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Biomedical subjects

Hua Yu

Publications and source records attributed to Hua Yu.

At least 19 recordsLinked to original sources
PubMed2007

Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.

Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.

Animals↗
PubMed2006

Selection of SARS-coronavirus-specific B cell epitopes by phage peptide library screening and evaluation of the immunological effect of epitope-based peptides on mice.

Antibodies to SARS-Coronavirus (SARS-CoV)-specific B cell epitopes might recognize the pathogen and interrupt its adherence to and penetration of host cells. Hence, these epitopes could be useful for diagnosis and as vaccine constituents. Using the phage-displayed peptide library screening method and purified Fab fragments of immunoglobulin G (IgG Fab) from normal human sera and convalescent sera from SARS-CoV-infected patients as targets, 11 B cell epitopes of SARS-CoV spike glycoprotein (S protein) and membrane protein (M protein) were screened. After a bioinformatics tool was used to analyze these epitopes, four epitope-based S protein dodecapeptides corresponding to the predominant epitopes were chosen for synthesis. Their antigenic specificities and immunogenicities were studied in vitro and in vivo. Flow cytometry and ELISPOT analysis of lymphocytes as well as a serologic analysis of antibody showed that these peptides could trigger a rapid, highly effective, and relatively safe immune response in BALB/c mice. These findings might aid development of SARS diagnostics and vaccines. Moreover, the role of S and M proteins as important surface antigens is confirmed.

Amino Acid Sequence↗
PubMed2006

Laribacter hongkongensis isolated from a patient with community-acquired gastroenteritis in Hangzhou City.

We describe the isolation of Laribacter hongkongensis in Hangzhou City, People's Republic of China. One strain of bacterium, named LHHZ242, had many of the same phenotypic and genotypic characteristics as Laribacter hongkongensis described in previous publications. This discovery proves that Laribacter hongkongensis is also associated with community-acquired gastroenteritis outside Hong Kong.

China↗
PubMed2006

Nonchromatographic "stir and filter approach" (SAFA) for isolating Sc3N@C80 metallofullerenes.

Separation difficulties have led to a paucity of purified metallic nitride fullerenes (MNFs). Fundamental research and application development has been hampered with limited sample availability. Separation techniques designed to remove contaminant empty-cage fullerenes (e.g., C(60), C(70)...C(2)(n)) and classical metallofullerenes (e.g., non-MNFs) traditionally require expensive and tedious chromatographic methods. Our motivation is an alternative purification approach to minimize dependence on HPLC. Herein we report the use of cyclopentadienyl (CPD) and amino functionalized silica to selectively bind contaminant fullerenes. This "Stir and Filter Approach" (SAFA) provides purified MNF samples at ambient and reflux conditions. Under reflux conditions, purified MNFs (80% recovery, 41 h) are obtained using CPD silica. However, at room temperature, there is an equilibrium established between fullerenes and CPD silica, and no purified MNF samples are obtained using SAFA. In contrast, purified MNF samples (99+%) are readily obtained at room temperature using amino, diamino, and triamino silica at recoveries of 93% (11 h), 76% (9 h), and 50% (6 h), respectively.

Filtration↗
PubMed2006

New steroidal alkaloids from the bulbs of Fritillaria puqiensis.

Six new steroidal alkaloids, namely puqienines C-E (1-3), puqiedine (4), 3alpha-puqiedin-7-ol (5), and puqietinedione (6), along with two known steroidal alkaloids puqiedinone (7) and peimisine (8), were isolated from the bulbs of Fritillaria puqiensis G.D. Yu et G.Y. Chen (Liliaceae). Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR experiments. Among these alkaloids, 1-3 had a veratramine-type skeleton, 4, 5, 7 a cevanine-type skeleton, 6 a secosolanidine-type skeleton, and 8 a jervine-type skeleton. The existence of multiple types of steroidal skeletons, especially of relatively large amount of veratramine-type alkaloids in one species is rare in the genus Fritillaria, and the results might be of chemotaxonomic significance for this species.

Fritillaria↗
PubMed2006

A promoter element of the CD-RAP gene is required for repression of gene expression in non-cartilage tissues in vitro and in vivo.

The cartilage-derived retinoic acid-sensitive protein (CD-RAP) gene is expressed predominately in cartilage. Previous studies in transgenic mice have shown that the DNA promoter segment from -2,251 bp to -2,068 bp of the CD-RAP gene contains elements critical for gene expression. Subsequent studies revealed both positive and negative regulatory motifs in this 183 bp element. Here we show that this element demonstrates activation or repression of gene expression in vitro and in vivo based on cell type and content of transcription factors. The distribution of Sox (positive) and C/EBP (negative) transcription factors in cell lines and in mouse tissues is consistent with their positive and negative roles. In transgenic mice, when the 183-bp element was removed from a 3,345-bp cartilage-specific CD-RAP promoter, expression of the reporter gene became widespread, being observed in muscle, bone, lung, and liver in addition to cartilage. In vitro, mutation of the C/EBP site activated the inactive 3,345-bp CD-RAP gene promoter in myoblastic cells, suggesting that this site is responsible for (-2,079 bp) repression. These results indicate that the 183-bp element plays an important role in cartilage-specific gene expression by acting as a chondrocyte-regulatory module repressing transcription in non-chondrocytes and contributing to activation in chondrocytes. This is the first report of a functional DNA element necessary for repression in non-cartilage tissues in vivo.

Animals↗
PubMed2005

Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity.

The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.

Analysis of Variance↗
PubMed2005

Molecular cloning and characterization of the human AKT1 promoter uncovers its up-regulation by the Src/Stat3 pathway.

Akt1, also known as protein kinase B (PKB) alpha, is frequently activated in human cancers and has been implicated in many cell processes by phosphorylation of downstream molecules. However, transcriptional regulation of Akt1 has not been documented. Here, we report the isolation and characterization of the human AKT1 promoter and demonstrate transcriptional up-regulation of AKT1 by the Src/Stat3 pathway. Protein and mRNA levels of AKT1 are elevated in cells expressing constitutively active Stat3 as well as in v-Src-transformed NIH3T3 cells. Knockdown of Stat3 reduces AKT1 expression induced by v-Src. Although the 4.2-kb region upstream of the transcription start site of the AKT1 promoter contains five putative Stat3-binding motifs, the promoter failed to be induced by Stat3 and/or Src. Further analysis reveals that major Stat3 response elements are located within exon 1 and intron 1 regions of the AKT1 gene, which is upstream of the AKT1 translation initiation site. In addition, ectopic expression of wild type AKT1 in Stat3(-/-) MEF cells largely rescues serum starvation-induced cell death. These findings indicate that the AKT1 promoter comprises exon 1 and intron 1, in addition to the sequence upstream of transcriptional start site. Our data further show that AKT1 is a direct target gene of Stat3 and contributes to Stat3 anti-apoptotic function.

Animals↗
PubMed2005

Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways.

Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis.

Animals↗
PubMed2005

Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects.

Infiltration of immune effector cells in tumors is critical for antitumor immune responses. However, what regulates immune cell infiltration of tumors remains to be identified. Stat3 is constitutively activated with high frequency in diverse cancers, promoting tumor cell growth and survival. Blocking Stat3 signaling in tumors in vivo results in tumor growth inhibition that involves killing of nontransfected tumor cells and infiltration of immune effector cells, suggesting that Stat3 activity in tumor cells might affect immune cell recruitment. However, dying tumor cells can also attract immune cells. In this study, we show in isogenic murine melanomas that natural Stat3 activity is associated with tumor growth and reduction of T cell infiltration. Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages. In addition, blocking Stat3 triggers tumor cells to produce soluble factors capable of activating macrophage production of NO in vitro and in vivo. TNF-alpha and IFN-beta, which are secreted by Stat3-inhibited tumor cells, are able to activate macrophage NO production, whereas neutralizing TNF-alpha in the tumor supernatant from Stat3-blocked tumor cells abrogates nitrite production. Moreover, interrupting Stat3 signaling in tumor cells leads to macrophage-mediated, nitrite-dependent cytostatic activity against nontransduced tumor cells. These results suggest that tumor Stat3 activity affects recruitment of diverse immune effectors and it can be manipulated to activate the effector phase of innate immune responses.

Animals↗
PubMed2005

Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation.

BACKGROUND: Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene expression profile could be demonstrated in patients with acute ischemic stroke. METHODS AND RESULTS: Using oligonucleotide microarrays, we compared the gene expression profile of an index cohort of 20 patients with confirmed ischemic stroke on neuroimaging studies with that of 20 referent subjects. Validation studies used quantitative real-time polymerase chain reaction to measure the levels of 9 upregulated genes in the index cohort, and an independent cohort of 9 patients and 10 referent subjects was prospectively studied to determine the accuracy of the Prediction Analysis for Microarrays list to classify stroke. After correction for multiple comparisons with the Bonferroni technique, 190 genes were significantly different between the stroke and referent groups. Broad classes of genes included white blood cell activation and differentiation (approximately 60%), genes associated with hypoxia and vascular repair, and genes potentially associated with an altered cerebral microenvironment. Real-time polymerase chain reaction confirmed increased mRNA expression in 9 of 9 upregulated stroke-associated genes in the index cohort. A panel of 22 genes derived from the Prediction Analysis for Microarrays algorithm in the index cohort classified stroke in the validation cohort with a sensitivity of 78% and a specificity of 80%. Control for the Framingham stroke risk score revealed only a partial dependence of the stroke gene expression profile in PBMCs on vascular risk. CONCLUSIONS: This study demonstrated an altered gene expression profile in PBMCs during acute ischemic stroke. Some genes with altered expression were consistent with an adaptive response to central nervous system ischemia.

Acute Disease↗
PubMed2005

Targeting STAT3 affects melanoma on multiple fronts.

As a point of convergence for numerous oncogenic signaling pathways, STAT3 is constitutively-activated at 50 to 90% frequency in diverse human cancers, including melanoma. A critical role of STAT3 in tumor cell survival, proliferation, angiogenesis, metastasis and immune evasion has been recently demonstrated. STAT3 contributes to tumor cell growth by regulating the expression of genes that are involved in cell survival and proliferation. STAT3 promotes metastasis and angiogenesis by inducing expression of the metastatic gene, MMP-2, and the potent angiogenic gene, VEGF. STAT3 participates in the regulation of tumor immune evasion by inhibiting expression of proinflammatory mediators while promoting expression of immune-suppressing factors, which in turn activates STAT3 signaling in dendritic cells leading to immune tolerance. Thus, targeting STAT3 for therapy assaults cancer on multiple fronts. Many of the studies that defined STAT3's role in oncogenesis were carried out in melanoma cells and tumor models. In this review, we summarize the key role of STAT3 in cancer in general and melanoma in particular. With the emergence of small-molecule drugs that directly inhibit STAT3 or the oncogenic signaling pathways upstream of STAT3 in melanoma, a promising novel approach for melanoma therapy is emerging.

Cell Proliferation↗
PubMed2005

L-arginine improves dystrophic phenotype in mdx mice.

A possible treatment for Duchenne muscular dystrophies would be to compensate for dystrophin loss by increasing the expression of utrophin, another cytoskeletal protein of the muscle membrane. We previously found that L-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma. Here, we have addressed the expected benefit in the mdx mice. Magnetic resonance imaging of lower limbs revealed a 35% reduction of the necrotic zones, confirmed by histological staining of muscles. This regression of the necrosis was also supported by the drastic reduction of Evans blue incorporation, a cell impermeable dye. The creatine kinase level in the serum decreased by 57%. Utrophin level increased 2- to 3-fold in muscles. Beta-dystroglycan was relocalised with utrophin to the membrane. In the diaphragm, the most affected muscle in mdx mice, the isometric tension increased by 30%, with regression of collagen and of cytoplasmic lipid overloading. Finally, molsidomine, a therapeutic agent that is converted to a NO donor, also attenuated the dystrophic phenotype. Our results suggest that pharmacological activators of the NO pathway may constitute a realistic treatment for Duchenne and Becker muscular dystrophies.

Animals↗
PubMed2005

Chinese herbal formula, Bing De Ling, enhances antitumor effects and ameliorates weight loss induced by 5-fluorouracil in the mouse CT26 tumor model.

The use of complementary and alternative medicines-including a variety of herbal therapies-by patients undergoing cancer chemotherapy has been well documented. Despite such widespread use, however, the benefits and potential mechanisms of such herbal medicines remain largely anecdotal. In this study we examined the effects of a Chinese herbal formula, Bing De Ling, when administered as an adjunct to chemotherapeutic agent 5-fluorouracil (5-FU) in the CT26 mouse colon cancer model. 5-FU and Bing De Ling were administered to both nave and CT26 mouse colon cancer-bearing BALB/c mice. Our results indicate that although the herbal formula alone did not result in antitumor effects under experimental conditions, it significantly enhanced 5-FU-induced tumor growth inhibition. Oral administration of Bing De Ling also increased survival rates of both tumor-bearing and tumor-free mice treated with 5-FU. Furthermore, oral administration of Bing De Ling reduced weight loss in tumor-free mice receiving 5-FU when compared to tumor-free mice that received 5-FU alone. Our data further show that 5-FU upregulates serum levels of IL-6, known to contribute to weight loss, in tumor-free mice, and that this increase in IL-6 is significantly less in mice that received Bing De Ling in addition to 5-FU. These data show Bing De Ling both enhances the antitumor responses of 5-FU and ameliorates side effects.

Administration, Oral↗
PubMed2005

Role of Stat3 in regulating p53 expression and function.

Loss of p53 function by mutation is common in cancer. However, most natural p53 mutations occur at a late stage in tumor development, and many clinically detectable cancers have reduced p53 expression but no p53 mutations. It remains to be fully determined what mechanisms disable p53 during malignant initiation and in cancers without mutations that directly affect p53. We show here that oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, Stat3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by Stat3 is likely to have an important role in development of tumors, and targeting Stat3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.

Animals↗
PubMed2005

[Analysis of prognostic factors in patients with cervical squamous cell carcinoma of stage Ib and IIa].

OBJECTIVE: To analyze the prognostic factors in patients with cervical squamous cell carcinoma of stage Ib and IIa treated by surgery, and to investigate their guide roles in available post-operation adjuvant therapy. METHODS: The clinicopathologic records of 306 patients with cervical squamous cell carcinoma of stage Ib and IIa who underwent radical hysterectomy and pelvic lymphadenectomy were retrospectively analyzed, and the prognostic factors were explored by univariate and multivariate methods. Independent prognostic factors were identified by COX proportional hazards regression model. RESULTS: The overall 5-year survival rate of these 306 patients was 78.1%. In univariate survival analysis, the poor prognostic factors included poor differentiation, positive pelvic lymph nodes, deep stromal invasion, parametrial extension, tumor size > or = 4 cm, and lymph vascular space involvement (P < 0.05). While in multivariate survival analysis, the independent prognostic factors included positive pelvic lymph nodes, deep stromal invasion and parametrial extension (P < 0.05). According to the risk factors, all patients were divided into low, intermediate and high risk groups with 5-year survival rate of 90.3%, 83.9% and 43.1%, respectively. In low risk group, no risk factor or only parametrial extension was involved, pelvic recurrence rate was only 2.2%. In intermediate risk group, deep stromal invasion or together with parametrial extension was involved. Pelvic recurrence rate and extra pelvic metastasis rate were 13.5% and 1.3%, respectively. In high risk group, lymph node metastasis or together with other high risk factors was involved, pelvic recurrence rate and extra pelvic metastasis rate were 25.9% and 48.3%, respectively, and 10.3% had both pelvic recurrence and extra pelvic metastasis. CONCLUSIONS: Lymph node metastasis, deep stromal invasion and parametrial extension were independent prognostic factors of stage Ib and IIa cervical squamous cell carcinoma patients undergoing radical hysterectomy and lymphadenectomy. The establishment of prognosis-predicting system based on high risk factors may be helpful to predict the risk of recurrence and metastasis, and guide adjuvant therapy after surgery.

Adult↗