CHST11-modified chondroitin 4-sulfate as a potential therapeutic target for glioblastoma.

Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied in vitro and in vivo. We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent in vitro and in vivo. C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells.

Targeting Chondroitin Sulphate Synthase 1 (Chsy1) Promotes Axon Growth Following Neurorrhaphy by Suppressing Versican Accumulation.

Versican is a chondroitin sulfate proteoglycan (CSPG), which deposits in perineurium as a physical barrier and prevents the growth of axons out of the fascial boundary. Several studies have indicated that the chondroitin sulfate (CS) chains on versican have several possible functions beyond the physical barrier, including the ability to stabilize versican core protein in the extracellular matrix. As chondroitin sulfate synthase 1 (Chsy1) is a crucial enzyme for CS elongation, we hypothesized that in vivo knockdown of Chsy1 at peripheral nerve lesion site may decrease CS and versican accumulation, and result in accelerating neurite regeneration. In the present study, end-to-side neurorrhaphy (ESN) in Wistar rats was used as an in vivo model of peripheral nerve injury to evaluate nerve regeneration after surgical intervention. The distribution and expression of versican and Chsy1 in regenerating axons after ESN was studied using confocal microscopy and western blotting. Chsy1 was silenced at the nerve lesion (surgical) site using in vivo siRNA transfection. The results indicated that Chsy1 was successfully silenced in nerve tissue, and its downregulation was associated with functional recovery of compound muscle action potential. Silencing of Chsy1 also decreased the accumulation of versican core protein, suggesting that transient treating of Chsy1-siRNA may be an alternative and an effective strategy to promote injured peripheral nerve regeneration.

Surgical anatomy of the gastroduodenal artery in Chinese adults and its clinical applications.

BACKGROUND/AIMS: Hemorrhage occurs in 15-25% of duodenal ulcers, mostly on the posterior wall of the proximal duodenum. Erosion of the gastroduodenal artery is responsible for serious hemorrhages. Therefore, the relationship between bile duct and gastroduodenal artery should be discerned to prevent bile duct injury. METHODOLOGY: Cadavers from 52 Chinese adults (44 males, 8 females) were dissected for the anatomic relationships of the GDA and bile duct. RESULTS: The gastroduodenal artery has many possible origins, with the common hepatic artery (92.3%) the most common. The mean distance between gastroduodenal artery and pylorus was 2.7 cm; arterial length (from its origin) was 1.2 cm. The relationships between gastroduodenal artery and bile duct could be divided into 4 anatomic types according to Prudhomme's classification. We found 22 samples (42%) of Type 1; 10 samples (19%) of Type 2; 14 samples (27%) of Type 3 (in 8 samples of Type 3, there was about 8mm thickness of pancreatic tissue between the artery and the bile duct); 6 samples (12%) of Type 4. In 12 cases (24%) there was no interposed pancreatic tissue. CONCLUSIONS: These anatomic variations could lead to injury during surgical intervention. Our study provides detailed information about anatomic variability in Chinese adults that may help avoid such injury to the common bile duct during duodenal bleeding hemostasis.