Baseline gut microbiome and metabolites are correlated with alcohol consumption in a zonisamide clinical trial of heavy drinking alcoholic civilians.

Development and severity of alcohol use disorder (AUD) has been linked to variations in gut microbiota and their associated metabolites in both animal and human studies. However, the involvement of the gut microbiome in alcohol consumption of individuals with AUD undergoing treatment remains unclear. To address this, stool samples (n=48) were collected at screening (baseline) and trial completion from a single site of a multi-site double-blind, placebo-controlled trial of Zonisamide in individuals with AUD. Alcohol consumption, gamma-glutamyl transferase (GGT), and phosphatidylethanol (PEth)levels were measured both at baseline and endpoint of 16-week trial period. Fecal microbiome was analyzed via 16S rRNA sequencing and metabolome via untargeted LC-MS. Both sex (p = 0.003) and psychotropic medication usage (p = 0.025) are associated with baseline microbiome composition. The relative abundance of 12 genera at baseline was correlated with percent drinking reduction, baseline and endpoint alcohol consumption, and changes in GGT and PeTH over the course of treatment (p.adj < 0.05). Overall microbiome community structure at baseline differed between high and low responders (67-100% and 0-33% drinking reduction, respectively; p = 0.03). A positive relationship between baseline fecal GABA levels and percent drinking reduction (R=0.43, p < 0.05) was identified by microbiome function prediction and confirmed by ELISA and metabolomics. Predicted microbiome function and metabolomics analysis have found that tryptophan metabolic pathways are over-represented in low responders. These findings highlight importance of baseline microbiome and metabolites in alcohol consumption in AUD patients undergoing zonisamide treatment.

Injectable hydrogels derived from marine polysaccharides as cell carriers for large corneal epithelial defects.

Injectable hydrogels have been employed for sutureless repair of corneal epithelial defects, which can perfectly fit the defect sites and minimize the associated discomfort. However, numerous hydrogels are ineffective in treating large corneal epithelial defects and still suffer from poor biocompatibility or weak applicability when used as cell carriers. Herein, hydroxypropyl chitin/carboxymethyl chitosan (HPCT/CMCS) temperature-sensitive hydrogels are fabricated, and their physicochemical properties and suitability for corneal epithelial repair are investigated. The results demonstrate that HPCT/CMCS hydrogels have excellent temperature sensitivity between 20 and 25 °C and a transparency of over 80 %. Besides, HPCT/CMCS hydrogels can promote cell proliferation and facilitate cell migration of primary rabbit corneal epithelial cells (CEpCs). A rabbit large corneal epithelial defect model (6 mm) is established, and CEpCs are transplanted into defect sites by HPCT/CMCS hydrogels. The results suggest that HPCT/CMCS/CEpCs significantly enhance the repair of large corneal epithelial defects with a healing rate of 99.6 % on day 8, while reducing inflammatory responses and scarring formation. Furthermore, HPCT/CMCS/CEpCs can contribute to the reconstruction of damaged tissues and the recovery of functional capacities. Overall, HPCT/CMCS hydrogels may be a feasible corneal cell carrier material and can provide an alternative approach to large corneal epithelial defects.

Recent Review on Selected Xenobiotics and Their Impacts on Gut Microbiome and Metabolome.

As it is well known, the gut is one of the primary sites in any host for xenobiotics, and the many microbial metabolites responsible for the interactions between the gut microbiome and the host. However, there is a growing concern about the negative impacts on human health induced by toxic xenobiotics. Metabolomics, broadly including lipidomics, is an emerging approach to studying thousands of metabolites in parallel. In this review, we summarized recent advancements in mass spectrometry (MS) technologies in metabolomics. In addition, we reviewed recent applications of MS-based metabolomics for the investigation of toxic effects of xenobiotics on microbial and host metabolism. It was demonstrated that metabolomics, gut microbiome profiling, and their combination have a high potential to identify metabolic and microbial markers of xenobiotic exposure and determine its mechanism. Further, there is increasing evidence supporting that reprogramming the gut microbiome could be a promising approach to the intervention of xenobiotic toxicity.

A Novel Porous Butyryl Chitin-Animal Derived Hydroxyapatite Composite Scaffold for Cranial Bone Defect Repair.

Bone defects, a common orthopedic problem in clinical practice, are a serious threat to human health. As alternative materials to autologous bone grafts, synthetic cell-free functionalized scaffolds have been the focus of recent research in designing scaffolds for bone tissue engineering. Butyryl chitin (BC) is a derivative of chitin (CT) with improved solubility. It has good biocompatibility, but few studies have investigated its use in bone repair. In this study, BC was successfully synthesized with a degree of substitution of 2.1. BC films were prepared using the cast film method and showed strong tensile strength (47.8 ± 4.54 N) and hydrophobicity (86.4 ± 2.46°), which was favorable for mineral deposition. An in vitro cytological assay confirmed the excellent cell attachment and cytocompatibility of the BC film; meanwhile, in vivo degradation indicated the good biocompatibility of BC. Hydroxyapatite (HA), extracted from bovine cancellous bone, had good cytocompatibility and osteogenic induction activity for the mouse osteoblast cell line MC3T3-E1. With the aim of combining the advantages of BC and HA, a BC-HA composite scaffold, with a good pore structure and mechanical strength, was prepared by physical mixing. Administered into skull defects of rats, the scaffolds showed perfect bone-binding performance and effective structural support, and significantly promoted the regeneration of new bone. These results prove that the BC-HA porous scaffold is a successful bone tissue engineering scaffold and has strong potential to be further developed as a substitute for bone transplantation.

Multifunctional effects of wound dressing based on chitosan-coordinated argentum with resistant bacterial penetration.

Third-degree scald, causing serious tissue destruction with continuous pain, easily leads to microbial infections and delayed wound healing. Therefore, a multifunctional treatment is attractive for seriously damaged tissue. Herein, carboxymethyl chitosan-coordinated argentum (Ag-CMC) was synthesized via a complexation method, and then the Ag+ release, antibacterial activity, biocompatibility, pain relief and wound healing properties of Ag-CMC were investigated in vitro and in vivo. The results revealed that Ag+ had interacted with carboxymethyl chitosan, containing approximately 1.2% of silver. The Ag-CMC (50-200 µg/mL) with Ag+ sustained release exhibited significant antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, drug-resistant E. coli, PA, MRSA and good biocompatibility with L929 cells. Furthermore, antibacterial and wound healing experiments demonstrated that Ag-CMC achieved an effective contraction rate of 90% after 28 days by accelerating re-epithelialization, regulating inflammation response, relieving pain and infections. Therefore, Ag-CMC is a safe multifunctional treatment for wound healing and infections.

Functional thermosensitive hydrogels based on chitin as RIN-m5F cell carrier for the treatment of diabetes.

Herein, the thermosensitive hydroxypropyl chitin (HPCT) hydrogel was prepared and the chemical structures, microstructures, rheological properties and degradation in vitro were investigated. The HPCT hydrogel possessed satisfactory biocompatibility in mouse fibroblast cells and Sprague Dawley rats. On the other hand, N-acetylglucosamine (NAG) and carboxymethyl chitosan (CMCS) provided favorable capacity for promoting cell proliferation, delaying cell apoptosis, and facilitating the insulin secretion of rat pancreatic beta cells (RIN-m5F) in three-dimensional culture. Most importantly, the effects of HPCT/NAG and HPCT/CMCS thermosensitive hydrogels as RIN-m5F cells carriers were evaluated via injection into different areas of diabetic rats. Our results demonstrated that HPCT/NAG and HPCT/CMCS hydrogels loaded RIN-m5F cells could keep cells survival, maintain insulin secretion and reduce blood glucose for one week. Overall, the functional thermosensitive hydrogels based on HPCT were effective cell carriers for RIN-m5F cells and might provide novel strategy for the treatment of diabetes via cell engineering.

Injectable self-crosslinking hydrogels based on hyaluronic acid as vitreous substitutes.

After vitrectomy, the ideal vitreous substitute should be implanted to maintain the normal function of the eye. However, the existing materials (such as silicone oil, air, perfluorocarbons, etc.) still have some shortcomings and cannot fully meet the clinical needs. In this study, thiolated hyaluronic acid (SH-HA) was prepared based on hyaluronic acid. The SH-HA hydrogel was formed by a simple transformation of the sulfhydryl group to the disulfide bond, which had high transparency, controllable swelling property, suitable mechanical strength, excellent biocompatibility and similar physical and chemical properties to natural vitreous. SH-HA hydrogel was filled into the eyes of experimental rabbits to replace their own vitreous after vitrectomy. During the 90 days follow-up period, SH-HA hydrogel showed excellent intraocular compatibility, maintained normal intraocular pressure (IOP), and no cataract, endophthalmitis, retinal detachment and other complications were observed. In general, SH-HA hydrogel has great potential as a vitreous substitute.

Novel dopamine-modified oxidized sodium alginate hydrogels promote angiogenesis and accelerate healing of chronic diabetic wounds.

Herein, the dopamine (DA) was grafted with oxidized sodium alginate (OSA) via Schiff base reduction reaction, aiming to fabricate novel DA-grafted OSA (OSA-DA) hydrogels with enhanced biocompatibility and suitable adhesion for clinical applications. The chemical structures of OSA-DA were characterized via UV-Vis, FTIR and 1H NMR spectroscopy analysis. The hydrogel characteristics, biocompatibility, as well as the chronic diabetic wound healing efficacy were investigated. Our results demonstrated that DA was grafted with OSA successfully with highest grafting rate of 7.50%. Besides, OSA-DA hydrogels possessed suitable swelling ratio and appropriate adhesion characteristics. Additionally, OSA-DA exhibited satisfactory cytocompatibility and cell affinity in L-929 cells, and superior biocompatibility in SD rats. Moreover, OSA-DA exerted remarkable promoting effects on migration and tube formation of human umbilical vein endothelial cells (HUVECs). Studies on full-thickness excision chronic diabetic wounds further revealed that OSA-DA hydrogels could accelerate healing via promoting angiogenesis, reducing inflammation response, and stimulating collagen deposition. Overall, our studies would provide basis for SA-based hydrogels as clinical wound dressings.

Preparation, biocompatibility, and wound healing effects of O-carboxymethyl chitosan nonwoven fabrics in partial-thickness burn model.

This study was aimed at preparing O-carboxymethyl chitosan (CM-CTS) fabrics, and examining the wound healing effects on partial-thickness burn. The functional polysaccharides were produced from chitosan needle-punched nonwovens reacted with chloroacetic acid. Then the biocompatibility and biological functions were evaluated through fibroblast L-929 and SD rats. CM-CTS fabrics were obtained with elongation at break more than 42%, tensile strength reaching 0.65 N/mm2, and water vapor transmission rate about 2600 g/m2∙24 h. Moreover, CM-CTS fabrics could effectively promote the mouse L-929 migration in vitro. CM-CTS fabrics yielded satisfactory results in angiogenesis, collagen deposition, interleukin-6 content, transforming growth factor level and healing rate, which were superior to the positive control and model groups after rats suffering with partial-thickness burn. In conclusion, CM-CTS fabrics possessed proper mechanical properties, air permeability, favorable biocompatibility, acceleration on fibroblasts migration and healing capacity for partial-thickness burn injury, and owned good potential as high-quality wound dressing.

Hemostatic performance of chitosan-based hydrogel and its study on biodistribution and biodegradability in rats.

Hemostasis is of great significance regardless of the smooth operation or postoperative recovery. Therefore, it is urgent to develop a hemostatic material with excellent biodegradability and biocompatibility. It is well known that both carboxymethyl chitosan and hyaluronic acid with biodegradability and biocompatibility have wound healing promoting property. Here, a degradable chitosan-based hydrogel was prepared based on carboxymethyl chitosan and cross-linked by oxidized hyaluronic acid. The hemostatic performance of the hydrogel in rat liver resection injury was evaluated which results showed that the hydrogel exhibited comparable hemostatic properties compared with Fibrin Sealant. In addition, the hydrogel proved to be rapidly absorbed by the body without significant accumulation in vivo, demonstrating good biodegradability and biocompatibility. The overall results suggested the hydrogel will be a promising hemostatic hydrogel for controlling bleeding.

A self-healing and injectable hydrogel based on water-soluble chitosan and hyaluronic acid for vitreous substitute.

Vitreous, an essential dioptric medium for the human eyes, must be filled with artificial materials once damaged. Carboxymethyl chitosan (CMCTS) is one of the most important water-soluble chitosan derivatives with improved biocompatibility and biodegradability. In this study, oxidized hyaluronic acid (OHA) was prepared as crosslinking reagent. CMCTS and OHA were used to develop a biocompatible, self-repairing and in-situ injectable hydrogel for vitreous substitutes. Results showed the hydrogel with controllable swelling properties, high transparency, acceptable cytocompatibility on mouse fibroblast L929 and histocompatibility in vivo. Furthermore, hydrogel was injected in-situ into the vitreous cavity after vitrectomy on New Zealand Rabbits, no significant and persistent adverse effects were observed during the 90-day follow-up period. In addition, the hydrogel maintained intraocular pressure of the operated eyes and the inherent position of the retina. Collectively, this injectable, biodegradable, nontoxic hydrogel possessed enormous potential to become a vitreous substitute material.

Effect of chitosan oligosaccharide-conjugated selenium on improving immune function and blocking gastric cancer growth.

Selenium (Se) is a potential chemopreventive or chemotherapeutic agent against malignant tumor. Selenium-oligosaccharides are important selenium source of dietary supplementation. Due to the insufficient natural production, it is therefore urgent to develop selenium-oligosaccharides by artificial synthesis. Chitosan, the N-deacetylated derivative of chitin, has been applied widely in biomedical field, owing to its nontoxicity, hydrophilicity, biocompatibility, and biodegradation. While chitosan is water insoluble at neutral pH, limiting its application in physiological conditions. Chitosan oligosaccharide (COS), the hydrolysate of chitosan, is readily soluble in water because of the shorter chain lengths of the oligomers and the free amino groups in the D-glucosamine units. This study was aimed at preparing COS-conjugated selenium (COS-Se) and examining the toxicity and ability on improving immune function and blocking gastric cancer growth. Our results demonstrated that COS-Se displayed directly co-mitogenic and mitogenic actions on mouse splenocytes proliferation in vitro. Besides, COS-Se treatment could effectively elevate phagocytosis and increase the secretion of anti-inflammatory cytokine in mouse peritoneal macrophages. Further in vivo experiments showed that COS-Se exhibited immuno-enhancing effects through promoting the phagocytic index, spleen index and thymus index with no obvious toxicity to Kunming mice. Moreover, COS-Se inhibited proliferation and metastasis of human gastric cancer cells, with non-toxic effects on the normal fibroblast cells in vitro. COS-Se supplementation could significantly repress the growth of gastric adenocarcinoma through reducing levels of CD34, vascular endothelial growth factor and matrix metalloproteinase-9 of nude mice. In conclusion, COS-Se was non-toxic and showed great potential as a functional food ingredient in cancer prevention.

Effects of carboxymethyl chitosan oligosaccharide on regulating immunologic function and inhibiting tumor growth.

Herein, the effects of carboxymethyl chitosan oligosaccharide (CM-COS) on regulating immunologic function and inhibiting hepatocellular tumor growth were evaluated. Results showed that CM-COS caused dramatic viability loss of hepatocellular carcinoma BEL-7402 with non-toxicity towards normal liver L-02 cells. CM-COS repressed tumor growth of hepatoma-22, and elevated the spleen index and thymus index of tumor-bearing mice. Contents of VEGF and MMP-9 were significantly down-regulated by CM-COS. Histological analyses revealed that CM-COS promoted tumor cell necrosis and produced no significant toxicity to spleen tissues. Moreover, expressions of Caspase-3 in tumor tissues and IL-2 in spleen tissues were significantly activated by CM-COS. Additionally, in vitro cell viability, phagocytic capability and NO production of mouse peritoneal macrophages exposed to CM-COS were significantly higher. CM-COS remarkably increased the in vivo phagocytosing capacity of peritoneal macrophages of Kunming mice. Taken together, our findings suggested that CM-COS might be potentially effective and non-toxic candidate as anti-hepatoma agents.

Studies on anti-hepatocarcinoma effect, pharmacokinetics and tissue distribution of carboxymethyl chitosan based norcantharidin conjugates.

Aiming to enhance therapeutic efficiency and reduce toxic effect of norcantharidin (NCTD), NCTD-conjugated carboxymethyl chitosan (CMCS) conjugates (CNC) were prepared and evaluated for the treatment of hepatocellular carcinoma. In vitro cellular assays revealed that CNC conjugates possessed potent inhibitory effects on the proliferation and migration of BEL-7402 cells. Besides, CNC could change nuclear morphology of tumor cells. In comparison with free NCTD at equivalent dose, CNC exerted enhanced therapeutic efficiency and diminished systemic toxicity in H22 tumor-bearing mice with a tumor inhibition rate of 56.20%. Further investigation about pharmacokinetics and tissue distribution by high performance liquid chromatography (HPLC) analysis indicated that CNC showed a longer retention time in blood circulation and reduced distribution in heart and kidney tissues, thereby exerting different antitumor efficacy and toxicity compared with free NCTD. Our results suggested that CNC conjugates based on CMCS as polymer carriers might be used as a potential clinical alternative for NCTD in tumor therapy.

Antitumor evaluation of carboxymethyl chitosan based norcantharidin conjugates against gastric cancer as novel polymer therapeutics.

Novel polymer-drug conjugates (CNC) were prepared from carboxymethyl chitosan (CMCS) and norcantharidin (NCTD) via amidation reaction and characterized by FTIR and 1H NMR spectroscopy. The aim of this study was to elucidate the antitumor efficacy of CNC on gastric cancer and the possible underlying mechanisms. The CNC conjugates possessed significant inhibitory effects on the proliferation of SGC-7901 cells and suppressed the migration as well as tube formation of HUVECs. Besides, Hoechst 33258 staining and Annexin V-FITC/PI detection suggested that the conjugates were more effective in triggering apoptosis of SGC-7901 cells compared with free NCTD. Moreover, CNC remarkably reduced systemic toxicity and enhanced the antitumor efficacy in vivo with a tumor suppression rate of 59.57% against SGC-7901 gastric tumor in BALB/c nude mice. Further investigation about the underlying mechanisms indicated that CNC could upregulate expressions of TNF-α and Bax, and downregulate expressions of VEGF, Bcl-2, MMP-2 and MMP-9, thereby inhibiting tumor metastasis and inducing apoptosis in vivo. Overall, our results demonstrated that CNC might be a promising and feasible polymer therapeutics for gastrointestinal tumor therapy.

Synthesis and anti-metastasis activities of norcantharidin-conjugated carboxymethyl chitosan as a novel drug delivery system.

Carboxymethyl chitosan (CMCS), a water-soluble derivative of chitosan possessing numerous enhanced physicochemical and biological properties, has emerged as a promising biopolymer carrier for new drug delivery. Norcantharidin (NCTD) is an effective anti-tumor compound with severe nephrotoxicity. In this study, norcantharidin-conjugated carboxymethyl chitosan (CMCS-NCTD) was synthesized to reduce systemic toxicity and improve anti-tumor efficiency of NCTD. Our results demonstrated that CMCS-NCTD could significantly inhibit migration of tumor cells both in vitro and in vivo in a dose-dependent manner (P < 0.05). The enhanced anti-tumor effects of CMCS-NCTD were confirmed by inhibiting the growth of solid tumors and extending survival time of tumor-bearing mice. Further investigation for the underlying mechanisms indicated that CMCS-NCTD could inhibit tumor angiogenesis and reduce degradation of extracellular matrix by regulating the expressions of VEGF, MMP-9 and TIMP-1. Overall, our findings suggested that CMCS-NCTD was an excellent polymer derivative for cancer treatment, and CMCS was a promising platform for efficient delivery of anti-cancer drugs.

Oregonin inhibits inflammation and protects against barrier disruption in intestinal epithelial cells.

BACKGROUND AND AIMS: Oregonin, a major diarylheptanoid derivative isolated from Alnus japonica, exerts anti-inflammatory effects; however, little is known about the effect of oregonin in intestinal inflammation. The current study investigated the potential of oregonin for clinical applications in the treatment of inflammatory bowel disease (IBD) and elucidated its underlying molecular mechanisms. METHODS: The anti-inflammatory effect of oregonin in tumor necrosis factor-α (TNF-α)-stimulated human intestinal epithelial HT-29 cells was investigated. In addition, the protective effect of oregonin was determined against disruption of the intestinal barrier in tert-butyl hydroperoxide (t-BH)-stimulated human intestinal epithelial Caco-2 cells. RESULTS: Oregonin suppressed the expression of cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), IL-8, and IL-1ß, and inhibited activation of nuclear factor κB (NF-κB) in HT-29 cells stimulated with TNF-α. Oregonin increased heme oxygenase-1 (HO-1) expression through the ERK1/2 and JNK-dependent signaling pathway, which contributed to the oregonin-mediated suppression of COX-2 expression in the HT-29 cells stimulated with TNF-α. Moreover, oregonin induced AMP-activated protein kinase (AMPK) activation. Knockdown of AMPK abolished the induction of HO-1 protein by oregonin and suppression of oregonin-mediated ICAM-1 and COX-2 expression in the HT-29 cells stimulated with TNF-α. Oregonin prevented the t-BH-induced increase in monolayer permeability through inhibition of the reduction in expression of zonula occludens-1 and occludin in Caco-2 cells. Targeting HO-1 by siRNA transfection attenuated the oregonin-mediated prevention of loss of tight junction proteins and increase in permeability. CONCLUSION: The findings of this study suggest that oregonin is a potential candidate for treatment of IBD by preventing mucosal inflammation and barrier disruption.

Preparation and pharmacological evaluation of norcantharidin-conjugated carboxymethyl chitosan in mice bearing hepatocellular carcinoma.

In this study, norcantharidin (NCTD), a small-molecule anticancer drug derived from Chinese traditional medicine blister beetle (Mylabris), was conjugated covalently onto carboxymethyl chitosan (CMCS). Then the hepatocellular carcinoma therapeutic properties and liver-protective effects were investigated through orthotopic transplantation tumor model. Results showed that the obtained CMCS-NCTD demonstrated remarkable anti-growth efficacy against hepatocellular 22 in mice. Significant improvement of the liver injury caused by cancer cells was observed in tumor-bearing mice administrated with CMCS-NCTD. Moreover, CMCS-NCTD remarkably increased the serum levels of TNF-α, IFN-γ, TIMP-1 and E-cadherin in mice treated for 12days. Administration of CMCS-NCTD significantly reduced the elevated serum ALT, AST, VEGF and MMP-9 levels of tumor-bearing mice. In addition, activities of SOD and GSH-Px in serum or homogenate of the CMCS-NCTD treated mice were significantly high when compared with model control group. Our data suggested that CMCS-NCTD was a promising candidate as an anti-hepatoma and liver-protection compound.

Study of a new biodegradable hernia patch to repair abdominal wall defect in rats.

A novel biodegradable chitin hernia patch was prepared by acetylation of chitosan fabric in our study. Physicochemical properties, cell compatibility and biodegradability of the chitin patch were quantified. Histopathological study of the functional experiment showed that this newly designed hernia patch promoted collagen deposition and neovascularization by significantly promoting the secretion of FGF1 and TGF-ß1 in the early postoperative (P<0.01). Chitin patch caused less inflammation by inhibiting excessive expression of IL-6 and TNF-α when compared to the polypropylene mesh (P<0.01). Acceptable fibrosis was consistent with the results of immunohistochemistry studies. The density of FGF1 and TGF-ß1 positive cells in the chitin patch group at 7 d was reduced to a lower level at 15 d (P<0.01). With regeneration of the defect abdominal wall, chitin patch degraded gradually, avoiding foreign body response and chronic complications. Our studies demonstrated that the newly designed chitin patch showed good promise for the hernia treatment.

Isoliquiritigenin inhibits TNF-α-induced release of high-mobility group box 1 through activation of HDAC in human intestinal epithelial HT-29 cells.

The suppression of pro-inflammatory cytokine-induced inflammation responses is an attractive pharmacological target for the development of therapeutic strategies for inflammatory bowel disease (IBD). In the present study, we evaluated the anti-inflammatory properties of flavonoid isoliquiritigenin (ISL) in intestinal epithelial cells and determined its mechanism of action. ISL suppressed the expression of inflammatory molecules, including IL-8, IL-1ß and COX-2, in TNF-α-stimulated HT-29 cells. Moreover, ISL induced activation of Nrf2 and expression of its target genes, such as HO-1 and NQO1. ISL also inhibited the TNF-α-induced NF-κB activation in HT-29 cells. High-mobility group box 1 (HMGB1), which is one of the critical mediators of inflammation, is actively secreted from inflammatory cytokine-stimulated immune or non-immune cells. ISL inhibited HMGB1 secretion by preventing TNF-α-stimulated HMGB1 relocation, whereas the RNA and protein expression levels of cellular HMGB1 did not change in response to TNF-α or ISL. Moreover, we found that HMGB1 acetylation was associated with HMGB1 translocation to the cytoplasm and the extracellular release in TNF-α-stimulated HT-29 cells; however, ISL significantly decreased the amount of acetylated HMGB1 in both the cytoplasm and extracellular space of HT-29 cells. Histone deacetylase (HDAC) inhibition by Scriptaid abrogated ISL-induced HDAC activity and reversed the ISL-mediated decrease in acetylated HMGB1 release in TNF-α-stimulated HT-29 cells, suggesting that, at least in TNF-α-stimulated HT-29 cells, ISL suppresses acetylated HMGB1 release via the induction of HDAC activity. Together, the current results suggest that inhibition of HMGB1 release via the induction of HDAC activity using ISL may be a promising therapeutic intervention for IBD.