A ß-1,3/1,6-glucan enhances anti-tumor effects of PD1 antibody by reprogramming tumor microenvironment.

Checkpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a ß-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhanced the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decrease in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.

Low molecular-weight polyguluronate phosphate: An immunostimulant by activating splenocyte/macrophage invitro and improving immune response invivo.

The substituents and backbones are two main factors affecting immune activities of polysaccharides. In the present study, we firstly evaluated the immunostimulating effects of phosphorylated, sulfated, H-phosphonated and nitrated derivatives of low-molecular-weight polymannuronate (LPM) and polyguluronate (LPG) on splenocytes and peritoneal macrophages in vitro. The results showed that the phosphate group was the best substituent to enhance the immune activities, and LPG phosphate (LPGP) had much better activity than LPM phosphate (LPMP). Further studies showed that LPGP not only promoted the proliferation of mouse splenocytes in the presence of either LPS or Con A, but also acted as an excellent peritoneal macrophage activator to enhance the cell phagocytosis, energy metabolism, cytokines release and activities of intracellular enzymes. The studies in RAW264.7 cells revealed that LPGP activated the TBK1-IκBα-NF-κB and the TBK1-IRF3 pathway. Moreover, LPGP rescued the immune response in the Cyclophosphamide-treated mice in vivo. In conclusion, LPGP is a potential alginate-based biological response modifier (BRM).

A Novel PTP1B Inhibitor-Phosphate of Polymannuronic Acid Ameliorates Insulin Resistance by Regulating IRS-1/Akt Signaling.

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). Low-molecular-weight polymannuronic acid phosphate (LPMP) was found to be a selective PTP1B inhibitor with an IC50 of 1.02 ± 0.17 µM. Cellular glucose consumption was significantly elevated in insulin-resistant HepG2 cells after LPMP treatment. LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Western blot and polymerase chain reaction (PCR) analysis demonstrated that LPMP could enhance insulin sensitivity through the PTP1B/IRS/Akt transduction pathway. Furthermore, animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. Taken together, LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed.

Long noncoding RNA LINC00460 targets miR-539/MMP-9 to promote meningioma progression and metastasis.

Emerging evidence reveal that long noncoding RNAs (lncRNAs) participates in the epigenetic regulation of pathophysiological process. However, the deepgoing role of lncRNAs on meningioma is still unclear. In present study, we investigate the roles of lncRNA LINC00460 in meningeoma tissue and uncover its molecular mechanism. Results revealed that LINC00460 expression level was significantly up-regulated in meningeoma tissues and malignant meningeoma cell lines (IOMM-Lee, CH157-MN). Mechanically, loss-of-function assays showed that LINC00460 knockdown significantly suppressed the proliferation ability, increased the apoptosis and decreased the proteins (MMP-2, MMP-9, ZEB1) expression. Bioinformatics tools predicted that miR-539 both targeted with the 3'-UTR of LINC00460 and MMP-9 mRNA, which was confirmed by luciferase reporter assay and western blot analysis. In summary, our study reveals that LINC00460 promotes MMP-9 expression through targeting miR-539, acting as an oncogenic RNA in the meningeoma malignancy and accelerating the proliferation and metastasis of meningeoma.

Propylene glycol guluronate sulfate (PGGS) reduces lipid accumulation via AMP-activated kinase activation in palmitate-induced HepG2 cells.

Cardiovascular disease (CVD) is the No. 1 cause of death worldwide. Hyperlipidemia is one of the major risk factors for CVD. Maintaining lipid homeostasis is an effective way to prevent CVD. We prepared propylene glycol guluronate sulfate (PGGS), a sulfated polysaccharide, and investigated its effect on lipid metabolism in HepG2 cells. We found that total cholesterol (TC) and triglycerides (TG) were significantly decreased in the cells after PGGS treatment. We have also shown that the AMPK signaling is activated after PGGS treatment as evidenced by changes in the expression of many AMPK downstream targets including SREBP-1c, SIRT-1, CPT1, PPARα, and FAS. Our results have demonstrated that PGGS is a potentially novel lipid-lowering agent for CVD prevention.