Application of In Situ Mucoadhesive Hydrogel with Anti-Inflammatory and Pro-Repairing Dual Properties for the Treatment of Chemotherapy-Induced Oral Mucositis.

Chemotherapy-induced oral mucositis (CIOM) is a prevalent complication of chemotherapy and significantly affects the treatment process. However, effective treatment for CIOM is lacking due to the unique environment of the oral cavity and the single effect of current drug delivery systems. In this present study, we propose an innovative approach by combining a methacrylate-modified human recombinant collagen III (rhCol3MA) hydrogel system with hyaluronic acid-epigallocatechin gallate (HA-E) and dopamine-modified methacrylate-alginate (AlgDA-MA). HA-E is used as an antioxidant and anti-inflammatory agent and synergizes with AlgDA-MA to improve the wet adhesion of hydrogel. The results of rhCol3MA/HA-E/AlgDA-MA (Col/HA-E/Alg) hydrogel demonstrate suitable physicochemical properties, excellent wet adhesive capacity, and biocompatibility. Notably, the hydrogel could promote macrophage polarization from M1 to M2 and redress human oral keratinocyte (HOK) inflammation by inhibiting NF-κB activation. Wound healing evaluations in vivo demonstrate that the Col/HA-E/Alg hydrogel exhibits a pro-repair effect by mitigating inflammatory imbalances, fostering early angiogenesis, and facilitating collagen repair. In summary, the Col/HA-E/Alg hydrogel could serve as a promising multifunctional dressing for the treatment of CIOM.

Naturally derived highly resilient and adhesive hydrogels with application as surgical adhesive.

The inadequacy of conventional surgical techniques for wound closure and repair in soft and resilient tissues may lead to poor healing outcomes such as local tissue fibrosis and contracture. Therefore, the development of adhesive and resilient hydrogels that can adhere firmly to irregular and dynamic wound interfaces and provide a "tension-free proximity" environment for tissue regeneration has become extremely important. Herein, we describe an integrated modeling-experiment-application strategy for engineering a promising hydrogel-based bioadhesive based on recombinant human collagen (RHC) and catechol-modified hyaluronic acid (HA-Cat). Molecular modeling and simulations were used to verify and explore the hypothesis that RHC and HA-Cat can form an assembly complex through physical interactions. The complex was synergistically crosslinked via a catechol/o-quinone coupling reaction and a carbodiimide coupling reactions, resulting in superior hydrogels with strong adhesion and resilience properties. The application of this bioadhesive to tissue adhesion and wound sealing in vivo was successfully demonstrated, with an optimum collagen index, epidermal thickness, and lowest scar width. Furthermore, subcutaneous implantation demonstrated that the bioadhesive exhibited good biocompatibility and degradability. This newly developed hydrogel may be a highly promising surgical adhesive for medical applications, including wound closure and repair.

Copper-Epigallocatechin Gallate Enhances Therapeutic Effects of 3D-Printed Dermal Scaffolds in Mitigating Diabetic Wound Scarring.

Morbid dermal templates, microangiopathy, and abnormal inflammation are the three most critical reasons for the scarred healing and the high recurrence rate of diabetic wounds. In this present study, a combination of a methacrylated decellularized extracellular matrix (ECMMA, aka EM)-based hydrogel system loaded with copper-epigallocatechin gallate (Cu-EGCG) capsules is proposed to fabricate bio-printed dermal scaffolds for diabetic wound treatment. Copper ions act as a bioactive element for promoting angiogenesis, and EGCG can inhibit inflammation on the wound site. In addition to the above activities, EM/Cu-EGCG (E/C) dermal scaffolds can also provide optimized templates and nutrient exchange space for guiding the orderly deposition and remodeling of ECM. In vitro experiments have shown that the E/C hydrogel can promote angiogenesis and inhibit the polarization of macrophages to the M1 pro-inflammatory phenotype. In the full-thickness skin defect model of diabetic rats, the E/C dermal scaffold combined with split-thickness skin graft transplantation can alleviate pathological scarring via promoting angiogenesis and driving macrophage polarization to the anti-inflammatory M2 phenotype. These may be attributed to the scaffold-actuated expression of angiogenesis-related genes in the HIF-1α/vascular endothelial growth factor pathway and decreased expression of inflammation-related genes in the TNF-α/NF-κB/MMP9 pathway. The results of this study show that the E/C dermal scaffold could serve as a promising artificial dermal analogue for solving the problems of delayed wound healing and reulceration of diabetic wounds.

Involvement of C/EBPß-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.

Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein ß (C/EBPß) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPß is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPß, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPß on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPß lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPß, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPß, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPß protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPß plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

Serum NOX2 as a new biomarker candidate for HBV-related disorders.

Growing evidence supports the notion that serum NAPDH oxidase 2 (NOX2) is an important regulator that contributes to the initiation and progression of various types of diseases. However, so far, it remains elusive about the relationship between levels of serum NOX2 and HBV-related diseases. The overall purpose of the study is to get a better insight into whether or not serum NOX2 is involved in HBV-related disorders. Serum levels of NOX2, from 105 patients with chronic hepatitis B, 58 patients with HBV-related cirrhosis, 48 patients with HBV-related hepatocellular carcinoma and 104 healthy individuals, were measured with sandwich ELISA kits that we developed. In this study, we found that NOX2 values were significantly higher in patients compared to healthy control (P < 0.01) and that the levels of serum NOX2 were significantly correlated with the serum levels of superoxide dismutase (SOD), interleukin-6 (IL-6), interferon-stimulated gene 15 (ISG15), alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) in chronic hepatitis B, cirrhosis and hepatocellular carcinoma patients. Interestingly, we found that a significant positive correlation between NOX2 and HBV viral load only in patients with chronic hepatitis B and cirrhosis. Therefore, Serum NOX2 levels maybe an important indicator of the pathogenesis of progression of HBV-related disorders.

ANP32E induces tumorigenesis of triple-negative breast cancer cells by upregulating E2F1.

Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor, and the HER2 receptor; it is highly proliferative and becomes the deadliest forms of breast cancer. Effective prognostic methods and therapeutic targets for TNBC are required to improve patient outcomes. Here, we report that acidic nuclear phosphoprotein 32 family member E (ANP32E), which promotes cell proliferation in mammalian development, is highly expressed in TNBC cells compared to other types of breast cancer. High expression of ANP32E correlates significantly with worse overall survival (OS; P < 0.001) and higher risks of disease recurrence (P < 0.001) in patients with TNBC. Univariate and multivariate Cox-regression models show that ANP32E is an independent prognostic factor in TNBC. Furthermore, we discovered that ANP32E promotes tumor proliferation in vitro by inducing G1/S transition, and ANP32E inhibition suppresses tumor formation in vivo. By examining the expression of E2F1, cyclin E1, and cyclin E2, we discovered that ANP32E promotes the G1/S transition by transcriptionally inducing E2F1. Taken together, our study shows that ANP32E is an efficient prognostic marker, and it promotes the G1/S transition and induces tumorigenesis of TNBC cells by transcriptionally inducing E2F1.