Dongwoo Khang

Biomimetic component coating on 3D scaffolds using high bioactivity of mesoporous bioactive ceramics

Background Mesoporous bioactive glasses (MBGs) are very attractive materials for use in bone tissue regeneration because of their extraordinarily high bone-forming bioactivity in vitro. That is, MBGs may induce the rapid formation of hydroxy apatite (HA) in simulated body fluid (SBF), which is a major inorganic component of bone extracellular matrix (ECM) and comes with both good osteoconductivity and high affinity to adsorb proteins. Meanwhile, the high bioactivity of MBGs may lead to an abrupt initial local pH variation during the initial Ca ion-leaching from MBGs at the initial transplant stage, which may induce unexpected negative effects on using them in in vivo application. In this study we suggest a new way of using MBGs in bone tissue regeneration that can improve the strength and make up for the weakness of MBGs. We applied the outstanding bone-forming bioactivity of MBG to coat the main ECM components HA and collagen on the MBG-polycarplolactone (PCL) composite scaffolds for improving their function as bone scaffolds in tissue regeneration. This precoating process can also expect to reduce initial local pH variation of MBGs. Methods and materials The MBG-PCL scaffolds were immersed in the mixed solution of the collagen and SBF at 37°C for 24 hours. The coating of ECM components on the MBG-PCL scaffolds and the effect of ECM coating on in vitro cell behaviors were confirmed. Results The ECM components were fully coated on MBG-PCL scaffolds after immersing in SBF containing dilute collagen-I solution only for 24 hours due to the high bone-forming bioactivity of MBG. Both cell affinity and osteoconductivity of MBG-PCL scaffolds were dramatically enhanced by this precoating process. Conclusion The precoating process of ECM components on MBG-PCL scaffold using a high bioactivity of MBG was not only effective in enhancing the functionality of scaffolds but also effective in eliminating the unexpected side effect. The MBG-PCL scaffold-coated ECM components ideally satisfied the required conditions of scaffold in tissue engineering, including 3D well-interconnected pore structures with high porosity, good bioactivity, enhanced cell affinity, biocompatibility, osteoconductivity, and sufficient mechanical properties, and promise excellent potential application in the field of biomaterials.

Tyrosol Suppresses Allergic Inflammation by Inhibiting the Activation of Phosphoinositide 3-Kinase in Mast Cells

Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenyl)ethanol) is a polyphenolic compound with diverse biological activities. In this study, we investigated whether tyrosol has anti-allergic inflammatory effects. Ovalbumin-induced active systemic anaphylaxis and immunoglobulin E-mediated passive cutaneous anaphylaxis models were used for the immediate-type allergic responses. Oral administration of tyrosol reduced the allergic symptoms of hypothermia and pigmentation in both animal models. Mast cells that secrete allergic mediators are key regulators on allergic inflammation. Tyrosol dose-dependently decreased mast cell degranulation and expression of inflammatory cytokines. Intracellular calcium levels and activation of inhibitor of κB kinase (IKK) regulate cytokine expression and degranulation. Tyrosol blocked calcium influx and phosphorylation of the IKK complex. To define the molecular target for tyrosol, various signaling proteins involved in mast cell activation such as Lyn, Syk, phosphoinositide 3-kinase (PI3K), and Akt were examined. Our results showed that PI3K could be a molecular target for tyrosol in mast cells. Taken together, these findings indicated that tyrosol has anti-allergic inflammatory effects by inhibiting the degranulation of mast cells and expression of inflammatory cytokines; these effects are mediated via PI3K. Therefore, we expect tyrosol become a potential therapeutic candidate for allergic inflammatory disorders.

Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines.

Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency

Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs). This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor-targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy.

Association between perfluorooctanoic acid exposure and degranulation of mast cells in allergic inflammation.

Perfluorooctanoic acid (PFOA) has wide applications, including as a raw material for converted paper and packaging products. With the widespread use of PFOA, concerns regarding its potential environmental and health impacts have increased. In spite of the known hepatotoxicity and genotoxicity of PFOA, correlation with PFOA and allergic inflammation is not well known. In this study, the effect of PFOA on the degranulation of mast cells and mast cell‐mediated allergic inflammation in the presence of FcεRI cross‐linking was evaluated. In immunoglobulin (Ig) E‐stimulated mast cells, PFOA increased the release of histamine and β‐hexosaminidase by the up‐regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro‐inflammatory cytokines, including tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, and IL‐8 by the activation of nuclear factor (NF)‐κB in IgE‐stimulated mast cells. Also, PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF‐α, IgE and IgG1 in the ovalbumin‐induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI‐mediated mast cell degranulation and allergic symptoms. Copyright

Triamcinolone–carbon nanotube conjugation inhibits inflammation of human arthritis synovial fibroblasts

Repetitive intra-articular corticosteroid injections are inevitable for treating synovial inflammation in advanced arthritis. However, short- and long-term use of corticosteroids usually triggers serious side effects (i.e., adrenal insufficiency, hyperglycemia, Cushing syndrome, osteoporosis, Charcot arthropathy, etc.). This study demonstrated that conjugation of a corticosteroid (triamcinolone) on polyethylene-glycol (PEG)-fabricated multi-walled carbon nanotubes enhances intracellular drug delivery via increased lysosome transport and ultimately suppresses the expression of major pro-inflammatory cytokines (i.e., TNF-α, IL-1β, and IL-6) and matrix metalloproteinase-1 and -3 from fibroblast-like synoviocytes at a very low drug dose. Specifically, conjugation of triamcinolone and multi-walled carbon nanotubes inactivated nuclear factor-κB via inhibition of the phosphorylation of mitogen-activated protein kinases and the serine/threonine kinase Akt. In summary, low-dose triamcinolone conjugation with carbon nanotubes significantly inhibited the inflammatory response of fibroblast-like synoviocytes by achieving highly efficient intracellular trafficking and suggested a potential drug candidate for resolving side effects associated with conventional arthritis treatment.

PEGylated anticancer-carbon nanotubes complex targeting mitochondria of lung cancer cells

Although activating apoptosis in cancer cells by targeting the mitochondria is an effective strategy for cancer therapy, insufficient targeting of the mitochondria in cancer cells restricts the availability in clinical treatment. Here, we report on a polyethylene glycol-coated carbon nanotube-ABT737 nanodrug that improves the mitochondrial targeting of lung cancer cells. The polyethylene glycol-coated carbon nanotube-ABT737 nanodrug internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis in advance of early endosomal escape and delivered into the mitochondria. Cytosol release of nanodrug led to apoptosis of lung cancer cells by abruption of the mitochondrial membrane potential, inducing Bcl-2-mediated apoptosis and generating intracellular reactive oxygen species. As such, this study provides an effective strategy for increasing the anti-lung cancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs.Although activating apoptosis in cancer cells by targeting the mitochondria is an effective strategy for cancer therapy, insufficient targeting of the mitochondria in cancer cells restricts the availability in clinical treatment. Here, we report on a polyethylene glycol-coated carbon nanotube (CNT)-ABT737 nanodrug that improves the mitochondrial targeting of lung cancer cells. The polyethylene glycol-coated CNT-ABT737 nanodrug internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis in advance of early endosomal escape and delivered into the mitochondria. Cytosol release of the nanodrug led to apoptosis of lung cancer cells by abruption of the mitochondrial membrane potential, inducing Bcl-2-mediated apoptosis and generating intracellular reactive oxygen species. As such, this study provides an effective strategy for increasing the anti-lung cancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs.

Anti-allergic and anti-inflammatory effects of aqueous extract of Pogostemon cablin

Allergic disease is caused by exposure to normally innocuous substances that activate mast cells. Mast cell-mediated allergic inflammation is closely related to a number of allergic disorders, such as anaphylaxis, allergic rhinitis, asthma and atopic dermatitis. The discovery of drugs for treating allergic disease is an interesting subject and important to human health. The aim of the present study was to investigate the anti‑allergic and anti-inflammatory effects of the aqueous extract of Pogostemon cablin (Blanco) Benth (AEPC) (a member of the Labiatae family) using mast cells, and also to determine its possible mechanisms of action. An intraperitoneal injection of compound 48/80 or a serial injection of immunoglobulin E and antigen was used to induce anaphylaxis in mice. We found that AEPC inhibited compound 48/80‑induced systemic and immunoglobulin E-mediated cutaneous anaphylaxis in a dose-dependent manner. The release of histamine from mast cells was reduced by AEPC, and this suppressive effect was associated with the regulation of calcium influx. In addition, AEPC attenuated the phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated expression of pro-inflammatory cytokines in mast cells. The inhibitory effects of AEPC on pro-inflammatory cytokines were dependent on the activation of nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). AEPC blocked the PMACI-induced translocation of NF-κB into the nucleus by hindering the degradation of IκBα and the phosphorylation of p38 MAPK. Our results thus indicate that AEPC inhibits mast cell‑mediated allergic inflammation by suppressing mast cell degranulation and the expression of pro-inflammatory cytokines caused by reduced intracellular calcium levels and the activation of NF-κB and p38 MAPK.

Perfluorooctane sulfonate exacerbates mast cell-mediated allergic inflammation by the release of histamine

BackgroundsMast cells play a major role in allergic inflammation by the release of histamine, an important mediator of type I hypersensitivity. Cencerns regarding potential harmful effects of perfluorooctane sulfonate (PFOS) have been raised. Previous studies reported that PFOS causes various adverse effects such as immunotoxicity and neurotoxicity. This report studied whether PFOS affects mast cells-mediated allergic inflammation.MethodsOvalbumin-induced active systemic anaphylaxis model was used to assess for the type I hypersensitivity. After sensitization, mice were orally administered with PFOS and then allergic symptoms such as hypothermia and increase of serum allergic mediator were measured. In additional, this study investigated whether PFOS deteriorate allergic inflammation in immunoglobulin E-stimulated mast cells.ResultsPFOS aggravated the allergic symptoms such as hypothermia, and increase of serum histamine, tumor necrosis factor-α and immunoglobulin (Ig) E/ G1. PFOS increased the release of histamine and β-hexosaminidase through the up-regulation of intracellular calcium in IgE-stimulated mast cells. PFOS also enhanced the gene expression of pro-inflammatory cytokines by activating nuclear factor-κB.ConclusionThis study demonstrated that PFOS more intensifies the mast cell-mediated allergic inflammation.

Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation

Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL) on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae), which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.