Effect of Ishige okamurae Extract on Osteoclastogenesis In Vitro and In Vivo.

We demonstrated the effect of Ishige okamurae extract (IOE) on the receptor activator of nuclear factor-κB ligand (RANKL)-promoted osteoclastogenesis in RAW 264.7 cells and confirmed that IOE inhibited RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity and osteoclast differentiation. IOE inhibited protein expression of TRAP, metallopeptidase-9 (MMP-9), the calcitonin receptor (CTR), and cathepsin K (CTK). IOE treatment suppressed the expression of activated T cell cytoplasmic 1 and activator protein-1, thus controlling the expression of osteoclast-related factors. Moreover, IOE significantly reduced RANKL-phosphorylated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). It also reduced the RANKL-induced phosphorylation of NF-κB and nuclear translocation of p65. IOE inhibited Dex-induced bone loss and osteoclast-related gene expression in zebrafish larvae. HPLC analysis shows that IOE consists of 3.13% and 3.42% DPHC and IPA, respectively. Our results show that IOE has inhibitory effects on osteoclastogenesis in vitro and in vivo and is a potential therapeutic for osteoporosis.

Inhibition of Polyphosphate Degradation in Synechocystis sp. PCC6803 through Inactivation of the phoU Gene.

Phosphorus is an essential but non-renewable nutrient resource critical for agriculture. Luxury phosphorus uptake allows microalgae to synthesize polyphosphate and accumulate phosphorus, but, depending on the strain of algae, polyphosphate may be degraded within 4 hours of accumulation. We studied the recovery of phosphorus from wastewater through luxury uptake by an engineered strain of Synechocystis sp. with inhibited polyphosphate degradation and the effect of this engineered Synechocystis biomass on lettuce growth. First, a strain (ΔphoU) lacking the phoU gene, which encodes a negative regulator of environmental phosphate concentrations, was generated to inhibit polyphosphate degradation in cells. Polyphosphate concentrations in the phoU knock-out strain were maintained for 24 h and then decreased slowly. In contrast, polyphosphate concentrations in the wild-type strain increased up to 4 h and then decreased rapidly. In addition, polyphosphate concentration in the phoU knockout strain cultured in semi-permeable membrane bioreactors with artificial wastewater medium was 2.5 times higher than that in the wild type and decreased to only 16% after 48 h. The biomass of lettuce treated with the phoU knockout strain (0.157 mg P/m2) was 38% higher than that of the lettuce treated with the control group. These results indicate that treating lettuce with this microalgal biomass can be beneficial to crop growth. These results suggest that the use of polyphosphate-accumulating microalgae as biofertilizers may alleviate the effects of a diminishing phosphorous supply. These findings can be used as a basis for additional genetic engineering to increase intracellular polyphosphate levels.

Zirconium-Based Metal-Organic Framework Capable of Binding Proinflammatory Mediators in Hydrogel Form Promotes Wound Healing Process through a Multiscale Adsorption Mechanism.

The regulation of proinflammatory mediators has been explored to promote natural healing without abnormal inflammation or autoimmune response induced by their overproduction. However, most efforts to control these mediators have relied on pharmacological substances that are directly engaged in biological cycles. It is believed that functional porous materials removing target mediators provide a new way to promote the healing process using their adsorption mechanisms. In this study, the Zr-based metal-organic frameworks (MOF)-808 (Zr6 O4 (OH)4 (BTC)2 (HCOO)6 ) crystals are found to be effective at removing proinflammatory mediators, such as nitric oxide (NO), cytokines, and reactive oxygen species (ROS) in vitro and in vivo, because of their porous structure and surface affinity. The MOF-808 crystals are applied to an in vivo skin wound model as a hydrogel dispersion. Hydrogel containing 0.2 wt% MOF-808 crystals shows significant improvement in terms of wound healing efficacy and quality over the corresponding control. It is also proven that the mode of action is to remove the proinflammatory mediators in vivo. Moreover, the application of MOF-808-containing hydrogels promotes cell activation, proliferation and inhibits chronic inflammation, leading to increased wound healing quality. These findings suggest that Zr-based MOFs may be a promising drug-free solution for skin problems related to proinflammatory mediators.

Effect of Silicone Patch Containing Metal-organic Framework on Hypertrophic Scar Suppression.

BACKGROUND/AIM: Hypertrophic scars (HS) are an abnormal cutaneous condition of wound healing characterized by excessive fibrosis and disrupted collagen deposition. This study assessed the potential of a silicone patch embedded with chemically stable zirconium-based metal-organic frameworks (MOF)-808 structures to mitigate HS formation using a rabbit ear model. MATERIALS AND METHODS: A silicone patch was strategically engineered by incorporating Zr-MOF-808, a composite structure comprising metal ions and organic ligands. Structural integrity of the Zr-MOF-808 silicone patch was validated using scanning electron microscopy and X-ray diffraction analysis. The animals were divided into three groups: a control, no treatment group (Group 1), a silicone patch treatment group (Group 2), and a group treated with a 0.2% loaded Zr-MOF-808 silicone patch (Group 3). HS suppression effects were quantified using scar elevation index (SEI), dorsal skin thickness measurements, and myofibroblast protein expression. RESULTS: Histopathological examination of post-treatment HS samples revealed substantial reductions in SEI (34.6%) and epidermal thickness (49.5%) in Group 3. Scar hyperplasia was significantly diminished by 53.5% (p<0.05), while collagen density declined by 15.7% in Group 3 compared to Group 1. Western blot analysis of protein markers, including TGF-ß1, collagen-1, and α-SMA, exhibited diminished levels by 8.8%, 12%, and 21.3%, respectively, in Group 3, and substantially higher levels by 21.9%, 27%, and 39.9%, respectively, in Group 2. On the 35th day post-wound generation, Zr-MOF-808-treated models exhibited smoother, less conspicuous, and flatter scars. CONCLUSION: Zr-MOF-808-loaded silicone patch reduced HS formation in rabbit ear models by inducing the proliferation and remodeling of the wound healing process.

Effect of Spatial Heterogeneity on the Unusual Uptake Behavior of Multivariate-Metal-Organic Frameworks.

The uniqueness of multivariate metal-organic frameworks (MTV-MOFs) has been widely explored to discover their unknown opportunities. While mesoscopic apportionments have been studied, macroscopic heterogeneity and its spatial effects remain unexplored in MTV-MOFs. In this study, we investigated the effect of macroscopic heterogeneity on MTV-MOFs on their uptake behaviors by comparing three types of MTV-MOFs having the functional groups in inner, outer, or entire parts of crystals. Their adsorption behavior for carbon dioxide (CO2) and water (H2O) brought out that functional groups located in the outer part of the crystals dominantly influence the sorption behavior of MTV-MOFs. These results are also visualized by observing iodine adsorption in the three types of MTV-MOFs using scanning transmission electron microscopy-electron energy loss spectroscopy. We believe that this finding provides new ways to decipher and design MTV-MOFs for their unusual properties.

Cathodes Coating Layer with Li-Ion Diffusion Selectivity Employing Interactive Network of Metal-Organic Polyhedras for Li-Ion Batteries.

Surface modification of cathodes using Ni-rich coating layers prevents bulk and surface degradation for the stable operation of Li-ion batteries at high voltages. However, insulating and dense inorganic coating layers often impede charge transfer and ion diffusion kinetics. In this study, the fabrication of dual functional coating materials using metal-organic polyhedra (MOP) with 3D networks within microporous units of Li-ion batteries for surface stabilization and facile ion diffusion is proposed. Zr-based MOP is modified by introducing acyl groups as a chemical linkage (MOPAC), and MOPAC layers are homogenously coated by simple spray coating on the cathode. The coating allow the smooth transport of electrons and ions. MOPAC effectively suppress side reactions between the cathode and electrolyte and protect active materials against aggressive fluoride ions by forming a Li-ion selective passivation film. The MOPAC-coated Ni-rich layered cathode exhibited better cycle retention and enhanced kinetic properties than pristine and MOP-coated cathodes. Reduction of undesirable gas evolution on the cathode by MOPAC is also verified. Microporous MOPAC coating can simultaneously stabilize both the bulk and surface of the Ni-rich layered cathode and maintain good electrochemical reaction kinetics for high-performance Li-ion batteries.

Predicting Responsiveness to Biofeedback Therapy Using High-resolution Anorectal Manometry With Integrated Pressurized Volume.

Background/Aims: Biofeedback therapy is widely used to treat patients with chronic constipation, especially those with dyssynergic defecation. Yet, the utility of high-resolution manometry with novel parameters in the prediction of biofeedback response has not been reported. Thus, we constructed a model for predicting biofeedback therapy responders by applying the concept of integrated pressurized volume in patients undergoing high-resolution anorectal manometry. Methods: Seventy-one female patients (age: 48-68 years) with dyssynergic defecation who underwent initial high-resolution anorectal manometry and subsequent biofeedback therapy were enrolled. The manometry profiles were used to calculate the 3-dimensional integrated pressurized volumes by multiplying the distance, time, and amplitude during simulated evacuation. Partial least squares regression was performed to generate a predictive model for responders to biofeedback therapy by using the integrated pressurized volume parameters. Results: Fifty-five (77.5%) patients responded to biofeedback therapy. The responders and non-responders did not show significant differences in the conventional manometric parameters. The partial least squares regression model used a linear combination of eight integrated pressurized volume parameters and generated an area under the curve of 0.84 (95% confidence interval: 0.76-0.95, P < 0.01), with 85.5% sensitivity and 62.1% specificity. Conclusions: Integrated pressurized volume parameters were better than conventional parameters in predicting the responsiveness to biofeedback therapy, and the combination of these parameters and partial least squares regression was particularly promising. Integrated pressurized volume parameters can more effectively explain the physiology of the anorectal canal compared with conventional parameters.

Single metal-organic framework-embedded nanopit arrays: A new way to control neural stem cell differentiation.

Stable and continuous supply of essential biomolecules is critical to mimic in vivo microenvironments wherein spontaneous generation of various cell types occurs. Here, we report a new platform that enables highly efficient neuronal cell generation of neural stem cells using single metal-organic framework (MOF) nanoparticle-embedded nanopit arrays (SMENA). By optimizing the physical parameters of homogeneous periodic nanopatterns, each nanopit can confine single nMOFs (UiO-67) that are specifically designed for long-term storage and release of retinoic acid (RA). The SMENA platform successfully inhibited physical interaction with cells, which contributed to remarkable stability of the nMOF (RA⊂UiO-67) structure without inducing nanoparticle-mediated toxicity issues. Owing to the continuous and long-term supply of RA, the neural stem cells showed enhanced mRNA expressions of various neurogenesis-related activities. The developed SMENA platform can be applied to other stem cell sources and differentiation lineages and is therefore useful for various stem cell-based regenerative therapies.

Comparing Internal and Interparticle Space Effects of Metal-Organic Frameworks on Polysulfide Migration in Lithium-Sulfur Batteries.

One of the critical issues hindering the commercialization of lithium-sulfur (Li-S) batteries is the dissolution and migration of soluble polysulfides in electrolyte, which is called the 'shuttle effect'. To address this issue, previous studies have focused on separators featuring specific chemical affinities or physical confinement by porous coating materials. However, there have been no studies on the complex effects of the simultaneous presence of the internal and interparticle spaces of porous materials in Li-S batteries. In this report, the stable Zr-based metal-organic frameworks (MOFs), UiO-66, have been used as a separator coating material to provide interparticle space via size-controlled MOF particles and thermodynamic internal space via amine functionality. The abundant interparticle space promoted mass transport, resulting in enhanced cycling performance. However, when amine functionalized UiO-66 was employed as the separator coating material, the initial specific capacity and capacity retention of Li-S batteries were superior to those materials based on the interparticle effect. Therefore, it is concluded that the thermodynamic interaction inside internal space is more important for preventing polysulfide migration than spatial condensation of the interparticle space.

Rapid Single-Step Growth of MOF Exoskeleton on Mammalian Cells for Enhanced Cytoprotection.

Mammalian cells are promising agents for cell therapy, diagnostics, and drug delivery. For full utilization of the cells, development of an exoskeleton may be beneficial to protecting the cells against the environmental stresses and cytotoxins to which they are susceptible. We report here a rapid single-step method for growing metal-organic framework (MOF) exoskeletons on a mammalian cell surface under cytocompatible conditions. The MOF exoskeleton coating on the mammalian cells was developed via a one-pot biomimetic mineralization process. With the exoskeleton on, the individual cells were successfully protected against cell protease (i.e., Proteinase K), whereas smaller-sized nutrient transport across the exoskeleton was maintained. Moreover, vital cellular activities mediated by transmembrane GLUT transporter proteins were also unaffected by the MOF exoskeleton formation on the cell surfaces. Altogether, this ability to control the access of specific molecules to a single cell through the porous exoskeleton, along with the cytoprotection provided, should be valuable for biomedical applications of mammalian cells.

Metal-Organic Fragments with Adhesive Excipient and Their Utilization to Stabilize Multimetallic Electrocatalysts for High Activity and Robust Durability in Oxygen Evolution Reaction.

Multimetallic electrocatalysts have shown great potential to improve electrocatalytic performance, but their deteriorations in activity and durability are yet to be overcome. Here, metal-organic fragments with adhesive excipient to realize high activity with good durability in oxygen evolution reaction (OER) are developed. First, a leaf-like zeolitic-imidazolate framework (ZIF-L) is synthesized. Then, ionized species in hydrogen plasma attack preferentially the organic linkers of ZIF-L to derive cobalt-imidazole fragments (CIFs) as adhesive excipient, while they are designed to retain the coordinated cobalt nodes. Moreover, the vacant coordination sites at cobalt nodes and the unbound nitrogen at organic linkers induce high porosity and conductivity. The CIFs serve to stably impregnate trimetallic FeNiMo electrocatalysts (CIF:FeNiMo), and CIF:FeNiMo containing Fe contents of 22% and hexavalent Mo contents show to enable high activity with low overpotentials (203 mV at 10 mA cm-2 and 238 mV at 100 mA cm-2 ) in OER. The near O K-edge extended X-ray absorption fine structure proves further that high activity for OER originates from the partially filled eg orbitals. Additionally, CIF:FeNiMo exhibit good durability, as demonstrated by high activity retention during at least 45 days in OER.

Exploiting the Specific Isotope-Selective Adsorption of Metal-Organic Framework for Hydrogen Isotope Separation.

Adsorptive separation using narrow-micropore adsorbents has demonstrated the potential to separate hydrogen isotopes. In this work, we employed an isotope-responsive separation using cobalt formate. A D2-responsive third sorption step was revealed, and consequently, a noticeable difference was observed in the uptakes of D2 and H2. This may have resulted from the additional space created for D2 due to its dense packing, as DFT calculations revealed that cobalt formate possesses 2.26 kJ/mol higher binding strength for D2 than for H2. The exploitation of this D2-responsive third sorption step renders a promising separation performance, with a D2/H2 selectivity of up to 44 at 25 K/1 bar. Lastly, cobalt formate was synthesized on a gram scale here, which makes it a prospect for commercialization.

Interwoven MOF-Coated Janus Cells as a Novel Carrier of Toxic Proteins.

Two major issues in cell-mediated drug delivery systems (c-DDS) are the availability of free cell surfaces for the binding of the cells to the target or to their microenvironment and internalization of the cytotoxic drug. In this study, the Janus structure, MOF nanoparticles, and tannic acid (TA) are utilized to address these issues. Janus carrier cells coated with metal-organic frameworks (MOFs) are produced by asymmetrically immobilizing the nanoparticles of a MOF based on zinc with cytotoxic enzymes that are internally encapsulated on the surface of carrier cells. By maintaining the biological and structural features of regular living cells, the MOF-coated Janus cells developed in the present study preserve the intrinsic binding capacity of the cells to their microenvironment. Interconnected MOFs loaded onto the other face of the Janus cells cannot penetrate the cell. Therefore, the carrier cells are protected from the cytotoxic drug contained in MOFs. These MOF-Janus carrier cells are demonstrated to successfully eliminate three-dimensional (3D) tumor spheroids when a chemotherapeutic protein of proteinase K is released from the MOF nanoparticles in an acid environment. The ease with which the MOF-Janus carrier cells are prepared (in 15 min), and the ability to carry a variety of enzymes and even multiple ones should make the developed system attractive as a general platform for drug delivery in various applications, including combination therapy.

Recent advances in process engineering and upcoming applications of metal-organic frameworks.

Progress in metal-organic frameworks (MOFs) has advanced from fundamental chemistry to engineering processes and applications, resulting in new industrial opportunities. The unique features of MOFs, such as their permanent porosity, high surface area, and structural flexibility, continue to draw industrial interest outside the traditional MOF field, both to solve existing challenges and to create new businesses. In this context, diverse research has been directed toward commercializing MOFs, but such studies have been performed according to a variety of individual goals. Therefore, there have been limited opportunities to share the challenges, goals, and findings with most of the MOF field. In this review, we examine the issues and demands for MOF commercialization and investigate recent advances in MOF process engineering and applications. Specifically, we discuss the criteria for MOF commercialization from the views of stability, producibility, regulations, and production cost. This review covers progress in the mass production and formation of MOFs along with future applications that are not currently well known but have high potential for new areas of MOF commercialization.

Protective Effects of Oenothera biennis against Hydrogen Peroxide-Induced Oxidative Stress and Cell Death in Skin Keratinocytes.

BACKGROUND: Oenothera biennis (evening primrose) produces bioactive substances with a diverse range of pharmacological functions. However, it is currently unknown whether extract prepared from the aerial parts of O. biennis (APOB) can protect the skin against oxidative stress. OBJECTIVE: The aim of this study is to investigate the protective effects of APOB against oxidative stress-induced damage in human skin keratinocytes (HaCaT) and elucidate the underlying mechanisms. METHODS: We pretreated HaCaT cells with various concentrations of APOB or the antioxidant N-acetyl-L-cysteine before applying H2O2. We then compared the cell viability, intracellular reactive oxygen species (ROS) production, and DNA and mitochondrial damage between pretreated and untreated control cells using a range of assays, flow cytometry, and Western blot analysis and also examined the reducing power and DPPH free radical scavenging activity of APOB. RESULTS: APOB pretreatment significantly increased cell viability, effectively attenuated H2O2-induced comet tail formation, and inhibited H2O2-induced phosphorylation of the histone γH2AX, as well as the number of apoptotic bodies and Annexin V-positive cells. APOB was found to have high reducing power and DPPH radical scavenging activity and also exhibited scavenging activity against intracellular ROS accumulation and restored the loss of mitochondrial membrane potential caused by H2O2. APOB pretreatment almost totally reversed the enhanced cleavage of caspase-3, the degradation of poly (ADP-ribose)-polymerase (PARP), DNA fragmentation that usually occurs in the presence of H2O2, and increased the levels of heme oxygenase-1 (HO-1), a potent antioxidant enzyme that is associated with the induction of nuclear factor-erythroid 2-related factor 2 (Nrf2). CONCLUSIONS: APOB can protect HaCaT cells from H2O2-induced DNA damage and cell death by blocking cellular damage related to oxidative stress via a mechanism that affects ROS elimination and by activating the Nrf2/HO-1 signaling pathway.

Comparison of the Immunogenicity and Safety of Three Enhanced Inactivated Poliovirus Vaccines from Different Manufacturers in Healthy Korean Infants: A Prospective Multicenter Study.

The enhanced inactivated poliovirus vaccine was first introduced in 2002, and several inactivated poliovirus vaccines are licensed in Korea. Reliable data by a prospective study on the immunogenicity and safety of the inactivated poliovirus vaccines in Korean infants are required. Normal healthy infants aged 6-12 weeks received three doses of the vaccine (IPVAX™, Imovax Polio™ or Poliorix™) in intervals of 2 months. Neutralizing antibody (NTAb) titers were measured before and 4-6 weeks after three-dose primary vaccination. Immunogenicity was evaluated by seroconversion rates and geometric mean titers obtained by analyzing NTAb titers. Local and systemic adverse events were recorded during 7 days after each vaccination. A total of 150 infants were included: 40 in IPVAX™, 52 in Imovax Polio™, and 58 in Poliorix™. The seroconversion rates for the group vaccinated with IPVAX™ were 100% in types 1, 2 and 3, while those of Imovax Polio™ were 98.1%, 96.2%, 96.2% and those of Poliorix™ were 98.3%, 100%, 100%, respectively. In all groups, injection site redness and irritability were the most common local and systemic adverse events. Neither serious adverse events nor adverse events above grade 2 were reported throughout the study. The currently used inactivated poliovirus vaccines was demonstrated to be safe and immunogenic in healthy Korean infants.

Autogenous Production and Stabilization of Highly Loaded Sub-Nanometric Particles within Multishell Hollow Metal-Organic Frameworks and Their Utilization for High Performance in Li-O2 Batteries.

Sub-nanometric particles (SNPs) of atomic cluster sizes have shown great promise in many fields such as full atom-to-atom utilization, but their precise production and stabilization at high mass loadings remain a great challenge. As a solution to overcome this challenge, a strategy allowing synthesis and preservation of SNPs at high mass loadings within multishell hollow metal-organic frameworks (MOFs) is demonstrated. First, alternating water-decomposable and water-stable MOFs are stacked in succession to build multilayer MOFs. Next, using controlled hydrogen bonding affinity, isolated water molecules are selectively sieved through the hydrophobic nanocages of water-stable MOFs and transferred one by one to water-decomposable MOFs. The transmission of water molecules via controlled hydrogen bonding affinity through the water-stable MOF layers is a key step to realize SNPs from various types of alternating water-decomposable and water-stable layers. This process transforms multilayer MOFs into SNP-embedded multishell hollow MOFs. Additionally, the multishell stabilizes SNPs by π-backbonding allowing high conductivity to be achieved via the hopping mechanism, and hollow interspaces minimize transport resistance. These features, as demonstrated using SNP-embedded multishell hollow MOFs with up to five shells, lead to high electrochemical performances including high volumetric capacities and low overpotentials in Li-O2 batteries.

WHO implementation workshop on guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 25-26 June 2019.

The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries. While the guidelines are gradually being implemented in some countries and also being considered in other countries, the need for regional workshops and further training on post-approval changes was a common theme reiterated by many participants. Given the complexities relating to post-approval changes in different regions/countries, there was a clear understanding among all participants that an efficient approach for product life-cycle management at a national level is needed to ensure faster availability of high standard, safe and efficacious medicines to patients as per the World Health Assembly Resolution 67.21.

Exploiting Microwave Chemistry for Activation of Metal-Organic Frameworks.

Microwave is thought of as a useful electromagnetic radiation tool because it is often used in real life as well as in a variety of chemical processes. Meanwhile, activation of metal-organic frameworks (MOFs), which must be essentially done to remove coordinating and pore-filling solvents before the use of MOFs for various applications, has been performed commonly with the methods of heat supply or solvent exchange. Here, we show a new methodological microwave activation (MA), realizing it with various MOFs such as HKUST-1, UiO-66, and MOF-74s. For instance, microwave irradiation to the MOF samples for 4-35 min leads to the complete activation of the MOFs without structural damage. As described below, we further demonstrate that the solvent-assisted MA, which is the MA process performed after the solvent exchange, can substantially reduce the time for the activation by 4 min.

Complete Genome Sequence of Leuconostoc kimchii Strain NKJ218, Isolated from Homemade Kimchi.

Leuconostoc kimchii strain NKJ218 was isolated from homemade kimchi in South Korea. The whole genome was sequenced using the PacBio RS II and Illumina NovoSeq 6000 platforms. Here, we report a genome sequence of strain NKJ218, which consists of a 1.9-Mbp chromosome and three plasmid contigs. A total of 2,005 coding sequences (CDS) were predicted, including 1,881 protein-coding sequences.