Rhamnan sulfate reduces atherosclerotic plaque formation and vascular inflammation.

OBJECTIVE: While lipid-lowering drugs have become a mainstay of clinical therapy these treatments only slow the progression of the disease and can have side effects. Thus, new treatment options are needed to supplement the effects of lipid lowering therapy for treating atherosclerosis. We examined the use of an inexpensive and widely available marine polysaccharide rhamnan sulfate as an oral therapeutic for limiting vascular inflammation and atherosclerosis. METHODS AND RESULTS: We found rhamnan sulfate enhanced the barrier function of endothelial cells, preventing the deposition of LDL and maintaining barrier function even in the presence of glycocalyx-degrading enzymes. Rhamnan sulfate was also found to bind directly to FGF-2, PDGF-BB and NF-κB subunits with high affinity. In addition, rhamnan sulfate was a potent inhibitor of NF-κB pathway activation in endothelial cells by TNF-α. We treated ApoE-/- mice with a high fat diet for 4 weeks and then an addition 9 weeks of high fat diet with or without rhamnan sulfate. Rhamnan sulfate reduced vascular inflammation and atherosclerosis in both sexes of ApoE-/- mice but had a stronger therapeutic effect in female mice. Oral consumption of rhamnan sulfate induced a significant decrease in cholesterol plasma levels in female mice but not in male mice. In addition, there was a marked reduction in inflammation for female mice in the liver and aortic root in comparison to male mice. CONCLUSIONS: Rhamnan sulfate has beneficial effects in reducing inflammation, binding growth factors and NF-κB, enhancing endothelial barrier function and reducing atherosclerotic plaque formation in ApoE-/- mice.

EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction.

Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, µM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 µM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 µM). Large scale atomistic simulations (>100 µs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG's anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

Pectic oligosaccharides hydrolyzed from citrus canning processing water by Fenton reaction and their antiproliferation potentials.

Citrus canning processing water contains a valuable and renewable source of biopolymers and bioactive compounds including pectic polysaccharides. Upgrading these processing wastes can not only alleviate environmental pollution but also add value to the commodity's production. In a previous study we recovered pectic polysaccharides from citrus canning processing water. In the present study, pectic polysaccharides recycled from citrus canning processing water was depolymerized by an optimized Fenton system. The hydrolyzate was fractionated via size-exclusion chromatography into six fractions: 500 Da < LMP1 < 3 kDa; 3 kDa < LMP2 < 5 kDa; 5 kDa < LMP3 < 12 kDa; 12 kDa < LMP4 < 25 kDa; 25 kDa < LMP5 < 100 kDa and LMP6 > 10 wDa. Structure analyses showed that LMP1 were homogalacturonans-enriched non-esterified polysaccharides. While LMP2 contained both HG and rhamnogalacturonan-I (RG-I). Further antitumor assay showed that in comparison with the native pectic polysaccharide with moderate antitumor activity, both LMP1 and LMP2 possessed significant antitumor activity, while the inhibitory effect of LMP1 was higher than that of LMP2, suggesting that the biological properties of LMPs was influenced by structural characteristics, including molecular weight and monosaccharide composition.