The antitumor effects of herbal medicine Triphala on oral cancer by inactivating PI3K/Akt signaling pathway: based on the network pharmacology, molecular docking, in vitro and in vivo experimental validation.

BACKGROUND: This research aimed to investigate the anti-tumor effects and underlying genetic mechanisms of herbal medicine Triphala (TRP) in oral squamous cell carcinoma (OSCC). METHODS: The target genes of Triphala (TRP) in oral squamous cell carcinoma (OSCC) were identified, and subsequent functional enrichment analysis was conducted to determine the enriched signaling pathways. Based on these genes, a protein-protein interaction network was constructed to identify the top 10 genes with the highest degree. Genes deregulated in OSCC tumor samples were identified to be hub genes among the top 10 genes. In vitro experiments were performed to investigate the influence of TRP extracts on the cell metabolic activity, migration, invasion, apoptosis, and proliferation of two OSCC cell lines (CAL-27 and SCC-9). The functional rescue assay was conducted to investigate the effect of applying the inhibitor and activator of an enriched pathway on the phenotypes of cancer cells. In addition, the zebrafish xenograft tumor model was established to investigate the influence of TRP extracts on tumor growth and metastasis in vivo. RESULTS: The target genes of TRP in OSCC were prominently enriched in the PI3K-Akt signaling pathway, with the identification of five hub genes (JUN, EGFR, ESR1, RELA, and AKT1). TRP extracts significantly inhibited cell metabolic activity, migration, invasion, and proliferation and promoted cell apoptosis in OSCC cells. Notably, the application of TRP extracts exhibited the capacity to downregulate mRNA and phosphorylated protein levels of AKT1 and ESR1, while concomitantly inducing upregulation of mRNA and phosphorylated protein levels in the remaining three hub genes (EGFR, JUN, and RELA). The functional rescue assay demonstrated that the co-administration of TRP and the PI3K activator 740Y-P effectively reversed the impact of TRP on the phenotypes of OSCC cells. Conversely, the combination of TRP and the PI3K inhibitor LY294002 further enhanced the effect of TRP on the phenotypes of OSCC cells. Remarkably, treatment with TRP in zebrafish xenograft models demonstrated a significant reduction in both tumor growth and metastatic spread. CONCLUSIONS: Triphala exerted significant inhibitory effects on cell metabolic activity, migration, invasion, and proliferation in OSCC cell lines, accompanied by the induction of apoptosis, which was mediated through the inactivation of the PI3K/Akt pathway.

Controllable Adaptive Molybdate-Oligosaccharide Nanoparticles Regulate M2 Macrophage Mitochondrial Function and Promote Angiogenesis via PI3K/HIF-1α/VEGF Pathway to Accelerate Diabetic Wound Healing.

The complex wound environment of diabetic wounds leads to poor treatment efficacy, and the inflammatory disorders and vascular injury are the primary causes of death in such patients. Herein, a sprayable, controllable adaptive, pH-responsive nanosystem of molybdate and oligosaccharide (CMO) is specially developed as an immunomodulatory and angiogenesis-promotion material for diabetic wound healing. CMO exhibited pH-responsive release of Mo2+ and oligosaccharide (COS), specifically in response to the alkalescent environment observed in diabetic wounds. CMO provide an anti-inflammatory environment by promoting M2 polarization through significantly stimulating macrophage mitochondrial function. Specifically, CMO with a certain concentration reduce reactive oxygen species (ROS) and tumor necrosis factor α (TNF-α) expression, and upregulated mitochondrial membrane potential (MMP), superoxide dismutase (SOD), and interleukin 10 (IL-10) expression in macrophages. Moreover, CMO facilitate angiogenesis via upregulating the PI3K/HIF-1α/VEGF pathway-a critical process for the formation of new blood vessels that supply nutrients and oxygen to the healing tissue. Remarkably, CMO promote cell viability and migration of endothelial cells, and enhance the expression of angiogenic genes. In vitro and in vivo studies suggest this simple but powerful nanosystem targeting mitochondrial function has the potential to become an effective treatment for diabetic wound healing.

SERPINB5 is a novel serum diagnostic biomarker for gastric high-grade intraepithelial neoplasia and plays a role in regulation of macrophage phenotypes.

BACKGROUND: Gastric cancer (GC) develops from gastric precancerous lesions (GPL), and early diagnosis and treatment at the premalignant stage may achieve a higher benefit‒cost ratio with a reduced necessity for surgery. However, reliable noninvasive screening biomarkers of GPL are currently lacking. METHODS: The marker genes of GPL encoding extracellular proteins were identified by bioinformatics analysis and further verified by immunofluorescence and immunohistochemistry assays. Serum samples were collected to measure the levels of SERPINB5, the diagnostic efficacy of which was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). Finally, the effect of SERPINB5 on the phenotypic conversion of macrophages was verified by public data and in vitro experiments. RESULTS: SERPINB5 was identified as an extracellular biomarker of GPL that had good diagnostic efficacy. High expression of SERPINB5 was observed in the epithelial cells and adjacent extracellular matrix on sections of gastric high-grade intraepithelial neoplasia (HGIN). Importantly, SERPINB5 determined in serum was significantly increased in the HGIN group, and the AUC for discriminating between HGIN and chronic gastritis or low-grade intraepithelial neoplasia was 0.9936 and 0.9750, respectively. Moreover, SERPINB5 expression was positively correlated with macrophage infiltration, and M1 marker NOS2 expression, but negatively correlated with M2 marker CSF1R expression. In THP-1-derived macrophages, SERPINB5 upregulated expression of M1-related cytokines TNF-α and IL-12, and M1 marker CD86, but suppressed production of M2-related cytokines TGF-ß and IL-10. CONCLUSIONS: Our study provides evidence that SERPINB5 may serve as a promising noninvasive serum biomarker for gastric HGIN screening and regulate macrophage phenotype conversion.

Synergistic effect of Mn-Si-COS on wound immune microenvironment by inhibiting excessive skin fibrosis mediated with ROS/TGF-ß1/Smad7 signal.

Excessive oxidative stress and inflammation often impede wound healing and ultimately lead to excessive skin fibrosis formation. It was known that the structural properties of biomaterials can affect the healing and immune response of surrounding tissues. In this work, a composite structure of Mn-Si-chitooligosaccharides (COS) was designed (COS@Mn-MSN) and the ability of regulating wound microenvironment for inhibiting skin fibrosis was investigated. In order to reduce the negative effects of Mn, the nano-level Mn was doped into MSN to minimize its content. The results show that Mn in COS@Mn-MSN showed significant ability of scavenging excess intracellular ROS within 1 d. The Si released from COS@Mn-MSN can shift M2 macrophage polarization in the later stage (1-3 d), showing anti-inflammatory effect. Macrophage (RAW264.7) were activated alternatively by COS released from COS@Mn-MSN, with upregulated expression of anti-inflammatory factors (IL-10 and CD206) and downregulated expression of pro-inflammatory factors (TNF-α, CD80, and IL-1ß) in the whole time. The expression of fibrosis associated factor TGF-ß1 and CD26 in fibroblast cells (L929) were inhibited by COS and Si. Besides, the inflammatory microenvironment mediated by COS@Mn-MSN downregulated Smad-7 gene expression and upregulated Col-1α gene expression. With the function of reducing oxidative stress (0-1 d), the TGF-ß1 inhibition (1-3 d) and anti-inflammatory effects (0-3 d), COS@Mn-MSN could inhibit excessive skin fibrosis formation mediated with ROS/TGF-ß1/Smad7 signal. Therefore, the prepared COS@Mn-MSN shows great potential to active scarless wound therapy.

Studying trabecular bone samples demonstrates a power law relation between deteriorated structure and mechanical properties - a study combining 3D printing with the finite element method.

Introduction: The bone volume fraction (BV/TV) significantly contributes to the mechanical properties of trabecular bone. However, when studies compare normal trabeculae against osteoporotic trabeculae (in terms of BV/TV decrease), only an "average" mechanical result has been determined because of the limitation that no two trabecular structures are the same and that each unique trabecular structure can be mechanically tested only once. The mathematic relation between individual structural deterioration and mechanical properties during aging or the osteoporosis process has yet to be further clarified. Three-dimensional (3D) printing and micro-CT-based finite element method (µFEM) can assist in overcoming this issue. Methods: In this study, we 3D printed structural-identical but BV/TV value-attenuated trabecular bones (scaled up ×20) from the distal femur of healthy and ovariectomized rats and performed compression mechanical tests. Corresponding µFEM models were also established for simulations. The tissue modulus and strength of 3D printed trabecular bones as well as the effective tissue modulus (denoted as Ez) derived from µFEM models were finally corrected by the side-artifact correction factor. Results: The results showed that the tissue modulus corrected, strength corrected and Ez corrected exhibited a significant power law function of BV/TV in structural-identical but BV/TV value-attenuated trabecular samples. Discussion: Using 3D printed bones, this study confirms the long-known relationship measured in trabecular tissue with varying volume fractions. In the future, 3D printing may help us attain better bone strength evaluations and even personal fracture risk assessments for patients who suffer from osteoporosis.

Microleakage, microgap, and shear bond strength of an infiltrant for pit and fissure sealing.

Objectives: This study aimed to evaluate the potential clinical application of an infiltrant with different etchants as pit and fissure sealants and to compare them with a conventional resin-based sealant. Materials and methods: Seventy-five molars were randomly divided into three groups (n = 25): phosphoric acid etchant + conventional resin-based sealant (Group A); 15% hydrochloric acid etchant + infiltrant (Group B); phosphoric acid etchant + infiltrant (Group C). Fifteen teeth in each group were subjected to pit and fissure sealing procedures. After 500 thermocycling and methylene blue dye penetration, ten specimens were sectioned and the pencentages of dye penetration were measured under a stereomicroscope. Another five teeth in each group were sectioned and the microgaps between materials and enamel surface were measured using electron microscope scanning. Ten teeth in each group were used to measure shear bond strength and the failure mode was analyzed. Results: The results showed that infiltrant exhibited significantly less microleakage and microgap than resin-based sealant, no matter which echant was used. Although there was no significant difference betweern the three groups, infiltrant applied with 15% hydrochloric acid etching showed higher shear bond strength than resin-based sealant etching with 35% phosphoric acid. Conclusions: The infiltrant has significant advantages in reducing the degree of microleakage and microgap. Moreover, the infiltrant could achieve the same bonding strength as conventional resin-based sealant. Although, manufacturers do not currently recommend the infiltrant for fissure sealing, the potential clinical application would be an off-label use.Clinical relevance This report provides a theoretical basis for the potential clinical application of the infiltrant as a pit and fissure sealant, and provides a new perspective for selecting pit and fissure sealants.

Combined computational analysis and cytology show limited depth osteogenic effect on bone defects in negative pressure wound therapy.

Background: The treatment of bone defects remains a clinical challenge. The effect of negative pressure wound therapy (NPWT) on osteogenesis in bone defects has been recognized; however, bone marrow fluid dynamics under negative pressure (NP) remain unknown. In this study, we aimed to examine the marrow fluid mechanics within trabeculae by computational fluid dynamics (CFD), and to verify osteogenic gene expression, osteogenic differentiation to investigate the osteogenic depth under NP. Methods: The human femoral head is scanned using micro-CT to segment the volume of interest (VOI) trabeculae. The VOI trabeculae CFD model simulating the bone marrow cavity is developed by combining the Hypermesh and ANSYS software. The effect of trabecular anisotropy is investigated, and bone regeneration effects are simulated under NP scales of -80, -120, -160, and -200 mmHg. The working distance (WD) is proposed to describe the suction depth of the NP. Finally, gene sequence analysis, cytological experiments including bone mesenchymal stem cells (BMSCs) proliferation and osteogenic differentiation are conducted after the BMSCs are cultured under the same NP scale. Results: The pressure, shear stress on trabeculae, and marrow fluid velocity decrease exponentially with an increase in WD. The hydromechanics of fluid at any WD inside the marrow cavity can be theoretically quantified. The NP scale significantly affects the fluid properties, especially those fluid close to the NP source; however, the effect of the NP scale become marginal as WD deepens. Anisotropy of trabecular structure coupled with the anisotropic hydrodynamic behavior of bone marrow; An NP of -120 mmHg demonstrates the majority of bone formation-related genes, as well as the most effective proliferation and osteogenic differentiation of BMSCs compared to the other NP scales. Conclusion: An NP of -120 mmHg may have the optimal activated ability to promote osteogenesis, but the effective WD may be limited to a certain depth. These findings help improve the understanding of fluid mechanisms behind NPWT in treating bone defects.

In vitro and in vivo antimicrobial activity of antimicrobial peptide Jelleine-I against foodborne pathogen Listeria monocytogenes.

As a human foodborne pathogen, Listeria monocytogenes can cause severe human listeriosis and develop resistance to antibiotics. Antimicrobial peptides (AMPs) are produced from all kingdoms of life and regarded as promising alternatives to conventional antibiotics. Jelleine-I is an AMP identified from honeybees royal jelly. In this study, we explored the activity and action mechanism of Jelleine-I against L. monocytogenes. We found its minimum inhibitory concentration to be 12.5 µg/mL. Membrane permeability analysis revealed that Jelleine-I increased L. monocytogenes cell membrane permeability, causing calcium leakage. Scanning, transmission electron microscopy and fluorescence microscopy revealed that Jelleine-I destroyed membrane integrity, disrupted intracellular structures and interacted with the bacterial DNA. DNA binding analysis demonstrated that Jelleine-I bound to bacterial genomic DNA. Results of reverse transcription-quantitative PCR revealed that Jelleine-I affected bacterial DNA replication gene expression levels. Moreover, Jelleine-I induced cellular reactive oxygen species (ROS) production from fluorescence intensity analysis, and inhibited bacterial biofilm formation. Results of immunomodulation in Galleria mellonella revealed that Jelleine-I increased host hemocyte counts, upregulated host AMP gene (Gloverin and Cecropin D) expression, and inhibited proinfammatory cytokine (tumor necrosis factor α and interleukin 6) production induced by bacterial infection. It efficiently killed bacteria and increased the survival rate of infected insects to 70 %. Furthermore, Jelleine-I increased the G1 to S phase transition in mammalian cells from cells cycle analysis, and cytotoxicity assay results indicated that it promoted cell proliferation without hemolysis or cytotoxicity. Collectively, Jelleine-I possesses antimicrobial, immunomodulatory and cell proliferative activities, and is a promising candidate for preventing L. monocytogenes emergence and dissemination.

3D printed trabeculae conditionally reproduce the mechanical properties of the actual trabeculae - A preliminary study.

Three-dimensional (3D) printing has been used to fabricate synthetic trabeculae models and to test mechanical behavior that cannot be recognized in the actual sample, but the extent to which 3D printed trabeculae replicate the mechanical behavior of the actual trabeculae remains to be quantified. The aim of this study was to evaluate the accuracy of 3D printed trabeculae in reproducing the mechanical properties of the corresponding actual trabeculae. Twelve human trabecular cubes (5 × 5 × 5 mm) were scanned by micro-CT to form the trabecular 3D model. Each trabecular 3D model was scaled ×2-, ×3-, ×4- and ×5-fold and then printed twice at a layer thickness of 60 µm using poly (lactic acid) (PLA). The actual trabecular cubes and the 3D-printed trabecular cubes were first compressed under a loading rate of 1 mm/min; another replicated stack of 3D-printed trabecular cubes was compressed under a strain rate of 0.2/min. The results showed that the stiffness of the printed cubes tended to increase, while the strength tended to converge when the magnification increased under the two loading conditions. The strain rate effect was found in the printed cubes. The correlation coefficient (R2) of the mechanical properties between the printed and actual trabeculae can reach up to 0.94, especially under ×3-, ×4- and ×5-fold magnification. In conclusion, 3D printing could be a potential tool to evaluate the mechanical behavior of actual trabecular tissue in vitro and may help in the future to predict the risk of fracture and even personalize the treatment evaluation for osteoporosis and other trabecular bone pathologies.

Identifying crosstalk genetic biomarkers linking a neurodegenerative disease, Parkinson's disease, and periodontitis using integrated bioinformatics analyses.

Objective: To identify the genetic linkage mechanisms underlying Parkinson's disease (PD) and periodontitis, and explore the role of immunology in the crosstalk between both these diseases. Methods: The gene expression omnibus (GEO) datasets associated with whole blood tissue of PD patients and gingival tissue of periodontitis patients were obtained. Then, differential expression analysis was performed to identify the differentially expressed genes (DEGs) deregulated in both diseases, which were defined as crosstalk genes. Inflammatory response-related genes (IRRGs) were downloaded from the MSigDB database and used for dividing case samples of both diseases into different clusters using k-means cluster analysis. Feature selection was performed using the LASSO model. Thus, the hub crosstalk genes were identified. Next, the crosstalk IRRGs were selected and Pearson correlation coefficient analysis was applied to investigate the correlation between hub crosstalk genes and hub IRRGs. Additionally, immune infiltration analysis was performed to examine the enrichment of immune cells in both diseases. The correlation between hub crosstalk genes and highly enriched immune cells was also investigated. Results: Overall, 37 crosstalk genes were found to be overlapping between the PD-associated DEGs and periodontitis-associated DEGs. Using clustering analysis, the most optimal clustering effects were obtained for periodontitis and PD when k = 2 and k = 3, respectively. Using the LASSO feature selection, five hub crosstalk genes, namely, FMNL1, MANSC1, PLAUR, RNASE6, and TCIRG1, were identified. In periodontitis, MANSC1 was negatively correlated and the other four hub crosstalk genes (FMNL1, PLAUR, RNASE6, and TCIRG1) were positively correlated with five hub IRRGs, namely, AQP9, C5AR1, CD14, CSF3R, and PLAUR. In PD, all five hub crosstalk genes were positively correlated with all five hub IRRGs. Additionally, RNASE6 was highly correlated with myeloid-derived suppressor cells (MDSCs) in periodontitis, and MANSC1 was highly correlated with plasmacytoid dendritic cells in PD. Conclusion: Five genes (i.e., FMNL1, MANSC1, PLAUR, RNASE6, and TCIRG1) were identified as crosstalk biomarkers linking PD and periodontitis. The significant correlation between these crosstalk genes and immune cells strongly suggests the involvement of immunology in linking both diseases.

Freeze-drying platforms design for batch fabrication of Haversian system mimicking scaffolds with enhanced osteogenesis.

The Haversian system is one of the most important pathways to repair bone defects, and it is the basic guarantee for the repair of bone defects, which means that the formation of the Haversian system indicates repairing of the defects. The integration of structure and function for tissue engineering scaffolds is of great importance in mimicking native bone tissue. However, in contrast to the increasing demands, how to rapidly prepare various sizes of such Haversian system mimicking scaffolds in batch becomes a major challenge. In this study, we designed three types of platforms with different sizes in combination with the freeze-drying approach. Chitosan/type I collagen composite materials were used to study the structure, morphology, and performance of the production, and the effects of the controlled architecture on osteogenesis. Results showed that the physicochemical effects of the mass fabricated scaffolds of various sizes met the requirements of bone repair materials. In addition, the scaffolds had good cytocompatibility and excellent in vivo bone repair performance, which have potential clinical applications.

High-Efficiency Near-Infrared Light Responsive Antibacterial System for Synergistic Ablation of Bacteria and Biofilm.

Bacterial infection is seriously threatening human health, and the design of high-efficiency and good biocompatibility antibacterial agents is an urgent problem to be solved. However, with the emergence of drug-resistant bacteria, the existing antibacterial agents have low killing efficiency, and the formation of biofilms has further weakened the therapeutic effect. Herein, we constructed an efficient antibacterial system mediated by near-infrared light for synergistic antibacterial and biofilm dissipation. Specifically, the ZnO/Ti3C2Tx with heterojunction was synthesized by hydrothermal growth of ZnO on the surface of lamellar Ti3C2Tx-MXene. The prepared ZnO/Ti3C2Tx had better photothermal ability than ZnO and Ti3C2Tx, respectively. The local thermal effect can not only destroy the integrity of the bacterial membrane but also promote the release of Zn2+ ions and further improve the antibacterial performance. ZnO/Ti3C2Tx achieved a 100% sterilization rate (better than either ZnO or Ti3C2Tx) at 150 µg mL-1. The biofilm dissipation experiment further proved its excellent biofilm ablation effect. More importantly, the results of in vitro cell culture and animal experiments have demonstrated its good biological safety. In summary, this new type of nanomaterial shows strong local chemical photothermal sterilization ability and has great potential to replace traditional antibacterial agents.

Blood compatibility evaluations of two-dimensional Ti3C2Txnanosheets.

Two-dimensional nanomaterial Ti3C2Txis a novel biomaterial used for medical apparatus. For its application, biosafety serves as a prerequisite for their usein vivo. So far, no research has systematically reported how Ti3C2Txinteracts with various components in the blood. In this work, we evaluated the hemocompatibility of Ti3C2Txnanosheets which we prepared by HF etching. Effects of the concentration and size of Ti3C2Txon the morphology and hemolysis rate of human red blood cells (RBCs), the structure and conformation of plasma proteins, the complement activation, as well asin vitroblood coagulation were studied. In general, Ti3C2Txtakes on good blood compatibility, but in the case of high concentration (>30 µg ml-1) and 'small size' (about 100 nm), it led to the rupture of RBCs membrane and a higher rate of hemolysis. Meanwhile, platelets and complement were inclined to be activated with the increased concentration, accompanying the changed configuration of plasma proteins dependent on concentration. Surprisingly, the presence of Ti3C2Txdid not significantly disrupt the coagulation.In vitrocell culture, the results prove that when the Ti3C2Txconcentration is as high as 60 µg ml-1and still has good biological safety. By establishing a fuzzy mathematical model, it was proved that the hemocompatibility of Ti3C2Txis more concentration-dependent than size-dependent, and the hemolysis rate is the most sensitive to the size and concentration of the Ti3C2Tx. These findings provide insight into the potential use of Ti3C2Txas biofriendly nanocontainers for biomaterialsin vivo.

Construction of biological factor-coated stent and its effect on promoting endothelialization.

Recently, just taking endothelialization of stent as an interventional treatment of aneurysms is unsatisfactory. This treatment also has impacts the occlusion rate of the aneurysm. In accordance with that, the authors aims to construct a novel biological factor-coated stent with dual biological effects of anticoagulation and endothelialization for the improvement of the occlusion rate of aneurysms and reduction of the risk for treatment of aneurysm with intravascular interventional therapy. The Ni-Ti alloy sheets loaded with VEGF and anti-CD34 antibody were put into use for stimulating the construction of the biological factor-coated stents, for the Ni-Ti alloy sheets could help improve the proliferation of endothelial cell (EC), recognize effectively and adhere to endothelial progenitor cell (EPC). Blood compatibility characterization methods (water contact angle, platelet activation test, clotting time evaluation and protein adsorption test) were applied for study the influence of the interaction between the Ni-Ti alloy sheets and blood. Cell experiments (HUVEC proliferation experiment, migration experiment and EPC capture experiment) were resorted to investigate the ability of the sheets to promote the proliferation of HUVEC and to capture EPCs. With the mature of the construction technology, the Enterprise stent with the biological factors were optimized accordingly, the biological function of that were verified by cell experiments. Studies showed that Ni-Ti alloy sheets and enterprise stents can successfully load with VEGF and anti-CD34 antibody. The below achievements can be realized including a better blood compatibility and effects of the constructed sheets and enterprise stents on promoting HUVEC proliferation and adhesion of EPC. It was meaningful of conversion to clinical application to improve the cure rate of the aneurysm and the safety of the intravascular treatment.

Impacts of chitosan oligosaccharide (COS) on angiogenic activities.

It has been proved that chitosan oligosaccharide (COS) has a more favorable therapeutic applications such as wound healing and anti-tumor treatment, and can affect angiogenesis. For better understanding the effect of COS on angiogenic activities at cellular level, COS with different concentration and degree of polymerization (DP) were used to culture human umbilical vein endothelial cells (HUVECs) in this work. Cell proliferation activity, cell morphology, cell migration and angiogenesis associated factor expression of HUVECs were evaluated. The results indicated that COS at a high concentration of 400 µg/mL (COS(400)) and DP of 6 (Chitinhexaose Hydrochloride, COS6) had inhibitory effect on angiogenic activities of HUVECs. Specifically, COS(400) and COS6 inhibited cell proliferation activity, cell migration, and vascular endothelial cell growth factor (VEGF) expression of HUVECs. While COS at a low concentration (<400 µg/mL) and suitable polymerization degrees (DP < 6) had little significant effect on cell proliferation, migration, and VEGF expression of HUVECs, showing dose-dependent effect. These findings provided insight for the potential use of COS, for broadening its future applications in biomedical fields and functional materials area. It also helped guide the design and synthesis of chitosan-based materials as an angiogenesis inhibitor for anti-angiogenic therapy.

Macrophage Polarization Mediated by Chitooligosaccharide (COS) and Associated Osteogenic and Angiogenic Activities.

The host response to implanted biomaterials can influence the functionality of the materials and modulate the tissue repair and remolding. Macrophages, key cells in the host response to biomaterials, can be polarized into different phenotypes, which are important in regenerative medicine. The objective of this study was to evaluate the effect of chitooligosaccharide (COS) on the modulation of macrophage (RAW 264.7) polarization and the associated osteogenic and angiogenic activities. The results demonstrate that COS can shift the macrophage response to an alternatively activated reparative response, which can then upregulate the expression of anti-inflammatory cytokines. COS can also create an immune-modulated microenvironment, with osteogenesis- and angiogenesis-related proteins and a biological process that further influences the osteogenic/angiogenic differentiation and promotion of bone mesenchymal stem cells (BMSCs) and vascular activation of human umbilical vein endothelial cells (HUVECs). In this work, at a low concentration of 4 µg/mL [COS(4)] and suitable polymerization degree of 5 (chitopentaose hydrochloride, COS5) of COS, the associated effect on an alternatively activated reparative response and upregulation of anti-inflammatory cytokine expression was better than that of COS at other concentrations or polymerization degrees. The supernatant from a culture of RAW 264.7 stimulated by COS(4) and COS5 [conditioned medium S-COS(4) and S-COS5] contained more osteogenesis- and angiogenesis-related proteins like DKK-1, OPN, osteoactivin, vascular endothelial growth factor (VEGF) R1, epidermal growth factor (EGF), and insulin-like growth factor binding protein-5 (IGFBP-5) for regulation of osteogenesis/angiogenesis. Specifically, the alkaline phosphatase (ALP) activity and typical osteogenesis-related proteins of BMSCs were significantly influenced by the conditioned media of COS-stimulated macrophages [S-COS(4) and S-COS5]. Furthermore, the conditioned media affected HUVEC proliferation and migration for vascularization. Our results suggest that COS at a low concentration and suitable polymerization degrees has a beneficial effect on immunity modulation (an alternatively activated reparative response) and can modulate osteogenesis/angiogenesis processes for tissue regeneration without using any inductive agent.

Fabrication of regular macro-mesoporous reduced graphene aerogel beads with ultra-high mechanical property for efficient bilirubin adsorption.

Three-dimensional graphene materials have been widely studied in many fields for their role as potential absorbent, especially for bilirubin adsorption. In this study, we developed a simple method to prepare reduced graphene aerogel beads as hemoperfusion materials for fast bilirubin adsorption. The graphene oxide (GO) aerogel beads were produced by self-assembly of GO nanosheet that cross-linked by Ca2+ previously in a coagulation bath, then it was reduced by ascorbic acid and lyophilized to yield the reduced graphene aerogel beads. The beads had a regular macroscopic spherical structure with a diameter of about 1.3-2 mm, where the macroporosity was about 10 µm and the mesoporosity was about 12 nm. The macro-mesoporous structure also gave the reduced graphene aerogel beads ultra-high mechanical strengths and high specific surface area, which were both important for hemoperfusion materials. Moreover, the fixed-bed column adsorption revealed that the reduced graphene aerogel beads manifested excellent bilirubin adsorption (649.512 mg/g) with a rapid adsorption equilibrium time (1.5 h) under the optimized conditions. Even in the bilirubin-enriched blood, the adsorption capacity of the beads could reach 367.14 mg/g. Furthermore, the aerogel beads had a low hemolysis ratio and improved anticoagulant property showing good blood compatibility. Hence, the spherical reduced graphene aerogel beads with millimeter-level size presented a good potential for clinical applications in hemoperfusion therapy.

Construction of blood compatible chitin/graphene oxide composite aerogel beads for the adsorption of bilirubin.

Excess bilirubin in blood can provoke hepatic damage and related malfunctions. Hereby we designed and constructed a novel bilirubin adsorbent, called chitin/graphene oxide (Ch/GO) composite aerogel beads, for efficient, fast and safe removal for bilirubin. The Ch/GO aerogel beads were prepared from chitin and GO in a NaOH/urea aqueous solution, followed dried by supercritical carbon dioxide. The morphology, structure and properties of the Ch/GO composite aerogel beads were characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and compressive strength measurement. The results indicated that GO was successfully bound to chitin matrix with enhanced surface area, thermal stability and mechanical strength. The adsorption capacity of Ch/GO composite aerogel beads for bilirubin was examined by UV-vis spectrophotometry. Moreover, batch adsorption results revealed that the Ch/GO composite aerogel beads showed excellent bilirubin adsorption capacity (484.1 ± 16.9 mg/g) and short adsorption equilibrium time (0.5 h) under optimized condition. Furthermore, the Ch/GO aerogel beads exhibited a lower hemolysis property and improved anticoagulant property. Hence, this work provided a new strategy to develop a novel blood compatible bilirubin adsorbent, which presented good application potential for bilirubin adsorption.

[Feasibility of multi models targeting home pain alleviation service used on 220 cases with advanced cancer].

OBJECTIVE: To investigate the feasibility and effectiveness of multiple modes on home pain alleviation service used for advanced cancer patients to in prove clinical therapy services. METHODS: The study was involved with 220 patients with advanced cancers to provide them with multimodal analgesia services at home, from February 2010 to February 2013. Patients in this study had been taking both opioid treatments. They were randomly divided into two groups with the number as 112 and 108 and were given different doses of morphine or other drugs. During the period of observation, data was collected under the M. D. Anderson symptom Inventory (MDASI) score and classification of score on pain. RESULTS: Differences of pain scores in the two groups and the MDASI score were significant and presented as skewed distribution. Scores on pain score were between groups were significantly different (Z = -9.735, P < 0.001). The average rankings of A group and B group were 76.68 and 162.79 respectively. Under the application of 0.4 mg alprazolam, the degree of pain alleviation seemed to be better. The differences on comprehensive scores between different drug groups were statistically significant (Z = -13.334, P < 0.001). The average rankings of groups A and B were respectively 59.87 and 179.08. Under the use of 0.4 mg of alprazolam, the results could be considered to show better improvements in symptomatic patients. Application of 0.4 mg alprazolam on patients with advanced-cancer-induced-pain showed a better symptomatic improvement than using morphine. CONCLUSION: Patients with advanced cancers receiving multimodal analgesia short-term sedation therapies at home, showed both ideal feasibility and good effectiveness. When morphine was combined used with midazolam at home, a better outcome could be seen in pain-releasing on patients with cancer, than single morphine analgesia was used.