A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer's dementia.

Background: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China.

A phase II randomized trial of sodium oligomannate in Alzheimer's dementia.

Background: Sodium oligomannate (GV-971), a marine-derived oligosaccharide, is a novel agent that may improve cognition in AD patients.

Methods: The 24-week multicenter, randomized, double-blind, placebo parallel controlled clinical trial was conducted in AD in China between 24 October 2011 and 10 July 2013. The study included a 4-week screening/washout period, followed by a 24-week treatment period.

JG6, a novel marine-derived oligosaccharide, suppresses breast cancer metastasis via binding to cofilin.

Cofilin, an actin-binding protein which disassembles actin filaments, plays an important role in invasion and metastasis. Here, we discover that JG6, an oligomannurarate sulfate, binds to cofilin, suppresses the migration of human breast cancer cells and cancer metastasis in breast cancer xenograft model. Mechanistically, JG6 occupies actin-binding sites of cofilin, thereby disrupting cofilin modulated actin turnover.

Oligomannurarate sulfate inhibits CXCL12/SDF-1-mediated proliferation and invasion of human tumor cells in vitro.

Aim: JG6 is a novel marine-derived oligosaccharide that has shown to inhibit angiogenesis and tumor metastasis. In this study, we sought to identify the potential target responsible for the anti-cancer activity of JG6.

Methods: Human liver cancer cell line Bel-7402 and human cervical cancer cell line HeLa were examined.

Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates Akt signaling.

O-linked N-acetylglucosamine glycosylations (O-GlcNAc) and O-linked phosphorylations (O-phosphate), as two important types of post-translational modifications, often occur on the same protein and bear a reciprocal relationship. In addition to the well documented phosphorylations that control Akt activity, Akt also undergoes O-GlcNAcylation, but the interplay between these two modifications and the biological significance remain unclear, largely due to the technique challenges. Here, we applied a two-step analytic approach composed of the O-GlcNAc immunoenrichment and subsequent O-phosphate immunodetection.

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors.

Aim: The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors.

Methods: The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system.

Sulfated polymannuroguluronate inhibits Tat-induced SLK cell adhesion via a novel binding site, a KKR spatial triad.

Aim: Sulfated polymannuroguluronate (SPMG), a candidate anti-AIDS drug, inhibited HIV replication and interfered with HIV entry into host T lymphocytes. SPMG has high binding affinity for the transactivating factor of the HIV-1 virus (Tat) via its basic domain. However, deletion or substitution of the basic domain affected, but did not completely eliminated Tat-SPMG interactions.

Oligomannurarate sulfate sensitizes cancer cells to doxorubicin by inhibiting atypical activation of NF-κB via targeting of Mre11.

Aberrant regulation of nuclear factor kappa B (NF-κB) transcription factor is involved in cancer development, progression and resistance to chemotherapy. JG3, a marine-derived oligomannurarate sulfate, was reported as a heparanase and NF-κB inhibitor to significantly block tumor growth and metastasis in various animal models. However, the detailed functional mechanism remains unclear.

PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo.

The central role of Src in tumor progression and metastasis has validated it as an attractive therapeutic target for the treatment of human breast cancer. The aim of this study was to identify potential Src kinase inhibitor, explore its activity, and mechanism of action in human breast cancer. A strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and high-throughput screening was adopted and a novel 6-hydrazinopurine-based inhibitor of c-Src kinase PH006 was obtained.

Oligomannurarate sulfate, a novel antimitotic agent, exerts anti-cancer activity by binding to tubulin on novel site.

Tubulin-binding agents have received considerable interest as potential anti-cancer drugs. These compounds interfere with tubulin dynamics and microtubule organization and thereby induce cell growth arrest at G(2)/M phase, and eventually lead to apoptotic cell death. Herein, we report that sulfated oligosaccharide JG3 was effective at inhibiting viability of cancer cells, and suppressing tumor growth in vivo.

Oligomannurarate sulfate blocks tumor growth by inhibiting NF-kappaB activation.

Aim: JG3, a novel marine-derived oligosaccharide, significantly inhibits angiogenesis and tumor metastasis by blocking heparanase activity. It also arrests tumor growth, an effect that is not fully explained by its anti-heparanase activity. Here we sought to identify the mechanisms underlying JG3-mediated inhibition of tumor growth.

MS80, a novel sulfated polysaccharide, inhibits CD40-NF-kappaB pathway via targeting RIP2.

In the previous studies, MS80 was found to be able to inhibit the pulmonary fibrosis. However, the target of MS80 remains unclear. To determine the target and the antifibrosis mechanisms of MS80, affinity column, MALDITOF-MS/MS, co-immunoprecipitation, and co-localization were used.

Marine-derived oligosaccharide sulfate (JG3) suppresses heparanase-driven cell adhesion events in heparanase over-expressing CHO-K1 cells.

Aim: To elucidate the detailed mechanisms underlying the appreciable effects of JG3, a novel marine-derived oligosaccharide, on cell migration using a Chinese hamster ovary (CHO) cell line stably over-expressing heparanase.

Methods: A retrovirus infection system was used to establish a CHO-K1 cell line stably transfected with heparanase. Immunocytochemistry was used to assess cell morphology.

The marine-derived oligosaccharide sulfate (MdOS), a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo.

Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA).

A triad of lys12, lys41, arg78 spatial domain, a novel identified heparin binding site on tat protein, facilitates tat-driven cell adhesion.

Tat protein, released by HIV-infected cells, has a battery of important biological effects leading to distinct AIDS-associated pathologies. Cell surface heparan sulfate protoglycans (HSPGs) have been accepted as endogenous Tat receptors, and the Tat basic domain has been identified as the heparin binding site. However, findings that deletion or substitution of the basic domain inhibits but does not completely eliminate Tat-heparin interactions suggest that the basic domain is not the sole Tat heparin binding site.

N-acetylglucosaminyltransferase V mediates cell migration and invasion of mouse mammary tumor cells 4TO7 via RhoA and Rac1 signaling pathway.

In tumor cells, alterations in cellular glycosylation may play a key role in their metastatic behavior. Using small interfering RNA against GnT-V, we found that the expression of GnT-V and beta1,6GlcNAc branching were significantly reduced which was particularly accompanied by the arrest in both cell migration and invasion as compared to the negative control. Moreover, the suppressed GnT-V expression by siRNA technique inactivated the signaling molecules including Rac1, cofilin, Erk and Akt, and activated RhoA levels in cells lacking GnT-V, but revealed no impact on Cdc42 activity.

Sulfated polymannuroguluronate, a novel anti-AIDS drug candidate, inhibits HIV-1 Tat-induced angiogenesis in Kaposi's sarcoma cells.

Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released from KS and host cells and HIV viral products-the protein Tat are reported to be involved in angiogenesis. Mounting evidence further suggests that multiple angiogenic activities of Tat contribute to AIDS-associated Kaposi's sarcoma (AIDS-KS).

Philinopside E, a new sulfated saponin from sea cucumber, blocks the interaction between kinase insert domain-containing receptor (KDR) and alphavbeta3 integrin via binding to the extracellular domain of KDR.

Vascular endothelial growth factor (VEGF) signaling pathway is essential for tumor angiogenesis and has long been recognized as a promising target for cancer therapy. Current view holds that physical interaction between alpha(v)beta(3) integrin and kinase insert domain-containing receptor (KDR) is important in regulating angiogenesis and tumor development. We have reported previously that a new marine-derived compound, philinopside E (PE), exhibited the antiangiogenic activity via inhibition on KDR phosphorylation and downstream signaling.

A new marine-derived sulfated polysaccharide from brown alga suppresses tumor metastasis both in vitro and in vivo.

Herein, we report that marine-derived sulfated polysaccharide (MSP), a new kind of polysaccharide extracted from brown alga, exhibits the anti-migration effect in vitro and potently suppress metastasis of Lewis lung carcinoma in vivo. Adhesion assays demonstrated that MSP inhibits the heterogenous adhesion on fibronectin. Further studies revealed that MSP decreased FN-induced MDA-MB-435 migration, accompanied by its potent regulatory effect on actin filament reassembling.

Oligomannurarate sulfate, a novel heparanase inhibitor simultaneously targeting basic fibroblast growth factor, combats tumor angiogenesis and metastasis.

Inhibitors of tumor angiogenesis and metastasis are increasingly emerging as promising agents for cancer therapy. Recently, heparanase inhibitors have offered a new avenue for such work because heparanase is thought to be critically involved in the metastatic and angiogenic potentials of tumor cells. Here, we report that oligomannurarate sulfate (JG3), a novel marine-derived oligosaccharide, acts as a heparanase inhibitor.

[Effects of acidic oligose on differentially expressed genes in the mice model of Alzheimer's disease by microarray].

Aim: To investigate the molecular mechanism of protective effect of acidic oligose 971 on Alzheimer's disease mouse model by using microarray.

Methods: Balb/c mice were randomly divided into control group, beta-AP(25-35) i.c.

Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin.

Tubulin-binding agents have received considerable interest as potential tumor-selective angiogenesis-targeting drugs. Herein, we report that pseudolarix acid B (PAB), isolated from the traditional Chinese medicinal plant Pseudolarix kaempferi Gordon, is a tubulin-binding agent. We further demonstrate that PAB significantly and dose-dependently inhibits proliferation, migration, and tube formation by human microvessel enthothelial cells.

Determination of the accessibility of acidic oligosaccharide sugar chain to blood-brain barrier using surface plasmon resonance.

There exist limitations in the detection of exogenous oligosaccharides due to their polydisperse and diversiform nature, and particularly the interference of endogenous glycosaminoglycans (GAGs). Herein, a surface plasmon resonance (SPR) assay for detecting acidic oligosaccharide sugar chain (AOSC), an anti-Alzheimer's drug candidate, in cerebrospinal fluid (CSF) was developed based on a carbohydrate antigen-antibody interaction. Rabbits were treated with AOSC intravenously and orally at 40 or 200 mg x kg(-1), respectively.

Sulfated polymannuroguluronate, a novel anti-AIDS drug candidate, inhibits T cell apoptosis by combating oxidative damage of mitochondria.

Sulfated polymannuroguluronate (SPMG) has entered the phase II clinical trial as the first anti-AIDS drug candidate in China. Herein, we report that SPMG was effective at protecting T lymphocytes against apoptosis. Further studies indicated that SPMG significantly elevated mitochondrial membrane potential (MMP) of T cells; inhibited mitochondrial release of cytochrome c (cyto c) in T cells; enhanced the activities of mitochondrial enzyme complex I, III, and V; and subsequently increased ATP level and ATP/ADP ratio.

Potentiation of T cell function by a marine algae-derived sulfated polymannuroguluronate: in vitro analysis of novel mechanisms.

Marine algae-derived sulfated polymannuroguluronate (SPMG), a candidate drug for AIDS treatment, was intraperitoneally injected into normal mice for 6 weeks, and the in vivo and in vitro mechanisms of SPMG for immunomodulation were investigated in isolated lymphocytes by MTT assay, flow cytometry, and surface plasmon resonance assay. SPMG treatment at 5 and 10 mg/kg enhanced concanavalin A (ConA)-induced T cell proliferation, cellular levels of CD69, interleukin-2 (IL-2), and interferon-gamma (IFN-gamma), as well as CD4/CD8 ratio, while decreasing tumor necrosis factor-alpha (TNF-alpha) level in T cells of peripheral blood mononuclear cells. In addition, 1 molecule of SPMG bound to 2/3 molecules of IL-2 with a K(D) of 9.