 0.92–1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high versus low, and P = 0.192 for moderate versus low). While a moderate consumption of soy-based foods did not significantly affect breast cancer risk, a high intake of soy-based foods associated with a lower risk of developing breast cancer. Considering specific foods, an increased the risk of developing breast cancer was seen with a moderate intake of formononetin, but no significant associations were found between breast cancer risk and other isoflavone-rich diets. Conclusions The present meta-analysis indicates that women with a high dietary intake of soy foods may experience a statistically significant reduction in breast cancer risk. However, moderate formononetin consumption may increase the risk of developing breast cancer.

Opisthorchiasis is an overlooked danger to Southeast Asia. High-resolution disease risk maps are critical but have not been available for Southeast Asia. Georeferenced disease data and potential influencing factor data were collected through a systematic review of literatures and open-access databases, respectively. Bayesian spatial-temporal joint models were developed to analyze both point- and area-level disease data, within a logit regression in combination of potential influencing factors and spatial-temporal random effects. The model-based risk mapping identified areas of low, moderate, and high prevalence across the study region. Even though the overall population-adjusted estimated prevalence presented a trend down, a total of 12.39 million (95% Bayesian credible intervals [BCI]: 10.10–15.06) people were estimated to be infected with O. viverrini in 2018 in four major endemic countries (i.e., Thailand, Laos, Cambodia, and Vietnam), highlighting the public health importance of the disease in the study region. The high-resolution risk maps provide valuable information for spatial targeting of opisthorchiasis control interventions.

Background Reproductive tract infections (RTIs) have become major but silent public health problems devastating women’s lives in Bangladesh. Accurately and precisely identifying high-risk areas of RTIs through high-resolution risk maps is meaningful for resource-limited settings. Methods We obtained data reported with RTI symptoms by women of childbearing age in the years 2007, 2011 and 2014 from Bangladesh Demographic and Health Survey. High-spatial Environmental, socio-economic and demographic layers were downloaded from different open-access data sources. We applied Bayesian spatial-temporal models to identify important influencing factors and to estimate the infection risk at 5 km spatial resolution across survey years in Bangladesh. Results We estimated that in Bangladesh, there were approximate 11.1% (95% Bayesian credible interval, BCI: 10.5–11.7%), 13.9% (95% BCI: 13.3–14.5%) and 13.4% (95% BCI: 12.8–14.0%) of women of childbearing age reported with RTI symptoms in 2007, 2011 and 2014, respectively. The risk of most areas shows an obvious increase from 2007 to 2011, then became stable between 2011 and 2014. High risk areas were identified in the southern coastal areas, the western Rajshahi Division, the middle of Khulna Division, and the southwestern Chittagong Division in 2014. The prevalence of Rajshahi and Nawabganj District were increasing during all the survey years. Conclusion The high-resolution risk maps of RTIs we produced can guide the control strategies targeted to priority areas cost-effectively. More than one eighth of women of childbearing age reported symptoms suggesting RTIs and the risk of RTIs varies in different geographical area, urging the government to pay more attention to the worrying situation of female RTIs in the country.

The present study aimed to clarify the clinical significance and biological effects of T-box (TBX)2 and its potential mechanism in gastric cancer (GC). TBX2 protein expression levels in human GC tissues were investigated using immunohistochemistry, and it was demonstrated that TBX2 was overexpressed in 55.9% (90/161) GC samples. TBX2 overexpression correlated with tumor invasion, advanced tumor node metastasis stage and presence of lymph node metastasis. In addition, TBX2 correlated with poor patient survival. To investigate the effect of TBX2 on biological behaviors, TBX2 plasmid transfection was performed in SGC-7901 cells and TBX2 small interfering RNA knockdown was carried out in BGC-823 cells. MTT and matrigel invasion assays demonstrated that TBX2 overexpression promoted proliferation and invasion, whereas TBX2 depletion inhibited proliferation and invasion. TBX2 overexpression also promoted epithelial-mesenchymal transition by downregulating E-cadherin and upregulating N-cadherin. TBX2 overexpression also upregulated matrix metalloproteinase (MMP)2, MMP9, cyclin E and phosphorylated-extracellular signal regulated kinase levels, however downregulated p21. In conclusion, TBX2 may serve as an effective predictor and therapeutic target in human GC.

New findings What is the central question of this study? Thoracic aortic aneurysm and dissection (TAAD) is characterized by extracellular matrix remodelling and an inflammatory response. Evidence suggests that ADAMTS1 is closely associated with TAAD development, but whether it contributes to the pathophysiology of TAAD remains unknown. What is the main finding and its importance? We generated inducible postnatal ADAMTS1 knockout mice and found that ADAMTS1 deficiency attenuated β-aminopropionitrile-dependent TAAD formation and rupture. Furthermore, ADAMTS1 deficiency suppressed neutrophil and macrophage infiltration by inhibiting inflammatory cytokine levels and macrophage migration during the early stage of β-aminopropionitrile-induced TAAD. ADAMTS1 could be a new therapeutic target for TAAD. Abstract Thoracic aortic aneurysm and dissection (TAAD), as a life-threatening cardiovascular disease, is characterized by extracellular matrix remodelling and an inflammatory response. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is an inflammation-related protein that is able to degrade extracellular matrix proteins in arteries. Herein, we investigated whether ADAMTS1 contributes to the pathophysiology of TAAD in mice. Using the mouse model of β-aminopropionitrile (BAPN)-induced TAAD, we found that ADAMTS1 expression was upregulated beginning in the early stage of TAAD development and localized predominantly in the aortic adventitia. ADAMTS1-floxed mice and whole-body tamoxifen-inducible ADAMTS1 knockout mice (ADAMTS1flox/flox Ubc-CreERT2+ , ADAMTS1 KO) were generated to investigate the direct causal role of ADAMTS1 in TAAD development. The incidence and rupture rates of BAPN-induced TAAD in ADAMTS1 KO mice were significantly lower than those in ADAMTS1flox/flox mice (45.5 versus 81.8% and 18.2 versus 42.4%, respectively). Aortas from BAPN-treated ADAMTS1flox/flox mice displayed profound destruction of the elastic lamellae, abundant neutrophil and macrophage accumulation in the adventitia, obviously increased neutrophil proportions in peripheral blood and significantly increased expression of inflammatory factors in the early stage of TAAD induction, all of which were markedly suppressed in ADAMTS1 KO mice. Furthermore, ADAMTS1-deficient macrophages exhibited abrogated migration capacity both in vivo and in vitro. In conclusion, ADAMTS1 plays a crucial role in postnatal TAAD formation and rupture by regulating inflammatory responses, suggesting that ADAMTS1 might be a new therapeutic target for TAAD.

Advanced gastric cancer (AGC) is a severe malignant tumor associated with high mortality. Targeted therapy is an important approach for improving the therapeutic effects of AGC treatment. This study evaluates the efficacy and safety of targeted agents for AGC patients. PubMed, EmBase, and the Cochrane Library were searched for double-blind randomized controlled trials (RCTs) of AGC treatments published prior to July 2017. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and severe adverse effects (AEs) were evaluated to determine the efficacy and safety of targeted agents. A network meta-analysis with a frequentist framework was performed to assess the effects of various targeted agents for AGC treatment. Our analysis included 16 articles involving 5371 patients and 11 types of agents. The network meta-analysis showed that apatinib (97.5%) was most likely to improve PFS, followed by regorafenib (86.3%) and rilotumumab (65.4%). Apatinib was similarly best for OS outcome, (95.5%) followed by rilotumumab (74.7%) and regorafenib (70%). Apatinib (89.6%) also had the best improvement on ORR, followed by rilotumumab (75.4%) and everolimus (68.4%). Bevacizumab (85.5%) was likely to get the lowest severe AEs, followed by sunitinib (63%). Apatinib, regorafenib, and rilotumumab improved patient PFS and OS. When combined with chemotherapy, ramucirumab and rilotumumab had high efficacy but low tolerability, and bevacizumab had moderate efficacy and tolerability for PFS. Without chemotherapy, ramucirumab and regorafenib had relatively high therapeutic efficacy tolerability for PFS.

Purpose: To date, no guidelines exist for elderly nasopharyngeal carcinoma (NPC) patients (60 years of age or older) due to a lack of prospective clinical trials. This study evaluated the efficacy of concurrent chemotherapy (CCRT) for NPC in elderly patients treated with intensity-modulated radiotherapy (IMRT). Methods: Patients were identified from a prospectively maintained database. A total of 198 consecutive cases of elderly patients with NPC receiving IMRT, including 103 patients treated with IMRT plus CCRT and 95 patients treated with IMRT alone, were analysed from January 2002 to December 2013. Multivariate analysis (MVA) using the Cox proportional hazards model and propensity score analysis (PSA) were performed for overall survival (OS) and disease-free survival (DFS). Finally, sensitivity analysis was performed. Results: The median follow-up time was 55.3 months (range, 3-135.6 months). In the entire cohort, both MVA and PSA models showed that compared with IMRT alone, IMRT plus CCRT significantly improved survival (hazard ratio [HR] 2.143, 95% confidence interval [95% CI] 1.180-3.890; HR 1.961, 95% CI, 1.117-3.443, for OS and DFS, respectively). Similar results were found in the subgroups with high levels of Epstein-Barr virus (EBV) DNA, except in the low-EBV-DNA cohort. The total rates of severe acute toxicity, including leukopenia, neutropenia, stomatitis, and emesis, were significantly higher in the IMRT+CCRT group than in the IMRT-alone group (P < 0.001) but were similar to the rates of severe late toxicity (P = 0.818). Sensitivity analysis confirmed the robustness of our analysis. Conclusions: In the era of IMRT, CCRT retained survival benefits at high EBV DNA levels but not at low EBV DNA levels for elderly NPC patients. Randomized clinical trials are needed to confirm our findings.

Background/Aims: This study aimed to explore the prognostic value of aldehyde dehydrogenase 1 (ALDH1) expression and vasculogenic mimicry (VM) in patients with breast cancer. Methods: ALDH1 expression and the presence of VM were examined by immunohistochemistry and CD31/PAS double staining, respectively, using formalin-fixed paraffin-embedded tissues from 202 breast cancer patients. The mean follow-up period ranged from 15 to 115 months. The Kaplan-Meier method was used to plot survival curves. Prognostic values were assessed by multivariate analysis using the Cox regression model. Results: ALDH1 expression was strongly associated with VM (P = 0.005). ALDH1 expression was positively correlated with histological grade (P = 0.011). Both ALDH1 expression and VM were negatively related to the status of the estrogen receptor and progesterone receptor and were statistically increased in triple-negative breast cancer. Patients with ALDH1 expression or VM displayed poorer disease-free survival (DFS) and overall survival (OS) than ALDH1-negative or VM-negative patients, with the worst OS and DFS observed in ALDH1/VM-double-positive patients. ALDH1-positive and VM-positive were independent survival risk factors for DFS and OS. Conclusion: ALDH1 expression and VM are correlated with the survival rate of patients with breast cancer. ALDH1 and VM, either alone or together, are prognostic factors in patients with breast cancer.

Background Neoadjuvant chemotherapy (NAC) is extensively used in the treatment of patients with gastric cancer (GC), particularly in high risk, advanced gastric cancer. Previous trials testing the efficacy of NAC have reported inconsistent results. Methods This study compares the combined use of NAC and surgery with surgery alone for GC by using a meta-analytic approach. We performed an electronic search of PubMed, EmBase, and the Cochrane Library to identify randomized controlled trials (RCTs) on NAC published before Oct 2015. The primary outcome of the studies was data on survival rates for patients with GC. The summary results were pooled using the random-effects model. We included 12 prospective RCTs reporting data on 1538 GC patients. Results Patients who received NAC were associated with significant improvement of OS (P = 0.001) and PFS (P

Dysregulation of TRIM32 has been implicated in several human cancers, however, its clinical significance and biological function in breast cancer have not been investigated. Using immunohistochemistry, we found that TRIM32 expression is upregulated in breast cancer tissues and that it correlates with advanced stage and poor prognosis. TRIM32 is also overexpressed in 4/7 breast cancer cell lines. CCK8 and colony formation assays showed that TRIM32 depletion inhibited proliferation and colony formation in the T47D cell line, while TRIM32 overexpression promoted MCF-7 cell growth and colony formation. Cell viability and Annexin V/PI staining demonstrated that TRIM32 maintained breast cancer cell survival and reduced apoptosis rate when cells were treated with cisplatin. Western blot analysis demonstrated that TRIM32 overexpression resulted in an upregulation of p-IκB, p-p65, cIAP1, and cIAP2 and a downregulation of p21 and p27 in MCF-7 cells. TRIM32 depletion in T47D cells demonstrated the opposite results, suggesting that TRIM32 may activate the NF-κB pathway. The NF-κB inhibitor BAY 11-7082 blocked the effects of TRIM32 on cisplatin resistance and cIAP1/2 protein regulation. Taken together, the present study demonstrates that TRIM32 downregulates p21/p27 and upregulates IAP family proteins to facilitate breast cancer cell growth and inhibit drug-induced apoptosis, possibly through the NF-κB signaling pathway.

The current study aims to investigate the biological roles and clinical significance of HCRP1 in human gastric cancer. The expression pattern of HCRP1 in gastric cancer tissue and adjacent non-cancerous tissue was detected by immunohistochemistry. HCRP1 downregulation was found in 57 of 137 human gastric cancer samples and correlated with advanced TNM stage, positive nodal status, and relapse. Log-rank test showed that HCRP1 downregulation also correlated with poor overall survival and reduced relapse-free survival. In addition, we found that HCRP1 overexpression inhibited proliferation, colony formation, and invasion in HGC-27 cells. On the other hand, HCRP1 depletion by small interfering RNA promoted proliferation, colony formation, and invasion in SGC-7901 cells. We also treated gastric cancer cells with cisplatin. MTT and Annexin V/PI analysis were carried out to examine change of chemoresistance. We found that HCRP1 overexpression sensitized HGC-27 cells to cisplatin while its depletion reduced sensitivity in SGC-7901 cells. Moreover, we found that HCRP1 overexpression negatively regulated cyclin D1, MMP-2, p-EGFR, p-ERK, and p-AKT. HCRP1 depletion showed the opposite effects. In conclusion, our results suggest that HCRP1 downregulation might serve as an indicator for poor prognosis in gastric cancer patients. HCRP1 reduces drug resistance through regulation of EGFR-AKT signaling.

Alcohol consumption is inconsistently associated with the risk of gastric cancer morbidity and mortality. The aim of this study was to systematically evaluate the association between alcohol consumption on gastric cancer risk. The PubMed, Embase, and Cochrane Library databases were searched from inception through April 2017. Prospective cohort studies evaluating the association between alcohol consumption and risk of gastric cancer which report its effect estimates with 95% confidence intervals (CIs) were included. The results summary was performed using the random-effect model. Twenty-two cohort studies involving 22,545 cases of gastric cancer and 5,820,431 participants were identified and included in our data analysis. Overall, drinking had little or no effect on gastric cancer as compared with non-drinkers. Furthermore, light and moderate alcohol consumption had no significant effect on gastric cancer risk when compared with non-drinkers. However, heavy alcohol consumption was associated with a greater risk of gastric cancer when compared with non-drinkers. The findings of the subgroup analyses indicated that light alcohol consumption was associated with a lower risk of gastric cancer in women, while heavy alcohol consumption was associated with an increased risk of gastric cancer regardless of country, gender, whether the study reported gastric cancer incidence, or whether the study adjusted for body mass index, educational attainment, or physical activity. The findings of this study suggest that light alcohol consumption might play a protective effect on gastric cancer in women, while heavy alcohol consumption is associated with a significantly increased risk of gastric cancer in all subgroups.

// Zheng He 1 , Ting-Ting Zhao 2 , Hui-Mian Xu 3 , Zhen-Ning Wang 3 , Ying-Ying Xu 2 , Yong-Xi Song 3 , Zhong-Ran Ni 3, 4 , Hao Xu 5 , Song-Cheng Yin 3 , Xing-Yu Liu 3 and Zhi-Feng Miao 3 1 Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China 2 Department of Breast Surgery, First Hospital of China Medical University, Shenyang, Liaoning Province, China 3 Department of Surgical Oncology, First Hospital of China Medical University, Shenyang, Liaoning Province, China 4 School of Life Science, University of Technology Sydney, Ultimo, New South Wales, Australia 5 Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China Correspondence to: Zhi-Feng Miao, email: zfmiao@cmu.edu.cn Keywords: gastric cancer, intraperitoneal chemotherapy, prognosis, meta-analysis Received: July 10, 2017 Accepted: August 23, 2017 Published: September 11, 2017 ABSTRACT Even when a curative gastrectomy is conducted, the majority of advanced gastric cancer patients with invasion die due to peritoneal recurrence. We performed electronic searches to identify randomized controlled trials published through April 2017 evaluating the effect of intraperitoneal chemotherapy (IPC) on survival rates. We included 23 trials reporting data on 2,767 patients with advanced gastric cancer. Overall, we noted that patients who received IPC had a significantly increased 1-year survival rate, and the treatment effect of IPC on 1-year survival was most prominent in studies conducted in Japan or those with a mean age of less than 60 years. IPC was also associated with an increased incidence of 2-year survival rate, but it was not seen to have this effect in studies conducted in China or Australia or with a mean age greater than 60 years. Similarly, IPC associated with a significantly increased 3-year survival rate, but this difference was not detected in studies conducted in Austria or with a mean age greater than 60 years. IPC has no significant effect on the 5-year survival rate. Finally, IPC was associated with a lower risk of recurrence in patients with advanced gastric cancer. The findings of this study suggest that gastric cancer patients who receive IPC associate with increased 1-year, 2-year, and 3-year survival rates, but this does not extend out to a 5-year survival rate. IPC is also shown to play a protective role against the risk of recurrence in patients with advanced gastric cancer.

The effect of chloride anions in electrolyte on formic acid oxidation (FAO) at Pd electrode is investigated by cyclic voltammetry and in situ surface-enhanced infrared absorption spectroscopy with attenuated total reflection (ATR-SEIRAS). Electrochemical measurement indicates that 1–2 × 10 − 5 M Cl − in 0.1 M HClO 4 + 0.1 M HCOOH solution leads to a significant decrease of formic acid oxidation current. Molecular level results from the ATR-SEIRAS indicate that such a small amount of chloride suppresses the adsorption of ClO 4 − and HCO 3 − , increased the CO coverage and somehow stabilized the bidentate formate (HCOO B ) species over the main oxidation potentials. The blocking of active Pd surface sites by Cl − and CO ad is mainly responsible for the oxidation current density decay, and the inconformity of υ(HCOO B ) band intensity and oxidation current implies that HCOO B is probably not the active intermediate in the direct pathway of formic acid oxidation.

Background Previous studies have revealed that gypenosides (GPS) improve the symptoms of anxiety disorders in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rat model of Parkinson’s disease (PD). The present study aimed to investigate the effects of GPS on memory deficits in an MPTP-lesioned mouse model of PD treated with L-3,4-dihydroxyphenylalanine (L-DOPA). Methods MPTP (30 mg/kg/day, 5 days)-lesioned mice were treated with GPS (50 mg/kg) and/or L-DOPA (10 and 25 mg/kg) for 21 days. After the final treatments, behavioral changes were assessed in all mice using passive avoidance and elevated plus-maze tests. We then evaluated the biochemical influences of GPS treatment on levels of tyrosine hydroxylase (TH), dopamine, N-methyl-D-aspartate (NMDA) receptors, extracellular signal-regulated kinase (ERK1/2), and cyclic AMP-response element binding protein (CREB) phosphorylation. Results MPTP-lesioned mice exhibited deficits associated with habit learning and spatial memory, which were further aggravated by treatment with L-DOPA (25 mg/kg). However, treatment with GPS (50 mg/kg) ameliorated memory deficits. Treatment with GPS (50 mg/kg) also improved L-DOPA (25 mg/kg)-treated MPTP lesion-induced decreases in retention latency on the passive avoidance test, as well as levels of TH-immunopositive cells and dopamine in the substantia nigra and striatum. GPS treatment also attenuated increases in retention transfer latency on the elevated plus-maze test and in NMDA receptor expression, as well as decreases in the phosphorylation of ERK1/2 and CREB in the hippocampus. Treatment with L-DOPA (10 mg/kg) also ameliorated deficits in habit learning and spatial memory in MPTP-lesioned mice, and this effect was further enhanced by treatment with GPS (50 mg/kg). Conclusion GPS ameliorate deficits in habit learning and spatial memory by modulating the dopaminergic neuronal and N-methyl-D-aspartate receptor-mediated signaling systems in MPTP-lesioned mice treated with L-DOPA. GPS may serve as an adjuvant therapeutic agent for memory deficits in patients with PD receiving L-DOPA.

This study investigated the effects of asarinin on dopamine biosynthesis and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in rat adrenal pheochromocytoma (PC12) cells. Treatment with asarinin (25-50 μM) increased intracellular dopamine levels and enhanced L-DOPA-induced increases in dopamine levels. Asarinin (25 μM) induced cyclic AMP-dependent protein kinase A (PKA) signaling, leading to increased cyclic AMP-response element binding protein (CREB) and tyrosine hydroxylase (TH) phosphorylation, which in turn stimulated dopamine production. Asarinin (25 μM) also activated transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Bad phosphorylation at Ser 112, both of which have been shown to promote cell survival. In contrast, asarinin (25 μM) inhibited sustained ERK1/2, Bax, c-Jun N-terminal kinase (JNK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and caspase-3 activity, which were induced by 6-OHDA (100 μM). These results suggest that asarinin induces dopamine biosynthesis via activation of the PKA-CREB-TH system and protects against 6-OHDA-induced cytotoxicity by inhibiting the sustained activation of the ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells.

Studies examining the relationship between diabetes mellitus (DM) and the risk of gastric cancer incidence or gastric cancer mortality have produced inconsistent results. The purpose of this study was to evaluate the evidence regarding the relationship between DM and subsequent gastric cancer incidence or gastric cancer mortality risk on the basis of cohort studies. A systematic search of articles in PubMed, EmBase, the Cochrane Library, and reference lists was conducted to identify relevant literature. Twenty-two cohort studies reporting data on 8,559,861 participants were included in the study. Overall, participants with DM had little or no change in the risk of gastric cancer, or gastric cancer mortality. There was no evidence of difference in the RR for gastric cancer between men and women. Participants with DM had a non-significant trend towards an increased risk of gastric cancer mortality in men. There was no significant difference between men and women for this relationship. Finally, although subgroup analysis suggested DM was associated with a significant impact on gastric cancer incidence and gastric cancer mortality risk in several specific populations, a significance based on gender difference was not observed. In conclusion, DM might increase the risk of gastric cancer in men when the study used standard incidence/mortality ratio as effect estimate. Further, DM were associated with higher risk of gastric cancer mortality in men if the mean age at baseline less than 55.0 years, used RR or HR as effect estimate, the study adjusted smoking or not, and the study not adjusted alcohol drinking.

This study investigated the effects of ethanol extract from Gynostemma pentaphyllum (GP-EX) on memory deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) (MPTP-lesioned mice). MPTP (30 mg/kg/day, 5 days)-lesioned mice showed deficits of habit learning memory and spatial memory, which were further aggravated by treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) (25 mg/kg, 21 days). However, treatment with GP-EX (50 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice treated with L-DOPA (25 mg/kg): GP-EX prevented the decreases in retention latency time in the passive avoidance test and tyrosine hydroxylase-immunopositive cells and dopamine levels in the nigrostriatum. GP-EX also reduced increases in retention transfer latency time of the elevated plus-maze test and expression of N-methyl-D-aspartate (NMDA) receptor and improved decreases in phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB) in the hippocampus in the same models. By contrast, L-DOPA treatment (10 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice, which were further improved by GP-EX treatment. These results suggest that GP-EX ameliorates habit learning memory deficits by activating dopaminergic neurons and spatial memory deficits by modulating NMDA receptor-ERK1/2-CREB system in MPTP-lesioned mice treated with L-DOPA. GP-EX may serve as an adjuvant phytonutrient for memory deficits in PD.

Background: Coronary intervention therapy is the main treatment for uremic patients with coronary heart disease. The studies on whether dialysis reduces the efficacy of dual antiplatelet drugs are limited. The aim of this study was to examine the effect of dialysis on antiplatelet drugs in uremic patients with coronary heart disease. Methods: This study included 26 uremic patients who had undergone percutaneous coronary intervention in China-Japan Friendship Hospital from November 2015 to May 2017. We examined their thromboelastography results before and after hemodialysis. Self-paired t-tests were employed to analyze changes in the inhibition rate of platelet aggregation. Results: The mean inhibition rates of arachidonic acid-induced platelet aggregation before and after hemodialysis were 82.56 ± 2.79% and 86.42 ± 3.32%, respectively (t = −1.278, P = 0.213). The mean inhibition rates of adenosine diphosphate-induced platelet aggregation before and after hemodialysis were 67.87 ± 5.10% and 61.94 ± 5.90%, respectively (t = 1.425, P = 0.167). There was no significant difference in the inhibition rates of platelet aggregation before or after hemodialysis. These results also applied to patients with different sensitivity to aspirin and clopidogrel. Conclusion: Dialysis did not affect the antiplatelet effects of aspirin and clopidogrel in uremic patients with coronary heart disease. Key words: Antiplatelet Drug; Coronary Intervention; Dialysis; Thromboelastography

This study investigated the effects of (-)-sesamin on chronic electric footshock (EF) stress-induced anxiety disorders in mice. Mice were treated with (-)-sesamin (25 and 50 mg/kg) orally once a day for 21 days prior to exposure to EF stress (0.6 mA, 1 s every 5 s, 3 min). Mice treated with (-)-sesamin (25 and 50 mg/kg) exhibited less severe decreases in the number of open arm entries and time spent on open arms in the elevated plus-maze test and the distance traveled in the open field test following exposure to chronic EF stress. Similarly, mice treated with (-)-sesamin exhibited significantly less severe decreases in brain levels of dopamine, norepinephrine, and serotonin following exposure to chronic EF stress. Increases in serum levels of corticosterone and expression of c-Fos were also less pronounced in mice treated with (-)-sesamin (25 and 50 mg/kg). These results suggest that (-)-sesamin may protect against the effects of chronic EF stress-induced anxiety disorders by modulating dopamine, norepinephrine, and serotonin levels, c-Fos expression, and corticosterone levels.

Gastric cancer is one of the most common malignant diseases, and poses a serious threat to the quality of human life. Gastric cancer stem/progenitor cells (GCSPCs) have critical effects on tumor formation, affecting specific features of self‐renewal and differentiation and playing a critical role in metastasis. The Notch‐1 pathway is crucially important to GCSPCs and is regulated by DLL4. In this study, DLL4 and Nestin levels were measured in 383 gastric cancer tissue samples by immunohistochemistry, and the clinico‐pathological features of patients assessed. After DLL4 silencing in selected gastric cancer cell lines, the expression of GCSPC markers and colony formation ability were analyzed and the self‐renewal and differentiation capacities of the cells were evaluated. The relationship between DLL4 levels and Notch‐1 signaling pathway effector amounts was assessed via Western blotting and immunofluorescence. Finally, the tumor formation ability of the gastric cancer cells was evaluated with different levels of DLL4 and multiple cell densities in vivo. Our results indicate that DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self‐renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch‐1 pathway, weakening invasion ability and resistance to 5‐FU chemotherapy. In vivo, DLL4 silencing inhibited the tumor formation ability of GCSPCs. In conclusion, DLL4 affects GCSPC stemness, altering their pathological behavior. DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch‐1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target.

This study investigated the effects of (-)-sesamin on memory deficits induced by chronic electric footshock (EF)-induced stress in mice. Mice were treated with (-)-sesamin (25 and 50mg/kg, p.o., daily for 21day) prior to chronic EF stress (0.6mA, 1s every 5s for 3min, daily for 21day). Transfer retention latencies in the elevated plus maze test and N-methyl-d-aspartate (NMDA) receptor (type 1) phosphorylation in the hippocampus increased with chronic EF stress, and they were reduced by treatment with (-)-sesamin at both doses. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-responsive element binding protein (CREB), which were reduced by chronic EF stress, were increased by treatment with (-)-sesamin. Retention latencies in the passive avoidance test and dopamine levels in the substantia nigra-striatum were also reduced by chronic EF stress, and similarly recovered with (-)-sesamin treatment. These results suggest that (-)-sesamin ameliorates the effects of chronic EF stress-induced spatial and habit learning memory deficits by modulating both NMDA receptor and dopaminergic neuronal systems.

Objective To observe the efficiency and safety of hematoporphyrin mono-methylether photodynamic therapy (HMME-PDT) in treating port-wine stains (PWS) with Chinese patients, and to evaluate the advantage of photograph,VISIA Complexion Analysis System, and dermoscopy in efficacy evaluation.Analyzing changes of pain during treatment and related adverse reactions. Method 62 patients were treated in our department during2017-2019 with HMME-PDT, among which, 20 cases were pink type, 32 cases were purple type and remain 11 cases were nodular thickening type. Initially, all patients received an intravenous injection of 5 mg/kg HMME, and then the lesion areas of the patients were exposed to 532 nm LED green light after 10 min. The irradiation power density was range between 80–100 mW/cm2. By utilization of photograph,VISIA system, and dermoscopy to evaluate the clearance after treatments, and then informing the patients to value the pain level during the treatment via visual analogue scale(VAS), and recording the adverse reactions. Result After 2 times treatments, 11 of the 62 cases were cured (17.74 %), 17 cases showed a good efficacy (27.42 %), 20 cases indicated alleviation (32.26 %), while 14 cases displayed no efficacy (22.58 %).By observation, The VISIA system combined with image analysis software is an excellent technique in assessing efficacy. Dermoscopy helps to classify PWS types.It showed that the pain level each patient could endure was distinct, and it’s remarkable that when receiving consecutive 12.09 ± 3.74 min of treatment, most of patients have showed severe pain.Patients with severe pain except young children who couldn't value the pain, had better efficacy.The side effects after treatment mainly displayed with edema, crust, hyperpigmentation. No recurrence within 2 years. Conclusion It shows that after treating with HMME-PDTt efficacy is remarkable, with advantage of safety and fewer side effects. HMME_PDT should undergo further research and promotion. VISIA system combined with image analysis software and dermoscopy are excellent techniques for evaluating efficacy.

This study aims to investigate the clinical significance and biological function of RASSF6 in human breast cancers. RASSF6 protein was found to be downregulated in 42 of 95 human breast cancer tissues by immunohistochemistry, which was associated with advanced TNM stage and nodal metastasis. The rate of RASSF6 downregulation was higher in Triple-negative breast cancer (TNBC). Downregulation of RASSF6 protein was also found in breast cancer cell lines, especially in TNBC cell lines. Overexpression RASSF6 inhibited cell growth rate and colony formation ability in MDA-MB-231 cell line. Depletion of RASSF6 promoted proliferation rate and colony formation ability in T47D cell line. Flow cytometry/PI staining demonstrated that RASSF6 inhibited cell cycle transition. AnnxinV/PI analysis showed that RASSF6 overexpression upregulated apoptosis induced by cisplatin (CDDP) while RASSF6 depletion inhibited apoptosis. JC-1 staining showed that RASSF6 overexpression inhibited mitochondrial membrane potential. Western blot analysis demonstrated that RASSF6 repressed cyclin D1, YAP while upregulated p21, cleaved caspase 3 and cytochrome c expression. In addition, RASSF6 activated Hippo signaling pathway by upregulating MST1/2 and LATS1 phosphorylation. Restoration of YAP inhibited cleaved caspase 3 and cytochrome c which were induced by RASSF6. Restoration of YAP also reduced the rate of CDDP induced apoptosis. In conclusion, this study provided evidence that RASSF6 functions as a potential tumor suppressor in human breast cancer through activation of Hippo pathway.

Background The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. Methods Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. Results 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male

The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD.

The tripartite motif protein tripartite motif-containing 24 (TRIM24) is involved in human cancer progression. However, the expression pattern and biological roles of TRIM24 in human gastric cancer have not been studied. Here, we report that expression of TRIM24 protein was upregulated in 65 of 133 gastric cancer specimens. TRIM24 upregulation positively correlated with clinical stage, local invasion, and poor patient prognosis. We overexpressed TRIM24 by transfection in SGC-7901 cells and used an siRNA strategy to knock down TRIM24 in MKN-1 cells. MTT and colony formation assays showed that transfection of TRIM24 plasmid accelerated, while its depletion inhibited cell proliferation rate. TRIM24 overxpression also induced chemoresistance to 5-FU in gastric cancer cells. Further analysis showed that TRIM24 overexpression upregulated cyclin D1 and Akt phosphorylation. Akt inhibitor LY294002 reversed the role of TRIM24 on chemoresistance. In conclusion, our study shows that TRIM24 is overexpressed in human gastric cancer and accelerates cell growth as well as induce chemoresistance, possibly through the Akt pathway.

Pleural dissemination is commonly associated with metastatic advanced lung cancer. The injury of pleural mesothelial cells (PMCs) by soluble factors, such as transforming growth factor-beta1 (TGF-β1), is a major driver of lung cancer pleural dissemination (LCPD). In this study, we examine the effects of TGF-β1 on PMC injury and the ability of TGF-β1 inhibition to alleviate this effect both in vitro and in vivo. PMCs were co-cultured with the high TGF-β1-expressing lung cancer cell line A549 and with various TGF-β1 signaling inhibitors. Expression of cleaved-caspase 3, cleaved-caspase 9, p21, and p16 were evaluated by Western blot and immunofluorescent confocal imaging. Apoptosis was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltrazoliumbromide assay and AnnexinV-propidium iodide (PI) staining. PMC senescence was assessed by staining for senescence-associated β-galactosidase (SA-β-Gal). The ability of lung cancer cells (LCCs) to adhere to injured PMCs was investigated using an LCC-PMC adhesion assay. In our mouse model, PMC injury status was monitored by hematoxylin–eosin (H&E) and Masson’s trichrome staining. LCCs expressing high levels of TGF-β1 induce apoptosis and senescence of PMCs in a co-culture system. Injured PMCs adhere to LCCs, which may further promote LCPD. Importantly, PMC monolayer injury could be reversed with TGF-β1 inhibitors. This was consistent with our in vivo data showing that the TGF-β1 inhibitor SB-431542 attenuated PMC barrier injury induced by A549 culture medium in our mouse model. Our study highlights the importance of TGF-β1 signaling in LCPD and establishes this signaling pathway as a potential therapeutic target in the disease.

Gastric cancers are one of the most common gastrointestinal tumors with proclivity to metastasis. Hypoxia is an important feature in solid tumor microenvironment; accumulating evidence suggests that chronic and repetitive exposure to hypoxia and reoxygenation seems to provide an advantage to tumor growth. However, mechanisms of intermittent hypoxia regulating gastric cancer metastatic potential remain to be elucidated. In the present study, we established the continuous and intermittent gastric cancer hypoxia models, and we compared the effects of these models on gastric cancer cell metastatic potential. Hypoxia-inducible factor-1α (HIF-1α) and hypoxia target protein/genes expression in response to different hypoxia models were analyzed by Western blot, immunofluorescence, and real-time PCR assays. Gastric cancer cell migration and invasion ability were analyzed by wound healing and Boyden chamber assay. Colony formation and tumor spheroid formation assays were used to assess the ability of self-renewal. Stem-related protein OCT4 and HIF-1α expression were also analyzed by confocal immunofluorescence in single tertiary generation spheroid. We demonstrated that the intermittent hypoxia model upregulated expression of both HIF-1α and hypoxia target protein/genes in a time-dependent manner compared with that of SGC-7901 cells cultured under normoxia. Remarkably, HIF-1α protein was more prone to being located in the nucleus of SGC-7901 cells under conditions of intermittent hypoxia. Gastric cancer cells' migration and invasion ability were significantly enhanced after hypoxic culture; moreover, intermittent hypoxia-conditioned SGC-7901 cells exhibited higher invasiveness than the continuous hypoxia-conditioned SGC-7901 cells. Gastric cancer stem/progenitor cell subpopulation was also enlarged which indicated an enhanced self-renewal ability in hypoxic cultured SGC-7901 cells. Our study emphasizes the significance of hypoxia in regulating gastric cancer cell metastasis potential. Compared with continuous hypoxia, intermittent hypoxia is a more effective and potent hypoxic stimulus. These results provide a new insight to investigate the hypoxic microenvironment within solid tumors.

A series of pyrazolyl-acylhydrazone derivatives (1e–20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC50 = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Peritoneal dissemination (PD) of tumor cells is the most frequent pattern of gastric cancer recurrence and the leading cause of death. Peritoneal milky spots are deemed as the site of origin of gastric cancer PD wherein the main cellular components are macrophages. A vaccine derived from the mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) has exhibit strong immune modulatory properties. In the present study, we tested the hypothesis whether the PA-MSHA vaccine activated peritoneal milky spot macrophages (PMSM) in a manner that would attenuate PD. It was observed that PA-MSHA activated PMSM towards a classical activation phenotype via a toll-like receptor4/9-dependent mechanism, which increased interleukin-12 levels and promoted the expression of co-stimulatory and antigen-presenting molecules like CD80, CD86, and MHC-II (P

Peritoneal dissemination (PD) is the most frequent metastatic pattern of advanced gastric cancer (GC) and the main cause of death in GC patients. Human peritoneal mesothelial cell (HPMC) injury induced by gastric cancer cells (GCCs) and GCC outgrowths supported by peritoneal milky spot macrophages (PMSMs) are the key events during gastric cancer peritoneal dissemination (GCPD). In this study, we investigated whether PMSMs remodeled by GCC can induce HPMC injury and create a favorable microenvironment for GCPD. We established a tumor-associated macrophage (TAM) model using in vitro cell coculture. Normal macrophages cocultured with GCCs down-regulated expression of antigen-presenting surface molecules CD80, CD86, and MHC-II, but, notably, they up-regulated expression of phagocytic scavenger receptor CD206, which is similar to the M2 macrophage phenotype. In further experiments, various experimental methods were applied to detect the injurious effect of TAMs on HPMCs in another TAM-HPMC coculture. Our results showed that GCCs can induce HPMC apoptosis by unregulated apoptosis associated with cleaved caspase3, cleaved caspase9, and p21 proteins. HPMC growth ceased, and both early- and late-stage apoptosis were observed. Additionally, GCCs can induce HPMC fibrosis via increased expression of epithelial cell marker E-cadherin and decreased expression of mesenchymal cell marker α-SMA. Our results demonstrate that, in the GCPD process, PMSMs were remodeled by GCCs, resulting in phenotypic and functional transformation. In turn, this transformation induced HPMC injury and provided a favorable microenvironment for GCC anchorage and growth. These results may provide new insight into the mechanisms of GCPD.

CARMA3 was recently reported to be overexpressed in several cancers and associated with malignant behavior of cancer cells. However, the expression pattern and biological roles of CARMA3 in breast cancer have not been reported. In the present study, we found that CARMA3 was overexpressed in 41.9 % of breast cancer specimens. Significant association was observed between CARMA3 overexpression and TNM stage (p = 0.0223), tumor size (p = 0.0227), and ErbB-2 status (p = 0.0049). Furthermore, knockdown of CARMA3 expression in MDA-MB-435 cells with high endogenous expression decreased cell proliferation and sensitized cell to paclitaxel-induced apoptosis, while overexpression of CARMA3 in MDA-MB-231 cell line promoted cell proliferation and inhibited apoptosis. Further analysis showed that CARMA3 depletion downregulated, and its overexpression upregulated cyclin D1, Bcl-2, and p-IκB levels. In conclusion, our study demonstrated that CARMA3 is overexpressed in breast cancers. CARMA3 facilitates proliferation and inhibits apoptosis through nuclear factor-kappaB signaling.

Crk-like (CRKL) is an adapter protein that has crucial roles in multiple biological processes, including cell proliferation, adhesion, and migration. However, the expression pattern of CRKL protein and its clinical significance in human breast cancers have not been well characterized. In this study, expression of CRKL was evaluated in 108 human invasive ductal carcinoma (IDC) tissues by immunohistochemistry. CRKL protein was upregulated in the cancer tissues compared with adjacent normal mammary glands. Overexpression of CRKL was found in 40 of 108 (37.03 %) breast cancer samples and correlated with advanced p-tumor-node-metastasis stage (p = 0.002), nodal metastasis (p = 0.0323), and tumor size (p = 0.0075). In addition, overexpression of CRKL in the MDA-MB-435 cell line promoted cell proliferation, and small interfering RNA knockdown of CRKL in the MDA-MB-453 cell line inhibited proliferation. Further analysis of cell cycle-related molecules showed that CRKL induced cyclin D1 and phosphorylated extracellular signal-regulated kinase expression. In conclusion, this study demonstrated that overexpression of CRKL correlated with progression and malignant proliferation of human breast cancers.

Objective The aim of the study is to evaluate the distribution and correlation of toxic and essential elements in whole blood from 0- to 6-year-old children from Jinan, China. Design and methods Levels of toxic and essential elements found in the whole blood of 1110 children were analyzed using an atomic absorption spectrometer. Distributions and correlations of trace elements in different age groups were analyzed and compared. Results The overall mean blood lead (Pb) and cadmium (Cd) levels (49.42 ± 20.16 and 1.47 ± 1.08 μg/L, respectively) were relatively stable among different age groups. The prevalence of Pb and Cd intoxication in all children was 1.4% and 0.4%, respectively. Calcium (Ca) levels decreased gradually with age, with an overall concentration of 1.82 ± 0.15 mmol/L. Whole levels of copper (Cu) and magnesium (Mg) were 17.79 ± 4.22 μmol/L and 1.52 ± 0.14 mmol/L, respectively. While 7.6% of all children showed Cu levels below the normal threshold, the levels of Mg were stable in different age groups. Though the overall mean blood zinc (Zn) and iron (Fe) concentrations (59.59 ± 15.15 μmol/L and 7.39 ± 0.74 mmol/L, respectively) gradually increased with age and the overall deficiency levels (59.8% and 59.5%, respectively) decreased with age, Zn and Fe deficiencies were still very common. Significant positive correlations were found when comparing Cu to Zn, Ca, Mg, and Fe; Zn to Mg and Fe; and Mg to Ca and Fe. Additionally, minor positive correlations were found when comparing Pb to Zn and Fe. Conclusion The degree of Pb and Cd intoxication in all the children studied was low; however, Pb and Cd exposure was still evident. The importance of Ca deficiency and supplementation is well recognized, but the severity of Fe and Zn deficiency is not as well documented.

The effects of berberine on long-term administration of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or L-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by L-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with L-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic L-DOPA administration. Long-term L-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms.

Ting-Ting Zhao,1 Ling-Ling Zhu,2 Meng Chen,1 Quan Zhou1 1Department of Pharmacy, 2VIP Care Ward, Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China Background: According to prescribing information for Myrtol standardized enteric-coated soft capsules, the medicine should be taken on an empty stomach. Some patients may experience stomach discomfort after oral administration in fasted state and would prefer to take the medicine after a meal. However, there is no literature addressing the effect of meal on absorption of this drug; therefore, it is desirable to explore the feasibility of taking the capsule after a meal from pharmacokinetic perspective.Methods: A gas chromatography coupled with triple quadruples mass spectrometry assay was established and validated for determining plasma concentrations of eucalyptol, a target component of Myrtol standardized capsules. A self-control clinical study was carried out in healthy male volunteers in fasted and fed states after a single oral dose of 300 mg capsules. Comparison of pharmacokinetic parameters in the two phases and bioequivalence evaluation were performed.Results: The specificity, sensitivity, accuracy, and precision of the assay satisfied the requirements for biopharmaceutical analysis. Pharmacokinetic parameters of eucalyptol (fasted vs fed) were as follows: maximal plasma concentrations (Cmax) (167.60±114.69 vs 518.89±314.47 ng·mL-1), time of maximum concentration (Tmax) (3.7±1.1 vs 4.8±0.7 h), elimination half-life (T1/2) (3.2±1.4 vs 2.6±0.7 h), area under the plasma concentration–time curve (AUC0–t) (584.91±369.90 vs 1,271.61±605.82 ng·h·mL-1), and AUC0–∞(690.36±467.26 vs 1,458.02±720.21 ng·h·mL-1). There was statistically significant difference in Cmax, AUC0–t, and AUC0–∞between the two dosing methods (P

The present study investigated the effects of (-)-sesamin on motor and memory deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) with l-3,4-dihydroxyphenylalanine (l-DOPA). MPTP-lesioned (30mg/kg/day, 5days) mice showed deficits in memory including habit learning memory and spatial memory, which were further aggravated by daily treatment with 25mg/kg l-DOPA for 21days. However, daily treatment with (-)-sesamin (25 and 50mg/kg) for 21days ameliorated memory deficits in an MPTP-lesioned mouse model of PD treated with l-DOPA (25mg/kg). Both (-)-sesamin doses reduced decreases in the retention latency time in the passive avoidance test, latency to fall of rotarod test and distance traveled in the open field test, and attenuated decreases in tyrosine hydroxylase (TH)-immunopositive cells, dopamine, and its metabolites in the substantia nigra-striatum. (-)-Sesamin reduced increases in the retention transfer latency time in the elevated plus-maze test and N-methyl-d-aspartate receptor (NMDAR) expression and reduced decreases in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB) in the hippocampus. In contrast, daily treatment with 10mg/kg l-DOPA for 21days ameliorated memory deficits in MPTP-lesioned mice, and this effect was further improved by treatment with (-)-sesamin (25 and 50mg/kg). These results suggest that (-)-sesamin protects against habit learning memory deficits by activating the dopamine neuronal system, while spatial memory deficits are decreased by its modulatory effects on the NMDAR-ERK1/2-CREB system. Accordingly, (-)-sesamin may act as an adjuvant phytonutrient for motor and memory deficits in patients with PD receiving l-DOPA.