Comorbidity profiling identifies potential subtype of elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Few studies have assessed the comprehensive associations among comorbid diseases in elderly patients with nasopharyngeal carcinoma (NPC). This study sought to identify potential comorbidity patterns and explore the relationship of comorbidity patterns with the mortality risk in elderly patients with NPC. METHODS: A total of 452 elderly patients with NPC were enrolled in the study. The network analysis and latent class analysis were applied to mine comorbidity patterns. Propensity score matching was used for adjusting confounders. A restricted cubic spline model was used to analyze the nonlinear association between age and the risk of all-cause mortality. RESULTS: We identified 2 comorbidity patterns, metabolic disease-related comorbidity (MDRC) and organ disease-related comorbidity (ODRC) in elderly patients with NPC. Patients in MDRC showed a significantly higher risk of all-cause mortality (71.41% vs 87.97%, HR 1.819 [95% CI, 1.106-2.994], P = .031) and locoregional relapse (68.73% vs 80.88%, HR 1.689 [95% CI, 1.055-2.704], P = .042). Moreover, in patients with MDRC pattern, we observed an intriguing inverted S-shaped relationship between age and all-cause mortality among patients aged 68 years and older. The risk of mortality up perpetually with age increasing in ODRC group, specifically within the age range of 68-77 years (HR 4.371, 1.958-9.757). CONCLUSION: Our study shed light on the potential comorbidity patterns in elderly patients with NPC, thereby providing valuable insights into the development of comprehensive health management strategies for this specific population.

Discovery of antibacterial agents targeting biofilm formation: total synthesis and in vitro investigation of amycolasporins.

Three monoterpene alkaloids amycolasporin A and (±) amycolasporins B and C have been synthesized for the first time from commercially available materials in yields of 31%, 14% and 21%, respectively. Their six analogues (18, 19, 30a and 30d-30f) were synthesized through a similar protocol. Meanwhile, the antibacterial activity of all synthesized molecules was evaluated, showing different levels of bioactivity. Among them, analogue 30d was screened as the most effective antibacterial candidate against E. coli (MIC value, 12.5 µg mL-1) and S. aureus (MIC value, 12.5 µg mL-1). Further investigation showed that 30d obviously inhibited biofilm formation and disrupted the preformed biofilm of E. coli and S. aureus by promoting intracellular ROS release.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease.

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Biomimetic synthesis and anti-inflammatory evaluation of violacin A analogues.

Violacin A, a chromanone derivative, isolated from a fermentation broth of Streptomyces violaceoruber, has excellent anti-inflammatory potential. Herein, a biogenetically modeled approach to synthesize violacin A and twenty-five analogues was described, which involved the preparation of aromatic polyketide precursor through Claisen condensation and its spontaneous cyclization. The inhibitory effect on nitric oxide (NO) production of all synthetic molecules was evaluated by lipopolysaccharide (LPS)-induced Raw264.7 cells. The results revealed that introduction of aliphatic amine moieties on C-7 obviously improved the anti-inflammation effect of violacin A, and also the aromatic ether instead of ketone group at side chain was favorable to increase the activity. Among them, analogue 7a and 16d were screened as the most effective anti-inflammatory candidates. Molecular mechanism research revealed that 7a and 16d acquired anti-inflammatory ability due to the inhibition of NF-κB signaling pathway.

Total synthesis and anti-inflammatory evaluation of violacin A and its analogues.

A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A as well as the preparation of thirty analogues of this lead from commercially available orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts acylation, the regioselective etherification and esterification of phenolic hydroxyl groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A. The deprotection reaction with Pd-catalytic was involved to avoid the elimination of the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO) production using lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives 11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for anti-inflammatory activities of violacin A derivatives. Additionally, Western blot results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines releases correlated with the suppression of NF-κB signaling pathway.

Comparison of Volatiles in Different Jasmine Tea Grade Samples Using Electronic Nose and Automatic Thermal Desorption-Gas Chromatography-Mass Spectrometry Followed by Multivariate Statistical Analysis.

Chinese jasmine tea is a type of flower-scented tea, which is produced by mixing green tea with the Jasminum sambac flower repeatedly. Both the total amount and composition of volatiles absorbed from the Jasminum sambac flower are mostly responsible for its sensory quality grade. This study aims to compare volatile organic compound (VOC) differences in authoritative jasmine tea grade samples. Automatic thermal desorption-gas-chromatography-mass spectrometry (ATD-GC-MS) and electronic nose (E-nose), followed by multivariate data analysis is conducted. Consequently, specific VOCs with a positive or negative correlation to the grades are screened out. Partial least squares-discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) show a satisfactory discriminant effect on rank. It is intriguing to find that the E-nose is good at distinguishing the grade difference caused by VOC concentrations but is deficient in identifying essential aromas that attribute to the unique characteristics of excellent grade jasmine tea.

Design, synthesis and antifungal evaluation of borrelidin derivatives.

Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 µg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 µg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).

The causal impact of complement C3d receptor 2 on head and neck cancer microenvironment and its implications for immunotherapy response prediction.

This research dives into the intricate immune landscape of head and neck cancer (HNC), with a keen focus on the roles of specific immune cell subpopulations and their linked genes. We used tumour RNA-seq (in-house cohort: n = 192, TCGA-HNSC: n = 546) and Mendelian randomization to pinpoint key SNPs in immune cells that have a causal connection to HNC. Our discoveries unveil a spectrum of tumour immune phenotypes that either offer protection against or increase the risk of HNC. We underscore the therapeutic promise of Complement C3d Receptor 2 (CR2), a gene closely tied to immune cells, with its increased expression in tumour tissues linked to a more favourable prognosis. This is correlated with heightened immune pathway activity, stronger resistance to radiochemotherapy, and improved immunotherapy responses. Our research emphasises the pivotal role of CR2 in immune regulation and the significance of immune cells in tumour progression, highlighting the potential of CR2-targeted therapeutic interventions.

Comparative evaluation of machine learning models in predicting overall survival for nasopharyngeal carcinoma using 18F-FDG PET-CT parameters.

PURPOSE: The objective of this study is to assess the prognostic efficacy of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET-CT) parameters in nasopharyngeal carcinoma (NPC) and identify the best machine learning (ML) prognostic model for NPC patients based on these 18F-FDG PET/CT parameters and clinical variables. METHOD: A cohort of 678 patients diagnosed with NPC between 2016 and 2020 was analyzed in this study. The model was constructed using four advanced ML algorithms, namely Random Forest (RF), Extreme Gradient Boosting (XGBoost), Least Absolute Shrinkage and Selection Operator (LASSO), and multifactor COX step-up regression. Statistical significance of the models was assessed using Kaplan-Meier (K-M) curves, with a significance level established at P < 0.05. The prognostic efficacy of the models was evaluated through the analysis of receiver operating characteristic (ROC) curves, with the area under the ROC curve (AUC) serving as a criterion for model selection. The decision curve analysis (DCA) and concordance index (C-index) were employed to assess the precision of the optimal model. RESULTS: Multivariate analysis revealed age, T stage, and metabolic tumor volume (MTV) for the primary nasopharyngeal tumor (MTVT) as significant independent prognostic factors for overall survival (OS) in NPC patients. Additionally, the LASSO model identified six key variables, including peak standardized uptake value (SUV-peak) for the primary nasopharyngeal tumor (SUV-peak(T)), MTVT, heterogeneity index for neck lymph nodes (HIN), age, pathological type, and T stage. Remarkably, the LASSO model demonstrated superior performance with a 5-year AUC of 0.849 compared to other models. Further assessment using the C-index and DCA confirmed the accuracy of the LASSO model. Subgroup analysis revealed notable risk factors, such as a high heterogeneity index (HI) for the primary nasopharyngeal tumor (HIT), MTV values for neck lymph nodes (MTVN), and HIN. CONCLUSIONS: We developed a novel prognostic machine learning model that integrates 18F-FDG PET-CT parameters and clinical characteristics, significantly enhancing prognosis prediction in NPC.

Machine learning-based survival prediction nomogram for postoperative parotid mucoepidermoid carcinoma.

Parotid mucoepidermoid carcinoma (P-MEC) is a significant histopathological subtype of salivary gland cancer with inherent heterogeneity and complexity. Existing clinical models inadequately offer personalized treatment options for patients. In response, we assessed the efficacy of four machine learning algorithms vis-à-vis traditional analysis in forecasting the overall survival (OS) of P-MEC patients. Using the SEER database, we analyzed data from 882 postoperative P-MEC patients (stages I-IVA). Single-factor Cox regression and four machine learning techniques (random forest, LASSO, XGBoost, best subset regression) were employed for variable selection. The optimal model was derived via stepwise backward regression, Akaike Information Criterion (AIC), and Area Under the Curve (AUC). Bootstrap resampling facilitated internal validation, while prediction accuracy was gauged through C-index, time-dependent ROC curve, and calibration curve. The model's clinical relevance was ascertained using decision curve analysis (DCA). The study found 3-, 5-, and 10-year OS rates of 0.887, 0.841, and 0.753, respectively. XGBoost, BSR, and LASSO stood out in predictive efficacy, identifying seven key prognostic factors including age, pathological grade, T stage, N stage, radiation therapy, chemotherapy, and marital status. A subsequent nomogram revealed a C-index of 0.8499 (3-year), 0.8557 (5-year), and 0.8375 (10-year) and AUC values of 0.8670, 0.8879, and 0.8767, respectively. The model also highlighted the clinical significance of postoperative radiotherapy across varying risk levels. Our prognostic model, grounded in machine learning, surpasses traditional models in prediction and offer superior visualization of variable importance.

Downregulated Phosphoglycerate Kinase 1 Attenuates Cerebral Ischemia-Reperfusion Injury by Reversing Neuroinflammation and Oxidative Stress through the Nuclear Factor Erythroid 2 Related Factor 2/ARE Pathway.

Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and oxidative injury in cerebral ischemia-reperfusion injury (CIRI). In this study, we investigated the regulatory effects of phosphoglycerate kinase 1 (PGK1) on inflammation and oxidative response after CIRI in male adult Sprague-Dawley (SD) rats and using primary astrocytes obtained from neonatal SD rats, and explored its related mechanisms. We established a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R) by suture occlusion, and an oxygen-glucose deprivation/reoxygenation model of astrocytes using oxygen-free, glucose-free, and serum-free cultures. AAV8-PGK1-GFP was injected into the left ventricle 24 h before modeling. Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, co-immunoprecipitation (CoIP) assay, fluorescence in situ hybridization (FISH), and western blotting were used to elucidate the in-depth mechanisms of PGK1 in CIRI. PGK1 overexpression significantly exacerbated neurological deficits, increased cerebral infarct volume, and aggravated nerve cell injury in rats after MCAO/R. Using FISH and CoIP assays, we verified the localization of PGK1 and Nrf2 in primary astrocytes. Further rescue experiments showed that Nrf2 knockdown eliminated the protective effect of CBR-470-1 (a PGK1 inhibitor) on CIRI. Lastly, we confirmed that PGK1 aggravates CIRI by inhibiting the Nrf2/ARE pathway. In conclusion, our findings suggest that inhibiting PGK1 attenuates CIRI by reducing the release of inflammatory and oxidative factors from astrocytes by activating the Nrf2/ARE signaling pathway.

Dynamic change of oligopeptides and free amino acids composition in five types of tea with different fermentation degree processed from the same batch of fresh tea (Camelilia Sinensis. L.) leaves.

Our previous studies have confirmed oligopeptides could be meaningful to tea taste and biofunction. As the total content of oligopeptide among different tea types were varied. It is a natural speculation that certain tea processing step could be vital for oligopeptides enrichment. In current study, five types of traditional Chinese tea were produced from the same batch of fresh leaves. Step processing samples were acquired through which to profile the oligopeptides and free amio acids composition change during tea processed. As a result, firstly, withering was the vital step for oligopeptide enrichment, followed by fermentation, yellowing and drying. Secondly, as the enrichment of oligopeptides was often accompanied by the increase of protein amino acids, suggesting certain proteins degradation in fresh leaves could be the main source of oligopeptides. Thirdly, a total of 166 abundant oligopeptides were screened out, through which 14 high degradation protein were also located by protomic approaching.

Quantification, identification and comparison of oligopeptides on five tea categories with different fermentation degree by Kjeldahl method and ultra-high performance liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry.

Peptides with different lengths or amino sequences could have specific tastes or bio-activities. So far, either the quantity or pattern differences of peptide among various of teas were unknown. Here, firstly, we developed a method for tea oligopeptide quantification and made comparison of their contents. Secondly, we applied ultra-high performance liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry (UHPLC-Quadrupole-Orbitrap-UHRMS) to sequence oligopeptides. As a result, the total amount of oligopeptides in white tea and dark tea were higher, followed by black tea and green tea, finally with oolong tea. It suggested that withering which undergoes with endogenous protease and post-fermented that undergoes with a participation of exotic micro-organisms were key in oligopeptide enrichment. Thirdly, a total of 902 abundant identified peptides, most of which were tripeptide, tetrapeptide, pentapeptide, and hexapeptide were screened against several existing peptide databases. There were a series of taste peptides and bio-active peptides existing.

Exosomes derived from immature bone marrow dendritic cells induce tolerogenicity of intestinal transplantation in rats.

BACKGROUND: Dendritic cells (DCs) secrete exosomes bearing major histocompatibility complex I and II (MHC I /II) and co-stimulatory molecules, and play a critical role in immune regulation. Because immature DCs can induce T-cell tolerance in vitro and in vivo, we explored the possibility of using exosomes derived from immature DCs (imDex) for the induction of intestinal transplant tolerance in rats. MATERIALS AND METHODS: ImDex were purified from F344 rat bone marrow immature DCs. The tolerizing capacities of imDex were analyzed in vitro and in vivo using a F344-to-Wistar intestinal transplantation model. RESULTS: In the context of a moderate level of MHC class II and a low co-stimulatory level expression, imDex significantly suppressed the alloreactive T-cell response with an increase in IL-10 in vitro. In vivo injection of the lower dose (20 µg) of donor (but not recipient) imDex can significantly prolong the survival of intestinal allografts. This effect was accompanied by a decrease in the anti-donor cellular response, with a significant increase in IL-10. The CD4+CD25+T cells percentage and FOXP3mRNA expression in splenic T-cells were also significantly increased in imDex treatment recipients at five days after transplantation. CONCLUSIONS: The results suggest that imDex can prolong the intestinal allograft survival and may be a potential strategy to facilitate induction of transplant tolerance.

Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure-Activity Relationship, In Vitro and In Vivo Investigations of Jamunones.

Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.

Exosomes derived from interleukin-10-treated dendritic cells can inhibit trinitrobenzene sulfonic acid-induced rat colitis.

OBJECTIVE: Inflammatory bowel disease (IBD), which mainly refers to Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. Recent reports have demonstrated that exosomes derived from interleukin-10 (IL-10)-treated bone marrow-derived dendritic cells (DCs) can reduce the incidence and severity of established collagen-induced arthritis (CIA) in mice. Based on the essential role of IL-10 in the development of normal mucosal immunity, we investigated whether exosomes derived from DCs treated with IL-10 (known as IL-10-exosomes) can suppress the trinitrobenzene sulfonic acid (TNBS)-induced colitis. MATERIAL AND METHODS: We used the rat TNBS-induced colitis model to address the therapeutic potential of IL-10-exosomes in vivo. More specifically, a rectal enema of TNBS was administered to Wistar rats, and IL-10-exosomes were injected intraperitoneally on Day 3. RESULTS: In the context of a high level of major histocompatibility complex class II (MHC II) and a low level of co-stimulatory molecule and membrane-bound IL-10 expression, IL-10-exosomes treatment substantially reduced all analyzed clinical, macroscopic, and histopathologic parameters of TNBS-induced colitis. The therapeutic effects of IL-10-exosomes were associated with a down-regulation mRNA expression of IL-2, IFN-γ and TNF-α in colon tissues. Importantly, treatment with IL-10-exosomes resulted in a pronounced up-regulation of IL-10mRNA expression in colon tissues and regulatory T cells (Tregs) in Colonic lamina propria. CONCLUSIONS: The results suggest that IL-10-exosomes treatment can suppress acute TNBS-induced colitis and may offer a promising new therapeutic strategy for IBD.

Short hairpin RNA targeting beta-catenin suppresses cell proliferation and induces apoptosis in human gastric carcinoma cells.

OBJECTIVE: Aberrant activation of Wnt/beta-catenin signaling is involved in various cancers, including human gastric cancer. Here we investigate the role of Wnt/beta-catenin signaling in regulating gastric cancer cell apoptosis. MATERIAL AND METHODS: Expression of beta-catenin was investigated after transfection with beta-catenin short hairpin RNA (shRNA) in gastric cancer cells by Western blotting and immunofluorescence analysis. beta-catenin/T-cell factor transcriptional activity was also investigated by using a luciferase reporter assay. Next, the effects of beta-catenin shRNA on cell proliferation and apoptosis were evaluated by the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide assay and flow cytometric analysis. To investigate the precise mechanism of these effects, a comprehensive analysis was performed using a cDNA microarray. RESULTS: shRNA targeting beta-catenin resulted in a significant decrease in beta-catenin expression, and its nuclear localization and cell proliferation. Meanwhile, increased cell apoptosis was confirmed. The comprehensive analysis showed that shRNA targeting beta-catenin upregulated 26 apoptosis-related genes (including PERP, TRAF3, PDCD2, TNFRSF25, AKT2 and YWHAZ) and downregulated 48 apoptosis-related genes (including MALT1, IRAK1, TNFAIP3, PPP1R13L, TRIP and YWHAB) in gastric cancer cells. Pathway analysis suggested that the nuclear factor-kappaB pathway was involved in beta-catenin knockdown-induced apoptosis. CONCLUSIONS: Attenuation of beta-catenin by shRNA resulted in suppressed cell proliferation and apparent apoptosis, suggesting that beta-catenin may be a target for therapy of gastric cancer.

Clinicopathological features associated with lymph node metastasis in early gastric cancer: analysis of a single-institution experience in China.

BACKGROUND: An accurate assessment of potential lymph node metastasis is an important issue for the appropriate treatment of early gastric cancer. Minimizing the number of invasive procedures used in cancer therapy is critical for improving the patient's quality of life. OBJECTIVE: To evaluate the clinicopathological features associated with lymph node metastasis of early gastric cancer in patients from a single institution in China. METHODS: A retrospective review of data from 410 patients surgically treated for early gastric cancer at the First Affiliated Hospital (Nanjing, China) between 1998 and 2007, was conducted. The clinicopathological variables associated with lymph node metastasis were evaluated. RESULTS: Lymph node metastasis was observed in 12.20% of patients. The macroscopic type, tumour size, location in the stomach, depth of gastric carcinoma infiltration, and presence of vascular or lymphatic invasion showed a positive correlation with the incidence of lymph node metastasis by univariate analysis. Multivariate analyses revealed histological classification, macroscopic type, tumour size, depth of gastric carcinoma infiltration, and the presence of vascular or lymphatic invasion to be significantly and independently related to lymph node metastasis. The depth of gastric carcinoma infiltration was the strongest predictive factor for lymph node metastasis. For intramucosal cancer, tumour size was the unique risk factor for lymph node metastasis. For submucosal cancer, histological classification and tumour size were independent risk factors for lymph node metastasis. CONCLUSIONS: Histological classification, macroscopic type, tumour size, depth of gastric carcinoma infiltration, and the presence of vascular or lymphatic invasion are independent risk factors for lymph node metastasis in patients with early gastric cancer in China. Minimal invasive treatment, such as endoscopic mucosal resection, may be possible for highly selected cancers.

Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways.

BACKGROUND: Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells. METHODS: Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells. RESULTS: Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells. CONCLUSION: This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial growth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT signaling pathways.

Tamoxifen can reverse multidrug resistance of colorectal carcinoma in vivo.

AIM: To investigate the effect of tamoxifen (TAM) on multidrug resistance (MDR) of colorectal carcinoma in vivo and its relationship with estrogen receptor (ER). METHODS: Multidrug resistance was determined by means of semi-quantitative retro-transcription polymerase chain reaction (RT-PCR) to test mdr1 gene mRNA and ER expression was studied by immunohistochemistry. Tumor tissues from three cases of human colon carcinoma, which had mdr1(+)/ER(+), mdr1(+)/ER(-), mdr1(-) expressions, were planted subcutaneously in the neck of nude mice to establish three xenograft models. These models were subdivided into four subgroups randomly: Doxorubicin (DOX)-treated group, TAM-treated group, DOX and TAM group and control group. The dimensions of these xenografts were measured after each course of treatment and the xenografts were removed at the end of the experiments for measurements of weight and the variation of mdr1 mRNA level with RT-PCR. In each course, TAM (15 mg/(kg/d)) was administrated orally per day in the first seven days and DOX (3.6 mg/kg) was injected peritoneally on the first day. Data was evaluated by q and t tests. RESULTS: In the animal models with mdr1(-) tumor, the weights and volumes of the planted tumor in DOX group ((39.1+/-2.29) mg, (31.44+/-1.61) mm(3)) and TAM and DOX group ((38.72+/-2.56) mg, (31.31+/-1.74) mm(3)), which were lesser than that of control group ((45.48+/-3.92) mg, (36.42+/-2.77)mm(3), P = 0.037, P = 0.016 respectively) significantly. In the animal models with mdr1(+)/ER(+) tumor, the weights and volumes of planted tumor were not affected by DOX or TAM treatment; however, in TAM and DOX group ((425.5+/-28.58) mg, (340.35+/-22.28) mm(3)), they were significantly less than that of control group ((634.23+/-119.41) mg, (507.45+/-93.34) mm(3), P = 0.022, P = 0.045 respectively), which are similar to that in the models with mdr1(+)/ER(-) tumor. No significant changes were found in the expressive level of mdr1 mRNA following these treatments. CONCLUSION: The expression of mdr1 gene corresponds to the sensitivity of colon cancer to anti-tumor drugs in vivo. TAM can reverse the MDR of colorectal carcinoma in nude mice, which is independent of the expression of ER; however, no change was observed in the expressive level of mdr1 mRNA.