GFPBW1, a ß-glucan from Grifola frondosa as vaccine adjuvant: APCs activation and maturation.

Adjuvants for vaccines with characteristics of improving adaptive immunity particularly via leverage of antigen presenting cells (APCs) are currently lacking. In a previous work we obtained a new soluble 300 kDa homogeneous ß-glucan named GFPBW1 from the fruit bodies of Granola frondosa. GFPBW1 could activate macrophages by targeting dendritic cell associated C-type lectin 1 (Dectin-1)/Syk/NF-κB signaling to achieve antitumour effects. In this study the adjuvant effects of GFPBW1 were explored with OVA-antigen and B16-OVA tumor model. We showed that GFPBW1 (5, 50, 500 µg/mL) dose-dependently promoted activation and maturation of APCs in vitro by increasing CD80, CD86 and MHC II expression. We immunized female mice with OVA in combination with GFPBW1 (50 or 300 µg) twice with an interval of two weeks. GFPBW1 markedly and dose-dependently increased OVA-specific antibody titers of different subtypes including IgG1, IgG2a, IgG2b and IgG3, suggesting that it could serve as an adjuvant for both Th1 and Th2 type immune responses. Furthermore, GFPBW1 in combination with aluminum significantly increased the titers of OVA-specific IgG2a and IgG2b, but not those of IgG1, suggesting that GFPBW1 could be used as a co-adjuvant of aluminum to compensate for Th1 deficiency. For mice immunized with OVA plus GFPBW1, no obvious pathological injury was observed in either major organs or injection sites, and no abnormalities were noted for any of the hematological parameters. When GFPBW1 served as an adjuvant in the B16-OVA cancer vaccine models, it could accomplish entire tumor suppression with preventive vaccines, and enhance antitumour efficacy with therapeutic vaccines. Differentially expressed genes were found to be enriched in antigen processing process, specifically increased tumor infiltration of DCs, B1 cells and plasma cells in the OVA plus GFPBW1 group, in accordance with its activation and maturation function of APCs. Collectively, this study systematically describes the properties of GFPBW1 as a novel potent and safe adjuvant and highlights its great potential in vaccine development.

Src is a target molecule of mannose against pancreatic cancer cells growth in vitro & in vivo.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. Mannose, a common monosaccharide taken up by cells through the same transporters as glucose, has been shown to induce growth retardation and enhance cell death in response to chemotherapy in several cancers, including PDAC. However, the molecular targets and mechanisms underlying mannose's action against PDAC are not well understood. In this study, we used an integrative approach of network pharmacology, bioinformatics analysis, and experimental verification to investigate the pharmacological targets and mechanisms of mannose against PDAC. Our results showed that the protein Src is a key target of mannose in PDAC. Additionally, computational analysis revealed that mannose is a highly soluble compound that meets Lipinski's rule of five and that the expression of its target molecules is correlated with survival rates and prognosis in PDAC patients. Finally, we validated our findings through in vitro and in vivo experiments. In conclusion, our study provides evidence that mannose plays a critical role in inhibiting PDAC growth by targeting Src, suggesting that it may be a promising therapeutic candidate for PDAC.

A homogalacturonan from Lonicera japonica Thunb. disrupts angiogenesis via epidermal growth factor receptor and Delta-like 4 associated signaling.

A homogeneous polysaccharide named as LJW2F2 was extracted and purified from the flowers of Lonicera japonica Thunb. Structural characteristic indicated that LJW2F2 was a homogalacturonan composed of α-1,4-D-galacturonic acid with a molecular weight of 7.2 kDa. Previous investigation suggested that homogalacturonan might impede angiogenesis, however the mechanism is still vague. Here we reported that LJW2F2 significantly disrupted capillary-like tube formation of human microvascular endothelia cells (HMEC-1) on matrigel as well as the cells migration. Mechanism study revealed that LJW2F2 might inactivate phosphorylation of epidermal growth factor receptor (EGFR), subsequently suppress Raf, mitogen-activated protein kinase (MEK) and extracellular-related kinase (ERK) phosphorylation. Moreover, LJW2F2 markedly decreased the expression of Notch1 and Delta-like ligand 4 (Dll4). Therefore, our results suggested that LJW2F2 might be a potential angiogenesis inhibitor via disturbing multiple signaling pathways.

GLCE regulates PC12 cell neuritogenesis induced by nerve growth factor through activating SMAD/ID3 signalling.

Neurodevelopment is orchestrated by a series of growth factor-HS (heparan sulfate) interactions which are involved in neuritogenesis. GLCE (glucuronic acid epimerase) is a critical enzyme involved in HS synthesis, which converts GlcA (D-glucuronic acid) into IdoA (L-iduronic acid). However, the function of GLCE in neuritogenesis is largely unknown. In the present study we showed that GLCE depletion caused arrested PC12 cell growth and promoted the cell neuritogenesis and differentiation induced by NGF (nerve growth factor). PC12 cell growth was boosted by overexpression of GLCE, and neuritogenesis was impaired when GLCE depletion was rescued. Interestingly, overexpression of wild-type GLCE with Y168A and Y222A mutations led to enhanced PC12 cell growth and attenuated the neuritogenesis triggered by GLCE silencing. We showed further that GLCE depletion blocked SMAD1/5/8 phosphorylation; however, this signalling could be restored by GLCE or the mutation of its active enzymatic site. In addition, the downstream effector of SMAD1/5/8, ID3 (inhibitor of DNA binding/differentiation 3) was induced by GLCE. ID3 silencing inhibited PC12 cell growth and induced cell neuritogenesis and differentiation. In addition, ectopic expression of ID3 partially rescued the phenotype caused by GLCE silencing. The results of the present study suggest that GLCE plays a key role in PC12 cell growth and neuritogenesis through SMAD/ID3 signalling.

[Technical improvement of transumbilical laparoendoscopic single-site nephrectomy].

OBJECTIVE: To summarize the technical modification and experiences of transumbilical laparoendoscopic single-site nephrectomy (LESS-N) by homemade device. METHODS: The clinical data of LESS nephrectomy performed from June 2010 to April 2013 in Peking University Third Hospital were analyzed retrospectively. All the cases were divided into two groups according to the technique method and operative date. Group 1 included 10 cases that underwent LESS radical nephrectomy and 2 that received LESS simple nephrectomy from June 2010 to April 2011. Group 2 included 7 cases that underwent LESS radical nephrectomy and 3 that received LESS simple nephrectomy from May 2011 to April 2013. The data on the general presentation, tumor size, tumor location, operative time, blood loss, complications, Visual Analog Pain Scale (VAPS), postoperative hospital stay, pathological results were collected to compare between the two groups. The modified technique included homemade single-ring glove technique, fast access to the pedicle, pulling-up technique to retract the kidney or liver. The kidney was dissociated after the renal vessel was cut off and extracted through the umbilical incision. RESULTS: All the procedures were finished without conversion to open radical nephrectomy. Compared with group 1, operative time showed significant difference in group 2 [Group 1:(220.6±51.0) min; Group 2: (178.9±34.0) min; P=0.04],and no difference was noted in other factors (P>0.05). There was no secondary bleeding, wound infection, intestinal obstruction, incision hernia and other severe postoperative complications. follow-up of 2 to 36 months showed no local recurrence. CONCLUSION: Transumbilical LESS-N is feasible, effective and safe. It gives a more mini-invasive and cosmetic option for young or female patients. Learning curve and operative time can be reduced by modified techniques, such as single-ring glove technique and pulling-up technique.

Assessment tool based on fatty acid metabolic signatures for predicting the prognosis and treatment response in bladder cancer.

Background: Fatty acid metabolism (FAM) is closely connected with tumorigenesis as well as disease progression and affects the efficacy of platinum-based drugs. Exploring biomarkers related to FAM in bladder cancer (BLCA) is essential to improve cancer prognosis. Methods: High-throughput sequencing data from The Cancer Genome Atlas (TCGA) were bioinformatically resolved to identify molecular subtypes of fatty acid metabolic profiles in BLCA using coherent clustering analysis. Based on fatty acid metabolic profile, a prognostic model was created using COX and LASSO COX models. CIBERSORT, Estimation of STromal and Immune cells in MAlignant Tumours using Expression (ESTIMATE), MCP-Count, and single sample gene set enrichment analysis (ssGSEA) were used to assess the differences in tumor microenvironment (TME) among different molecular subtypes, prognostic groups. Kaplan-Meier (K-M) survival curve was plotted to assess patients' prognosis. Receiver operating characteristic curve (ROC) and the clinical prognostic value of prognostic models was evaluated by the Nomogram. Results: Three molecular subtypes (FAMC1, FAMC2, FAMC3) of fatty acid metabolic patterns were determined. FAMC1 showed significant prognostic advantage with immunoreactivity. Five key prognostic FAMGs were identified and RiskScore was developed. We found that patients with low RiskScore showed significantly better immune microenvironment status, survival and response to immunotherapy. Similarly, both Nomogram and RiskScore demonstrated excellent prognostic value. Conclusions: In conclusion, our study showed that the RiskScore was closely related to the clinical traits of BLCA patients. The RiskScore may provide essential clinical guidance for predicting prognosis and treatment response in bladder cancer.

A novel peptidoglycan isolated from Semiaquilegia adoxoides inhibits Aß42 production via activating autophagy.

The accumulation of amyloid ß (Aß) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aß clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycan on Aß42 secretion and the underlying mechanism. Briefly, we extracted a novel peptidoglycan named SA02C using hot water extraction and alcohol precipitation with the Mw of 13.72 kDa. SA02C contains 73.33% carbohydrate and 27.83% protein. The structure characterization revealed that its glycan part might mainly composed of galacturonic acid with minor rhamnose in backbone, and branched with glucose, galactose, arabinose, xylose and galacturonic acid. The protein or peptide moiety in SA02C was bonded to the polysaccharide via threonine. Bioactivities test showed that SA02C could reduce Aß42 production in a dose dependent manner with no obvious cytotoxicity. Mechanism study demonstrated that SA02C could modulate APP processing by upregulating the expression of ADAM10, sAPPα and downregulating BACE1, sAPPß. Furthermore, SA02C also could stimulate autophagy by promoting the expression of the markers of autophagy such as LC3B and ATG5, resulting in the promotion of Aß42 phagocytosis.

A novel branched galacturonan from Gardenia jasminoides alleviates liver fibrosis linked to TLR4/NF-κB signaling.

Gardenia jasminoides (GJ) is a classic edible medicine in China of which the fruit has been proved to alleviate liver damage. We hypothesized whether polysaccharide in the fruit could have comparable bioactivity. To address this, a novel polysaccharide GJE0.2-2, is purified from the fruit of Gardenia jasminoides. Indeed, GJE0.2-2 may attenuate CCl4-induced liver fibrosis in mice and impede the expression of critical fibrogenesis associated molecules such as α-SMA, FN1, and Collagen I induced by TGF-ß in human hepatic stellate LX-2 cells. Mechanism studies suggest that this bioactivity may be implicated in TLR4/NF-κB signaling pathway via directly binding to TLR4. The structure characterization shows that the backbone of this polysaccharide is mainly composed of galacturonic acid with minor rhamnose, branched with galactose and arabinose, galacturonic acid, and esterified hexenuronic acid (HexpA). These findings provide evidence for a novel pectin-linked polysaccharide-based new drug candidate development for liver fibrosis therapy.

Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04563936.

A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-κB signaling and improves survival in mouse models of sepsis.

AIM: To characterize a small molecule compound HK-156 as a novel inhibitor of the nuclear factor κB (NF-κB) signaling pathway. METHODS: THP-1 monocytes and HEK293/hTLR4A-MD2-CD14 cells were tested. HK-156 and compound 809, an HK-156 analogue, were synthesized. A luciferase assay was used to evaluate the transcriptional activity of NF-κB. The levels of cytokines were measured with cytokine arrays, ELISA and quantitative PCR. An electrophoretic mobility shift assay (EMSA), immunofluorescence, Western blot and mass spectrometry were used to investigate the molecular mechanisms underlying the actions of the agent. BALB/c mice challenged with lipopolysaccharide (LPS, 15 mg/kg, ip) were used as a mouse experimental endotoxemia model. RESULTS: In HEK293hTLR4/NF-κB-luc cells treated with LPS (1000 ng/mL), HK-156 inhibited the transcriptional activity of NF-κB in a concentration-dependent manner (IC50=6.54 ± 0.37 µmol/L). Pretreatment of THP-1 monocytes with HK-156 (5, 10 and 20 µmol/L) significantly inhibited LPS-induced release and production of TNF-α and IL-1ß, attenuated LPS-induced translocation of NF-κB into the nucleus and its binding to DNA, and suppressed LPS-induced phosphorylation and degradation of IκBα, and phosphorylation of IKKß and TGFß-activated kinase (TAK1). Meanwhile, HK-156 (5, 10 and 20 µmol/L) slightly suppressed LPS-induced activation of p38. The effect of HK-156 on LPS-induced activation of NF-κB signaling was dependent on thiol groups of cysteines in upstream proteins. In mouse models of sepsis, pre-injection of HK-156 (50 mg/kg, iv) significantly inhibited TNFα production and reduced the mortality caused by the lethal dose of LPS. CONCLUSION: HK-156 inhibits LPS-induced activation of NF-κB signaling by suppressing the phosphorylation of TAK1 in vitro, and exerts beneficial effects in a mouse sepsis model. HK-156 may therefore be a useful therapeutic agent for treating sepsis.

A Novel Pectin-Like Glycopeptide Isolated from the Fruit of Fructus Mori Impedes Aggregation and Production of Aß42.

The fruit of Fructus Mori is food and medicine, which has been demonstrated to have a significant neuroprotective effect. However, the effective constituent remains unknown. We speculate that the glycopeptide in the extract of the fruit has similar activity. To address this hypothesis, we isolated a novel pectin-like glycopeptide (FMP-6-S4) with a molecular weight of 11.23 kDa from the fruit. It contains about 20% of peptide comprising 17 amino acids and 80% glycan consisting of L-rhamnose (L-Rha), D-galactose (D-Gal), D-galacturonic acid (D-GalA), L-arabinose (L-Ara) and d-glucose (D-Glc) in molar ratios of 7.25:4.62:77.66:5.62:4.85. The backbone of the glycan part consisted of 1,4-linked α-D-GalpA and 1, 2-linked α-L-Rhap, while the branches were composed of hexenuronic acid (HexA) substituted at the C-3 position of partial galacturonic acid, and traces of galactose, glucose, and arabinose were substituted at the C-4 position of rhamnose. The in vitro experiments revealed that FMP-6-S4 might inhibit Aß42 (ß-amyloid peptides 42) aggregation and decrease Aß42 production by modulating APP (amyloid precursor protein) processing.

Cordycepin inhibits pancreatic cancer cell growth in vitro and in vivo via targeting FGFR2 and blocking ERK signaling.

Cordycepin (3'-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo. Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2 (checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2 (KD = 7.77 × 10-9) very potently to inhibit pancreatic cancer cells growth by blocking Ras/ErK pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.

Effects of electroacupuncture at Shangjuxu (ST 37) on interleukin-1beta and interleukin-4 in the ulcerative colitis model rats.

OBJECTIVE: To probe into the mechanisms of electroacupuncture (EA) at Shangjuxu (ST 37) for treatment of the ulcerative colitis (UC). METHODS: Forty male Wistar rats were randomly divided into 4 groups: a normal group, a model group, a Shangjuxu group and a non-acupoint group, 10 rats in each group. The UC rat model was made with enema of trinitro-benzenesulfonic acid (TNBSA), and the changes of interleukin-1beta (IL-1beta) and interleukin-4 (IL-4) contents after EA at Shangjuxu (ST 37) were observed. RESULTS: EA at Shangjuxu (ST 37) could significantly decrease the IL-1beta content and increase the IL-4 content in the colic tissues of the UC rats with significant differences as compared with the model group and the non-acupoint group (P<0.05 or P<0.01). CONCLUSION: The mechanisms of EA at Shangjuxu (ST 37) for treatment of the UC rats is possibly related with the decrease of IL-1beta, a inflammation-promoting cytokine, and the increase of IL-4, a anti-inflammatory cytokine.

HH1-1, a novel Galectin-3 inhibitor, exerts anti-pancreatic cancer activity by blocking Galectin-3/EGFR/AKT/FOXO3 signaling pathway.

Pancreatic ductal adenocarcinoma is a highly malignant gastrointestinal tumor. Molecular targeting therapy for pancreatic cancer is still limited. High expressed Galectin-3 in pancreatic cancer is positively correlated with disease progression, indicating that Galectin-3 can be employed as a predictor of poor prognosis. From safflower, we isolated and purified a homogeneous polysaccharide, HH1-1, which could bind to and inhibit Galectin-3. HH1-1 could block the interaction between Galectin-3 and EGFR. Following HH1-1 treatment, the binding ability between EGFR and Galectin-3 was reduced by 245.28 folds. HH1-1 could suppress pancreatic cancer cell proliferation, arrest the cell cycle in S phase, induce cell apoptosis, inhibit angiogenesis and impede tumor cell migration and invasion. Moreover, HH1-1 affected the Galectin-3/EGFR/AKT/FOXO3 signaling pathway and possessed anti-pancreatic cancer activity in vitro and in vivo, especially in patient-derived xenografts. Further study suggested that HH1-1 had almost no toxicity both in vitro and in vivo. This adds new evidence to suggest that HH1-1 could be a promising therapeutic agent and support the pursuit of the Galectin-3 as a target in pancreatic cancer treatment.

A pectin from fruits of Lycium barbarum L. decreases ß-amyloid peptide production through modulating APP processing.

Here, a pectin LBP1C-2 with the molecular weight of 99.8 kDa was purified from fruits of Lycium barbarum L. Its structure was elucidated as a backbone of alternate 1, 2-linked α-Rhap and 1, 4-linked α-GalpA, with branches of terminal (T) -, 1, 3-, 1, 6- and 1, 3, 6-linked ß-Galp, T-, 1, 5- and 1, 3, 5-linked α-Araf and T-linked ß-Rhap substituted at C-4 of 1, 2, 4-linked α-Rhap. The cell-based experiments indicated that LBP1C-2 suppressed Aß42 production in a dose-dependent manner with no cytotoxicity. Further study showed that expression of ß-site APP cleaving enzyme 1 (BACE1) was attenuated by LBP1C-2, while expression of ADAM10 was up-regulated by LBP1C-2. Moreover, LBP1C-2 promoted the expression of insulin-degradation enzyme (IDE). These results suggested that LBP1C-2 might be a leading compound for anti-Alzheimer's disease therapy by decreasing Aß42 production through mediating BACE1 and ADAM10 as well as IDE expression.

An arabinogalactan from fruits of Lycium barbarum L. inhibits production and aggregation of Aß42.

The ß amyloid (Aß) induced neurodegeneration is believed to be one of pathological mechanisms of Alzheimer's disease (AD). The inhibition of Aß production or aggregation is one of the promising therapeutic strategies for anti-AD drug discovery. Here, a homogeneous neutral polysaccharide designated LBP1A1-1 with an average molecular weight of 45.0 kDa was purified from fruits of Lycium barbarum L. Its structure was characterized to possess a backbone of 1, 3-linked ß-Galp, 1, 6-linked ß-Galp, 1, 4-linked α-Glcp with branches substituted at C-3 position of 1, 6-linked ß-Galp or C-6 position of 1, 3-linked ß-Galp. The branches contained terminal (T)-linked ß-Galp, T-linked α-Araf, T-linked ß-Araf, 1, 5-linked α-Araf and T-linked ß-Rhap. The in vitro experiments revealed that LBP1A1-1 could inhibit Aß42 production and impede Aß42 aggregation in a dose-dependent-manner without cytotoxicity. These results suggested that LBP1A1-1 might have the multiple potential for the treatment of AD.

Chemoenzymatically synthesized GM3 analogues as potential therapeutic agents to recover nervous functionality after injury by inducing neurite outgrowth.

Ganglioside GM3 is implicated in a variety of physiological and pathological processes. Due to GM3 exposes on the outer surface of cell membranes, it is strongly associated with cell adhesion, motility and differentiation. Neurite outgrowth is a key process in the development of functional neuronal circuits and regeneration of the nervous system after injury. In the present study, we used enzymatic hydrolysis and chemical synthesis to obtain novel galactose containing GM3 analogues. By enzymatic hydrolysis to prepare GM3 building block, we can avoid multiple chemical procedures. Next, we employed the PC12 cells as a model to evaluate the effects of GM3 analogues on neurite outgrowth with or without NGF induction. The biological tests showed that GM3 analogues could induce neurite outgrowth, which provides the valuable sights for potential nervous system treatment after injury.

microRNA-149 targets caspase-2 in glioma progression.

Malignant gliomas are the most common form of intrinsic primary brain tumors worldwide. Alterations in microRNAs play a role in highly invasive malignant glioma, but detail mechanism still unknown. In this study, the role and mechanism of microRNA-149 (miR-149) in glioma are investigated. We show that miR-149 is expressed at substantially higher levels in glioma than in normal tissues. Stable overexpression of miR-149 augments potent prosurvival activity, as evidenced by promotion of cell viability, inhibition of apoptosis, and induced xenografted tumor growth in vivo. We further show that Caspase-2 is identified as a functional target of miR-149 and expression of caspase-2 is inversely associated with miR-149 in vitro. In addition, miR-149 promotes tumor survival in the U87-MG and A172 cell lines and it targets caspase-2 via inactivation of the p53 and p21 pathways. There results support a special role for miR-149 by targeting Caspase-2 to impact on p53 signaling pathway. We speculate that miR-149 has distinct biological functions in p53 wild type cells and p53 mutation cells, and the mechanisms involved remain to be explored in future. Our study suggests that targeting miR-149 may be a novel therapy strategy for treating p53 wild type glioma tumors in humans.

Sulfated fucoidan FP08S2 inhibits lung cancer cell growth in vivo by disrupting angiogenesis via targeting VEGFR2/VEGF and blocking VEGFR2/Erk/VEGF signaling.

Fucoidan may inhibit angiogenesis. However, its functional target molecule and the underlying mechanism are still vague. In the present study, we showed that sulfated fucoidan FP08S2 from Sargassum fusiforme inhibited tube formation as well as migration and invasion of human microvascular endothelial cells (HMEC-1). In addition, FP08S2 was confirmed to disrupt VEGF-induced angiogenesis both in vitro and in vivo. Further study indicated that FP08S2 could bind to both VEGF and VEGFR2 to interfere with VEGF-VEGFR2 interaction. Moreover, VEGFR2/Erk/VEGF signaling pathway was blocked by FP08S2 in HMEC-1 cells. Importantly, FP08S2 impeded the growth and microvessel formation of A549 cancer cell xenograft in nude mice. These results suggested that FP08S2 presented remarkable anti-angiogenic activity via blocking VEGF signaling and could be a potential novel leading compound to inhibit lung cancer cell growth.