Immune responses and transcription landscape of adults with the third dose of homologous and heterologous booster vaccines of COVID-19.

Background: Heterologous booster vaccines are more effective than homologous booster vaccines in combating the coronavirus disease 2019 (COVID-19) outbreak. However, our understanding of homologous and heterologous booster vaccines for COVID-19 remains limited. Methods: We recruited 34 healthy participants from two cohorts who were primed with two-dose inactivated COVID-19 vaccine before, vaccinated with COVID-19 inactivated vaccine and adenovirus-vectored vaccine (intramuscular and aerosol inhalation of Ad5-nCoV) as a third booster dose. We assessed the immune responses of participants before and 14 days after vaccination, including levels of neutralizing antibodies, IgG, and cytokines, and quantified the transcriptional profile of peripheral blood mononuclear cells (PBMCs). Results: The Ad5-nCoV group showed a significantly higher neutralizing antibody geometric mean titer (GMT) compared to the ICV group after 14 days of heterologous boosting. The intramuscular Ad5-nCoV group had a GMT of 191.8 (95% CI 129.0, 285.1) compared to 38.1 (95% CI 23.1, 62.8) in the ICV1 group (p<0.0001). The aerosolized Ad5-nCoV group had a GMT of 738.4 (95% CI 250.9-2173.0) compared to 244.0 (95% CI 135.0, 441.2) in the ICV2 group (p=0.0434). Participants in the aerosolized Ad5-nCoV group had median IFN-γ+ spot counts of 36.5 (IQR 15.3-58.8) per 106 PBMCs, whereas, both intramuscular Ad5-nCoV and CoronaVac immunization as the third dose showed lower responses. This suggests that a third dose of booster Ad5-nCoV vaccine (especially aerosolized inhalation) as a heterologous vaccine booster induces stronger humoral and cellular immune responses, which may be more potent against VOCs than the use of inactivated vaccine homologs. In transcriptomic analyses, both aerosolized inhalation/intramuscular injection of the Ad5-nCoV vaccine and inactivated vaccine induced a large number of differentially expressed genes that were significantly associated with several important innate immune pathways including inflammatory responses, regulation of the defense response, and regulation of cytokine production. In addition, we identified crucial molecular modules of protective immunity that are significantly correlated with vaccine type and neutralizing antibodies level. Conclusion: This study demonstrated that inhalation/intramuscular injection of the Ad5-nCoV vaccine-mediated stronger humoral and cellular immune responses compared with the inactivated vaccine, and correlated significantly with innate immune function modules, supporting a heterologous booster immunization strategy.

Cobalt-containing borate bioactive glass fibers for treatment of diabetic wound.

Impaired angiogenesis is one of the predominant reasons for non-healing diabetic wounds. Cobalt is well known for its capacity to induce angiogenesis by stabilizing hypoxia-inducible factor-1α (HIF-1α) and subsequently inducing the production of vascular endothelial growth factor (VEGF). In this study, Co-containing borate bioactive glasses and their derived fibers were fabricated by partially replacing CaO in 1393B3 borate glass with CoO. Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (NMR) analyses were performed to characterize the effect of Co incorporation on the glass structure, and the results showed that the substitution promoted the transformation of [BO3] into [BO4] units, which endow the glass with higher chemical durability and lower reaction rate with the simulated body fluid (SBF), thereby achieving sustained and controlled Co2+ ion release. In vitro biological assays were performed to assess the angiogenic potential of the Co-containing borate glass fibers. It was found that the released Co2+ ion significantly enhanced the proliferation, migration and tube formation of the Human Umbilical Vein Endothelial Cells (HUVECs) by upregulating the expression of angiogenesis-related proteins such as HIF-1α and VEGF. Finally. In vivo results demonstrated that the Co-containing fibers accelerated full-thickness skin wound healing in streptozotocin (STZ)-induced diabetic rat model by promoting angiogenesis and re-epithelialization.

Hollow Hydroxyapatite Microspheres Loaded with rhCXCL13 to Recruit BMSC for Osteogenesis and Synergetic Angiogenesis to Promote Bone Regeneration in Bone Defects.

Introduction: Bone tissue engineering is a promising method to treat bone defects. However, the current methods of preparing composite materials that mimic the complex structure and biological activity of natural bone are challenging for recruitment of bone marrow mesenchymal stem cells (BMSCs), which affects the application of these materials in situ bone regeneration. Hollow hydroxyapatite microspheres (HHMs) possess a natural porous bone structure, good adsorption, and slow release of chemokines, but have low ability to recruit BMSCs and induce osteogenesis. In this study, The HHM/chitosan (CS) and recombinant human C-X-C motif chemokine ligand 13 (rhCXCL13)-HHM/CS biomimetic scaffolds that optimize bone regeneration and investigated their mechanism of BMSC recruitment and osteogenesis through cell and animal experiments and transcriptomic sequencing. Methods: Evaluate the physical characteristics of the HHM/CS and rhCXCL13-HHM/CS biomimetic scaffolds through Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), and the cumulative release curve of rhCXCL13. Transwell migration experiments and co-culture with BMSCs were conducted to study the recruitment ability and osteogenic differentiation of the scaffolds. Transcriptomic sequencing was performed to analyze the osteogenic differentiation mechanism. The osteogenesis and bone healing performance were evaluated using a rabbit radial defect model. Results: SEM demonstrated that the rhCXCL13-HHM/CS scaffold comprised hydroxyapatite microspheres in a porous three-dimensional network. The rhCXCL13 showed excellent sustained release capability. The rhCXCL13-HHM/CS scaffold could recruit BMSCs and induce bone regeneration. Transcriptome sequencing and experimental results showed that the osteogenesis mechanism of rhCXCL13-HHM/CS was through the PI3K-AKT pathway. In vivo, the rhCXCL13-HHM/CS scaffold significantly promoted osteogenesis and angiogenesis at 12 weeks after surgery. Conclusion: The rhCXCL13-HHM/CS scaffold demonstrates excellent potential for BMSC recruitment, osteogenesis, vascularized tissue-engineered bone reconstruction, and drug delivery, providing a theoretical basis for material osteogenesis mechanism study and promising clinical applications for treating large bone defects.

Efficacy and safety of regorafenib in combination with immune checkpoint inhibitor therapy as second-line and third-line regimen for patients with advanced hepatocellular carcinoma: a retrospective study.

Background: Despite the emergence of immune checkpoint inhibitors (ICIs) as first-line treatment for advanced hepatocellular carcinoma (HCC), there is an unmet need regarding subsequent treatments in patients that fail ICI. Regorafenib is a vascular endothelial growth factor receptor (VEGFR) inhibitor, which could increase programmed death-ligand 1 (PD-L1) expression in tumors and increase intra-tumoral CD8+ T-cell infiltration by normalizing the cancer vasculature and improving the efficacy of the programmed cell death protein 1 (PD-1) antibody. Thus, we evaluated the combination of regorafenib and a PD-1 inhibitor for advanced HCC patients that had failed combined tyrosine kinase inhibitors (TKIs) plus ICI. Methods: Data of patients with advanced HCC who had failed combined TKIs plus ICI treatment and were afterwards treated with combined regorafenib plus a PD-1 inhibitor were reviewed. All patients had received PD-1 inhibitors as part of the first-line treatment and regorafenib every 4 weeks until disease progression, intolerable toxicities, or physician/patient withdrawal. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events (AEs) during follow-ups were recorded. Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 was used to evaluate AEs and Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 was used to evaluate response. The primary endpoint was safety, and the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and duration of response (DOR). Results: From November 15, 2020, to January 31, 2022, data of 17 patients with advanced HCC that met the criteria were reviewed. The cohort included 16 men and 1 woman with a median age of 54 years (interquartile range, 46 to 63 years). Sixteen patients had Child-Pugh class A (n=16, 94.12%) and one with class B (n=1, 15.9%) liver disease. Thirteen patients received second-line treatment, and the remaining patients received third-line treatment. All patients received at least 1 dose of PD-1 inhibitors. The median follow-up duration was 7.62 months. Twelve recipients experienced treatment-related AEs. The most frequent AE (≥5%) included fatigue (17.64%), diarrhea (17.65%), proteinuria (5.88%), bleeding gums (11.76%), and hypertension (11.76%). No grade-4 AE or new safety signals were identified. The ORR and DCR were 41.2% and 64.7%, respectively, and the median PFS was 5.09 months. Conclusions: Regorafenib combined with PD-1 inhibitor is a promising regimen in treating patients with advanced HCC owing to its safety and effectiveness as well as low incidence of serious AEs with its use.

Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial.

OBJECTIVE: This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy. METHODS: Initially, 20 patients with HCC were screened and 18 patients with resectable HCC were enrolled in this open-label, single-arm, phase II clinical trial. Patients received three cycles of neoadjuvant therapy including three doses of camrelizumab concurrent with apatinib for 21 days followed by surgery. Four to 8 weeks after surgery, patients received eight cycles of adjuvant therapy with camrelizumab in combination with apatinib. Major pathological reactions (MPR), complete pathological reactions (pCR), objective response rate (ORR), relapse-free survival (RFS), and adverse events (AE) were assessed. In addition, cancer tissue and plasma samples were collected before and after treatment, and genetic differences between responding and non-responding lesions were compared by tumor immune microenvironment (TIME) analysis, circulating tumor DNA (ctDNA) analysis and proteomics analysis. RESULTS: In 18 patients with HCC who completed neoadjuvant therapy, 3 (16.7%) and 6 (33.3%) patients with HCC reached ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST criteria, respectively. Of the 17 patients with HCC who received surgical resection, 3 (17.6%) patients with HCC reported MPR and 1 (5.9%) patient with HCC achieved pCR. The 1-year RFS rate of the enrolled patients was 53.85% (95% CI: 24.77% to 75.99%). Grade 3/4 AEs were reported in 3 (16.7%) of the 18 patients, with the most common AEs being rash (11.1%), hypertension (5.6%), drug-induced liver damage (5.6%), and neutropenia (5.6%) in the preoperative phase. The 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) infiltration was better in responding tumors than in non-responding tumors. Our results of ctDNA revealed a higher positive rate (100%) among patients with HCC with stage IIb-IIIa disease. When comparing patients with pCR/MPR and non-MPR, we observed more mutations in patients who achieved pCR/MPR at baseline (6 mutations vs 2.5 mutations, p=0.025). Patients who were ctDNA positive after adjuvant therapy presented a trend of shorter RFS than those who were ctDNA negative. Proteomic analysis suggested that abnormal glucose metabolism in patients with multifocal HCC might be related to different sensitivity of treatment in different lesions. CONCLUSION: Perioperative camrelizumab plus apatinib displays a promising efficacy and manageable toxicity in patients with resectable HCC. DCs infiltration might be a predictive marker of response to camrelizumab and apatinib as well as patients' recurrence. ctDNA as a compose biomarker can predict pathological response and relapse. Abnormal glucose metabolism in patients with multifocal HCC may be related to different sensitivity of treatment in different lesions. TRIAL REGISTRATION NUMBER: NCT04297202.

Circulating circRNA predicting the occurrence of hepatocellular carcinoma in patients with HBV infection.

A microarray-based high-throughput screening of human circulating circular RNA (circRNA) was applied with five patients newly diagnosed with hepatocellular carcinoma (HCC), five patients with HBV-positive chronic hepatitis (CH) and five healthy controls (NC) enrolled. The plasma of HCC patients after hepatectomy was also collected. After multiple staged validation, we obtained five circRNAs as candidate. Based on the stratified risk score analysis, three increased circRNAs including circ_0009582, circ_0037120 and circ_0140117 were confirmed as candidate circulating fingerprints for distinguishing HCC from CH or NC group. With the combination of AFP, higher sensitivity and specificity were further guaranteed, suggesting that circ_0009582, circ_0037120 and circ_0140117 may serve as potential biomarkers for predicting the occurrence of HCC in patients with HBV infection.

Stimulatory Effects of Boron Containing Bioactive Glass on Osteogenesis and Angiogenesis of Polycaprolactone: In Vitro Study.

Polycaprolactone (PCL) has attracted great attention for bone regeneration attributed to its cost-efficiency, high toughness, and good processability. However, the relatively low elastic modulus, hydrophobic nature, and insufficient bioactivity of pure PCL limited its wider application for bone regeneration. In the present study, the effects of the addition of boron containing bioactive glass (B-BG) materials on the mechanical properties and biological performance of PCL polymer were investigated with different B-BG contents (0, 10, 20, 30, and 40 wt.%), in order to evaluate the potential applications of B-BG/PCL composites for bone regeneration. The results showed that the B-BG/PCL composites possess better tensile strength, human neutral pH value, and fast degradation as compared to pure PCL polymers. Moreover, the incorporation of B-BG could enhance proliferation, osteogenic differentiation, and angiogenic factor expression for rat bone marrow stromal cells (rBMSCs) as compared to pure PCL polymers. Importantly, the B-BG also promoted the angiogenic differentiation for human umbilical vein endothelial cells (HUVECs). These enhanced effects had a concentration dependence of B-BG content, while 30 wt.% B-BG/PCL composites achieved the greatest stimulatory effect. Therefore the 30 wt.% B-BG/PCL composites have potential applications in bone reconstruction fields.

Transforming growth factor-ß-Expressing Mesenchymal Stem Cells Induce Local Tolerance in a Rat Liver Transplantation Model of Acute Rejection.

Acute rejection is commonly encountered for long-term survival in liver transplant (LT) recipients and may impact their long-term survival if rejection is severe or recurrent. The aim of this study is to examine the therapeutic potential of transforming growth factor (TGF-ß)-overexpressing mesenchymal stem cells (MSCs) in inducing a local immunosuppression in liver grafts after transplantation. MSCs were transduced with a lentiviral vector expressing the human TGF-ß1 gene; TGF-ß1-overexpressing MSCs (designated as TGF/MSCs) were then transfused into the liver grafts via the portal vein of a rat LT model of acute rejection. Rejection severity was assessed by clinical and histologic analysis. The immunity suppression effects and mechanism of TGF/MSCs were tested, focusing on their ability to induce generation of regulatory T cells (Tregs) in the liver grafts. Our findings demonstrate that transfusion of TGF/MSCs prevented rejection, reduced mortality, and improved survival of rats after LT. The therapeutic effects were associated with the immunosuppressive effects of MSCs and TGF-ß1. Their reciprocal effects on Tregs induction and function resulted in more CD4 + Foxp3 + Helios- induced Tregs, fewer Th17 cells, and improved immunosuppressive effects in local liver grafts. Thus, TGF/MSCs can induce a local immunosuppressive effect in liver grafts after transplantation. The immunomodulatory activity of TGF-ß1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation. Stem Cells 2016;34:2681-2692.

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma.

Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC.

The Ser326Cys polymorphism of hOGG1 is associated with intrahepatic cholangiocarcinoma susceptibility in a Chinese population.

OBJECTIVE: Intrahepatic cholangiocarcinoma is a rare disease whose etiology is far from clear, the Ser326Cys polymorphism in human 8-hydroxyguanine glycosylase (hOGG1) has been shown associated with various cancers, however, the association of Ser326Cys (rsl052133) polymorphism and intrahepatic cholangiocarcinoma susceptibility has not been clarified. The purpose of this study is to investigate whether this polymorphism is related to the genetic susceptibility of intrahepatic cholangiocarcinoma. METHODS: A total 150 patients and 150 normal people were included in this study, the Ser326Cys polymorphisms in each group were genotyped using PCR-RFLP method. RESULTS: We found that individuals carrying Cys/Cys genotype were exposed to higher riskof intrahepatic cholangiocarcinoma (OR=2.924, 95% CI=1.475-5.780) compared with the individuals with wild type genotype Ser/Ser. Further analysis revealed that male individuals carrying Cys/Cys genotype also had increased risk (OR=2.762, 95% CI=1.233-6.173), whereas no significant difference was observed in female group. CONCLUSIONS: Therefore, our data indicates that the Ser326Cys (rs1052133) polymorphism is associated with intrahepatic cholangiocarcinoma susceptibility, and it shows preference in male population.

PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis.

BACKGROUND AND AIM: One single-nucleotide polymorphisms (SNPs) rs738409 in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD) across different populations. One meta-analysis confirmed this association, but within it, only two Asian studies were included. This meta-analysis aimed to investigate the association in Asian population. METHODS: All eligible case-control studies were identified by searching through PubMed and Chinese language databases (CNKI and WanFang) up to July 1, 2014. Pooled estimates (odds ratio [OR] and standardized mean difference) were used to assess the strength of associations in fixed or random-effects models. RESULTS: A total of 12 studies with 4495 cases and 7431 controls were included. SNP rs738409 G allele was confirmed as a risk factor for NAFLD (G allele vs C allele: OR = 1.92, 95% confidence interval [95%CI]: 1.54-2.39). In addition, based on studies with certain clinical measurements data, G allele carriers were more likely to have higher level of serum alanine aminotransferase (ALT) (standard mean difference [SMD] = 7.03, 95% CI: 2.47-11.60), and higher fibrosis score (SMD = 0.39, 95% CI: 0.18-0.60). CONCLUSION: This study provided evidence of SNP rs738409 G allele as a strong risk factor of NAFLD susceptibility and higher level of serum ALT in Asian population.

BMP2-loaded hollow hydroxyapatite microspheres exhibit enhanced osteoinduction and osteogenicity in large bone defects.

The regeneration of large bone defects is an osteoinductive, osteoconductive, and osteogenic process that often requires a bone graft for support. Limitations associated with naturally autogenic or allogenic bone grafts have demonstrated the need for synthetic substitutes. The present study investigates the feasibility of using novel hollow hydroxyapatite microspheres as an osteoconductive matrix and a carrier for controlled local delivery of bone morphogenetic protein 2 (BMP2), a potent osteogenic inducer of bone regeneration. Hollow hydroxyapatite microspheres (100±25 µm) with a core (60±18 µm) and a mesoporous shell (180±42 m(2)/g surface area) were prepared by a glass conversion technique and loaded with recombinant human BMP2 (1 µg/mg). There was a gentle burst release of BMP2 from microspheres into the surrounding phosphate-buffered saline in vitro within the initial 48 hours, and continued at a low rate for over 40 days. In comparison with hollow hydroxyapatite microspheres without BMP2 or soluble BMP2 without a carrier, BMP2-loaded hollow hydroxyapatite microspheres had a significantly enhanced capacity to reconstitute radial bone defects in rabbit, as shown by increased serum alkaline phosphatase; quick and complete new bone formation within 12 weeks; and great biomechanical flexural strength. These results indicate that BMP2-loaded hollow hydroxyapatite microspheres could be a potential new option for bone graft substitutes in bone regeneration.

Hollow hydroxyapatite microspheres/chitosan composite as a sustained delivery vehicle for rhBMP-2 in the treatment of bone defects.

Composite scaffold comprised of hollow hydroxyapatite (HA) and chitosan (designated hHA/CS) was prepared as a delivery vehicle for recombinating human bone morphogenetic protein-2 (rhBMP-2). The in vitro and in vivo biological activities of rhBMP2 released from the composite scaffold were then investigated. The rhBMP-2 was firstly loaded into the hollow HA microspheres, and then the rhBMP2-loaded HA microspheres were further incorporated into the chitosan matrix. The chitosan not only served to bind the HA microspheres together and kept them at the implant site, but also effectively modified the release behavior of rhBMP-2. The in vitro release and bioactivity analysis confirmed that the rhBMP2 could be loaded and released from the composite scaffolds in bioactive form. In addition, the composite scaffolds significantly reduced the initial burst release of rhBMP2, and thus providing prolonged period of time (as long as 60 days) compared with CS scaffolds. In vivo bone regenerative potential of the rhBMP2-loaded composite scaffolds was evaluated in a rabbit radius defect model. The results revealed that the rate of new bone formation in the rhBMP2-loaded hHA/CS group was higher than that in both negative control and rhBMP2-loaded CS group. These observations suggest that the hHA/CS composite scaffold would be effective and feasible as a delivery vehicle for growth factors in bone regeneration and repair.

Never in mitosis gene A-related kinase 6 promotes cell proliferation of hepatocellular carcinoma via cyclin B modulation.

Never in mitosis gene A-related kinase (Nek) 6 is a recently identified Nek that is required for mitotic cell cycle progression; however, the role and mechanism of Nek6 activity during hepatocarcinogenesis is not well known. The aim of this study was to investigate the potential roles and internal mechanism of Nek6 in hepatocellular carcinoma (HCC) development. In the present study, Nek6 was found to be overexpressed in HCC samples and cell lines by florescent real-time quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. Furthermore, it was evidenced to contribute to oncogenesis and progression. The ectopic overexpression of Nek6 promoted cell proliferation and colony formation, whereas gene silencing of Nek6 inhibited these phenotypes, as documented in Huh7, PLC/PRF/5, Hep3B and HepG2 HCC cell lines. Mechanistic analyses indicated that Nek6 regulates the transcription of cyclin B through cdc2 activation, and promotes the accumulation of G0/G1-phase cells. In conclusion, the findings of the current study suggested that Nek6 contributes to the oncogenic potential of HCC, and may present as a potential therapeutic target in this disease.

IL-22 is related to development of human colon cancer by activation of STAT3.

BACKGROUND: It has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC). METHODS: The expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model. RESULTS: Our results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22. CONCLUSION: In this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.

Lithium exacerbates hepatic ischemia/reperfusion injury by inhibiting GSK-3ß/NF-κB-mediated protective signaling in mice.

Lithium (an inhibitor of GSK-3ß activity) has beneficial effects on ischemia/reperfusion (I/R) injury in the central nervous system, heart and kidney. However, the role of lithium in hepatic I/R injury is unknown. The aim of this study was to assess the effects of lithium on hepatic I/R injury in a mouse model of partial hepatic I/R. Previous studies showed that lithium chloride (LiCl) can phosphorylate residue Ser9, inhibit GSK-3ß activity, and improve I/R injury in other organs. In the present study, mice were pretreated with either vehicle or LiCl, which had similar effects on GSK-3ß activity. Surprisingly, treatment with LiCl significantly exacerbated hepatic I/R injury, which was determined by serological and histological analyses. Acute and chronic LiCl treatment caused serious damage in hepatic I/R injury, including increased apoptosis and oxidative stress. To gain insight into the mechanism involved in this damage, the activity of nuclear factor-κB (NF-κB) (GSK-3ß can regulate the transcriptional complex of NF-κB) was analyzed, which revealed that LiCl treatment significantly down-regulated the activity of NF-κB. The NF-κB-mediated protective genes were then further evaluated, including anti-apoptotic genes (RAF2, cIAP 2, Bfl-1 and cFLIP) and the antioxidant gene MnSOD. The expression of these protective genes was obviously suppressed compared with the vehicle group. Taken together, these findings show that lithium exacerbates hepatic I/R injury by suppressing the expression of GSK-3ß/NF-κB-mediated protective genes.

SOD mimetic improves the function, growth, and survival of small-size liver grafts after transplantation in rats.

BACKGROUND: Small-for-size syndrome (SFSS) may occur when graft volume is less than 45% of the standard liver volume, and it manifests as retarded growth and failure of the grafts and more mortality. However, its pathogenesis is poorly understood, and few effective interventions have been attempted. AIMS: The present study aimed to delineate the critical role of oxidant stress in SFSS and protective effects of a superoxide dismutase mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), on graft function, growth, and survival in the recipient rats. METHODS: Small size graft liver transplantation (SSGLT) was performed to determine the survival, graft injury, and growth. MnTBAP was administered in SSGLT recipients (SSGLT+MnTBAP). RESULTS: Serum alanine aminotransferase levels were sustained higher in SSGLT recipients, which were correlated with an increased apoptotic cell count and hepatocellular necrosis in liver sections. Malondialdehyde content, gene expression of tumor necrosis factor α and interleukin 1ß, and DNA binding activity of nuclear factor-κB in the grafts were increased significantly in SSGLT recipients compared with sham-operated controls. Both phosphorylated p38 mitogen-activated protein kinase and nuclear c-Jun were increased in SSGLT. All these changes were strikingly reversed by the administration of MnTBAP, with an increase in serum superoxide dismutase activity. Moreover, in situ bromodeoxyuridine incorporation demonstrated that graft regeneration was much more profound in the SSGLT+MnTBAP group than in the SSGLT group. Finally, the survival of recipients with MnTBAP treatments was significantly improved. CONCLUSIONS: Enhanced oxidant stress with activation of the p38/c-Jun/nuclear factor-κB signaling pathway contributes to SFSS-associated graft failure, retarded graft growth, and poor survival. MnTBAP effectively reversed the pathologic changes in SFSS-associated graft failure.

The effect of hepatocyte growth factor on the initiation phase of liver regeneration after cold ischemia in a rat model of small-for-size liver transplantation.

BACKGROUND/AIMS: In this study, adenovirus carrying human HGF gene (Ad-HGF) was administered to investigate whether hepatocyte growth factor (HGF) can restore liver regeneration after prolonged cold ischemia, especially during the initiation phase, in a rat model of small-for-size liver transplantation. METHODOLOGY: A rat model was established using 30% small-for-size liver grafts. Before hand, the grafts were preserved at 4°C for 45min, 2h, 6h and 10h in UW solution. A recombinant adenoviral vector carrying HGF and Ad-HGF or adenovirus encoding enhanced green fluorescent protein (Ad-EGFP) was administered to the 10h group. Survival rates, serum levels of alanine aminotransferase, recovery of the graft weight, hepatic architecture, proliferating cell nuclear antigen (PCNA), cell signaling pathways and several immediate early genes (e.g. jun-B, c-fos) were assessed. RESULTS: Injury to the grafts and extent of inflammation of the small grafts increased due to prolonged cold ischemia, while the number of PCNA- positive hepatocytes decreased and liver regeneration mechanism was affected. These factors resulted in low levels of interleukin (IL)-6, tumor necrosis factor receptor (TNFR)- α , and phosphorylated signal transducer and activator of transcription 3 (p-Stat3) in liver tissue. Ad-HGF administration markedly improved the survival rate, but it did not significantly affect the other parameters. CONCLUSIONS: Prolonged cold ischemia significantly impaired the regenerative ability of small grafts. Ad-HGF promoted liver regeneration but had no observable effect on the initiation phase of liver regeneration.

Preparation and characterization of temperature-responsive magnetic composite particles for multi-modal cancer therapy.

The temperature-responsive magnetic composite particles were synthesized by emulsion-free polymerization of N-isopropylacrylamide (NIPAAm) and acrylamide (Am) in the presence of oleic acid-modified Fe(3)O(4) nanoparticles. The magnetic properties and heat generation ability of the composite particles were characterized. Furthermore, temperature and alternating magnetic field (AMF) triggered drug release behaviors of vitamin B(12)-loaded composite particles were also examined. It was found that composite particles enabled drug release to be controlled through temperature changes in the neighborhood of lower critical solution temperature. Continuous application of AMF resulted in an accelerated release of the loaded drug. On the other hand, intermittent AMF application to the composite particles resulted in an "on-off", stepwise release pattern. Longer release duration and larger overall release could be achieved by intermittent application of AMF as compared to continuous magnetic field. Such composite particles may be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release.

Precise adsorption behavior and mechanism of Ni(II) ions on nano-hydroxyapatite.

The goal of this study was to synthesize use of hydroxyapatite as a high-efficiency adsorbent for Ni(II) ions, and to study its adsorption behavior. Three tests--Fourier-transform infrared spectroscopy, transmission electron microscopy, and Brunauer-Emmett-Teller were carried out to determine the chemical functionality of the hydroxyapatite powders, to observe its crystal morphology, and to measure the specific surface area. Results indicate that proves the n-HA synthesized by chemical precipitation is an effective adsorbent for the removal of Ni(II) ions from water solution. The synthesized, needle-like nano-hydroxyapatite (n-HA) have a uniform average size of 31.9 X 21.3nm, a large specific surface area (135 m2/g), and typically is a weak crystal with a broad pore distribution. The adsorption isotherm shows the Langmuir model is applicable only when the initial Ni2+ concentration is lower than 0.1 mol/L. Multilayer adsorption was attributed to uneven pore distribution that occurred at higher Ni2+ concentration. The adsorption of Ni2+ onto n-HA was attributed to electrostatic attraction, ion exchange, and dissolution-precipitation reaction. As the result, Ni2+ substitutes Ca2+ and binds with the oxygen atom on the surface, which resulted from the change in crystal-phase composition and in the binding energy of surface elements of n-HA before and after adsorption.