Medical treatment of osteoarthritis: botanical pharmacologic aspect.

Osteoarthritis (OA) is the most common form of arthritis, and its prevalence is expected to further increase as our society ages. Despite many approaches to cure OA, no drugs are currently proven to modulate the progression of OA. Nowadays, new OA treatment options are holistically developed and one of the approaches of treatment option is botanical drugs. Some botanical drugs for OA have shown both therapeutic effect comparable to refined drugs in small studies and fewer side effects. Hence, there are various health functional foods which are known to relieve symptoms of OA. However, since there are many botanical products, clinicians are not familiar to the efficacy of each botanical product, making it challenging to use them appropriately in clinical practice. Here, we summarize the botanical products available for treating OA, including prescription botanical drugs and health functional foods available in Korea. Further studies and the purification of effective molecules from botanical products will be necessary in future.

Through-hole composite membrane with an ultrathin oxide shell for highly robust and transparent air filters.

Exploring pore structures that are optically transparent and have high filtration efficiency for ultrafine dust is very important for realizing passive window filters for indoor air purification. Herein, a polyester track-etched (PETE) membrane with vertically perforated micropores is investigated as a cost-effective candidate for transparent window filters. The pore size, which governs transparency and filtration efficiency, can be precisely tuned by conformally depositing an ultrathin oxide layer on the PETE membrane via atomic layer deposition. The maximum visible light transmittance (∼81.2 %) was achieved with an alumina layer of approximately 55 nm, and the resulting composite membrane exhibited competitive filtration efficiency compared to commercial products. The chemically inert alumina layer also increased resistance to various external stimuli and enabled simple cleaning of the contaminated membrane surface with a solvent. The membrane installed on an insect screen effectively maintained its filtration performance (∼85 % for PM2.5) even after 10 reuse cycles under extremely harsh conditions (PM2.5 concentration: ∼5000 µg cm-3). The proposed through-hole composite membrane can expand the choice of aesthetic window filters to situations that require high outside visibility and daylighting.

A review of osteoarthritis signaling intervention using small-molecule inhibitors.

Numerous small-molecule inhibitors (SMIs) have been approved as adjuvant or first-line therapies for malignancies. Based on cancer treatment using SMIs, next-generation SMIs that can be used to optimize the therapeutic index, overcome drug resistance, and establish combination therapies are in development. Osteoarthritis (OA) is the most common chronic joint disease with senescence, and there are various approaches to OA treatment; however, the gold standard treatment is controversial. Therefore, in this manuscript, we demonstrated the potential of using SMIs in OA treatment and described the general strategies for using SMIs in OA treatment.

Revisit to functional data analysis of sleeping energy expenditure.

In this paper, we consider the classification problem of functional data including the sleeping energy expenditure (SEE) data, focusing on functional classification. Many existing classification rules are not effective in distinguishing the two classes of SEE data, because the trajectories of each observation have very different patterns for each class. It is often observed that some aspect of data such as the variability of paths is helpful in classification of functional data. To reflect this issue, we introduce a variable measuring the length of path in functional data and then propose a logistic model with fused lasso that considers the behavior of fluctuation of path as well as local correlations within each path. Our proposed model shows a significant improvement over some models used in the existing literature on the classification accuracy rate of functional data such as SEE data. We carry out simulation studies to show the finite sample performance and the gain that it makes in comparison with fused lasso without considering path length. With two more real datasets studied in some existing literature, we demonstrate that the new model achieves better or similar accuracy rate than the best accuracy rates reported in those studies.

Efficient integration of aggregate data and individual participant data in one-way mixed models.

Often both aggregate data (AD) studies and individual participant data (IPD) studies are available for specific treatments. Combining these two sources of data could improve the overall meta-analytic estimates of treatment effects. Moreover, often for some studies with AD, the associated IPD maybe available, albeit at some extra effort or cost to the analyst. We propose a method for combining treatment effects across trials when the response is from the exponential family of distribution and hence a generalized linear model structure can be used. We consider the case when treatment effects are fixed and common across studies. Using the proposed combination method, we study the relative efficiency of analyzing all IPD studies vs combining various percentages of AD and IPD studies. For many different models, design constraints under which the AD estimators are the IPD estimators, and hence fully efficient, are known. For such models, we advocate a selection procedure that chooses AD studies over IPD studies in a manner that force least departure from design constraints and hence ensures an efficient combined AD and IPD estimator.

Adaptive local false discovery rate procedures for highly spiky data and their application RNA sequencing data of yeast SET4 deletion mutants.

Chromatin dynamics are central to the regulation of gene expression and genome stability. In order to improve understanding of the factors regulating chromatin dynamics, the genes encoding these factors are deleted and the differential gene expression profiles are determined using approaches such as RNA sequencing. Here, we analyzed a gene expression dataset aimed at uncovering the function of the relatively uncharacterized chromatin regulator, Set4, in the model system Saccharomyces cerevisiae (budding yeast). The main theme of this paper focuses on identifying the highly differentially expressed genes in cells deleted for Set4 (referred to as Set4 Δ mutant dataset) compared to the wild-type yeast cells. The Set4 Δ mutant data produce a spiky distribution on the log-fold changes of their expressions, and it is reasonably assumed that genes which are not highly differentially expressed come from a mixture of two normal distributions. We propose an adaptive local false discovery rate (FDR) procedure, which estimates the null distribution of the log-fold changes empirically. We numerically show that, unlike existing approaches, our proposed method controls FDR at the aimed level (0.05) and also has competitive power in finding differentially expressed genes. Finally, we apply our procedure to analyzing the Set4 Δ mutant dataset.

Effect of C-terminus Conjugation via Different Conjugation Chemistries on In Vivo Activity of Albumin-Conjugated Recombinant GLP-1.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone with tremendous therapeutic potential for treating type 2 diabetes mellitus. However, the short half-life of its native form is a significant drawback. We previously prolonged the plasma half-life of GLP-1 via site-specific conjugation of human serum albumin (HSA) at position 16 of recombinant GLP-1 using site-specific incorporation of p-azido-phenylalanine (AzF) and strain-promoted azide-alkyne cycloaddition (SPAAC). However, the resulting conjugate GLP1_8G16AzF-HSA showed only moderate in vivo glucose-lowering activity, probably due to perturbed interactions with GLP-1 receptor (GLP-1R) caused by the albumin-linker. To identify albumin-conjugated GLP-1 variants with enhanced in vivo glucose-lowering activity, we investigated the conjugation of HSA to a C-terminal region of GLP-1 to reduce steric hindrance by the albumin-linker using two different conjugation chemistries. GLP-1 variants GLP1_8G37AzF-HSA and GLP1_8G37C-HSA were prepared using SPAAC and Michael addition, respectively. GLP1_8G37C-HSA exhibited a higher glucose-lowering activity in vivo than GLP1_8G16AzF-HSA, while GLP1_8G37AzF-HSA did not. Another GLP-1 variant, GLP1_8A37C-HSA, had a glycine to alanine mutation at position 8 and albumin at its C-terminus and exhibited in vivo glucose-lowering activity comparable to that of GLP1_8G37C-HSA, despite a moderately shorter plasma half-life. These results showed that site-specific HSA conjugation to the C-terminus of GLP-1 via Michael addition could be used to generate GLP-1 variants with enhanced glucose-lowering activity and prolonged plasma half-life in vivo.

Empirical Treatment With Carbapenem vs Third-generation Cephalosporin for Treatment of Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Third-generation cephalosporins (TGCs) are recommended as first-line antibiotics for treatment of spontaneous bacterial peritonitis (SBP). However, antibiotics against multidrug-resistant organisms (such as carbapenems) might be necessary. We aimed to evaluate whether carbapenems are superior to TGC for treatment of SBP. METHODS: We performed a retrospective study of 865 consecutive patients with a first presentation of SBP (275 culture positive; 103 with TGC-resistant bacterial infections) treated at 7 referral centers in Korea, from September 2013 through January 2018. The primary outcome was in-hospital mortality. We made all comparisons using data from patients whose baseline characteristics were balanced by inverse probability of treatment weighting. RESULTS: Of patients who initially received empirical treatment with antibiotics, 95 (11.0%) received carbapenems and 655 (75.7%) received TGCs. Among the entire study cohort, there was no significant difference in in-hospital mortality between the carbapenem (25.8%) and TGC (25.3%) groups (adjusted odds ratio [aOR], 0.97; 95% CI, 0.85-1.11; P = .66). In the subgroup of patients with high chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores (score of 7 or greater, n = 314), carbapenem treatment was associated with lower in-hospital mortality (23.1%) than in the TGC group (38.8%) (aOR, 0.84; 95% CI, 0.75-0.94; P=.002). In contrast, among patients with lower CLIF-SOFA scores (n = 436), in-hospital mortality did not differ significantly between the carbapenem group (24.7%) and the TGC group (16.0%) (aOR, 1.06; 95% CI, 0.85-1.32; P = .58). CONCLUSIONS: For patients with a first presentation of SBP, empirical treatment with carbapenem does not reduce in-hospital mortality compared to treatment with TGCs. However, among critically ill patients (CLIF-SOFA scores ≥7), empirical carbapenem treatment was significantly associated with lower in-hospital mortality than TGCs.

Association between hemoglobin variability and incidence of hypertension over 40 years: a Korean national cohort study.

Hemoglobin level determines blood viscosity and as hemoglobin level rises, blood pressure rises. However, hemoglobin level in individuals is not fixed and change in hemoglobin is affected by various clinical conditions. The purpose of this study is to investigate whether the hemoglobin variability affects the development of hypertension using Korean cohort database. This study was conducted with 94,798 adults (age ≥ 40 years) who visited the health screening in 2006 or 2007 (index year) and had at least 3 health screenings from 2002 to 2007. Hemoglobin variability was assessed by 3 indices of coefficient of variation (CV), standard deviation, and variability independent of the mean. Cox proportional hazard regression analysis was performed for each index of quartile groups (Q1-Q4). A total of 29,145 participants (30.7%) had the incidence of hypertension during a median follow-up of 7.4 ± 2.5 years. In the multivariable adjusted model, the hazard ratio and 95% confidence interval for incidence of hypertension of Q2, Q3, and Q4 compared with Q1 of hemoglobin variability CV were 1.014 [0.981-1.047], 1.064 [1.030-1.099] and 1.094 [1.059-1.131] respectively. The results were consistent in various sensitivity and subgroup analyses. This study showed that hemoglobin variability could be associated with hypertension development.

High-Contrast Optical Modulation from Strain-Induced Nanogaps at 3D Heterogeneous Interfaces.

The realization of high-contrast modulation in optically transparent media is of great significance for emerging mechano-responsive smart windows. However, no study has provided fundamental strategies for maximizing light scattering during mechanical deformations. Here, a new type of 3D nanocomposite film consisting of an ultrathin (≈60 nm) Al2O3 nanoshell inserted between the elastomers in a periodic 3D nanonetwork is proposed. Regardless of the stretching direction, numerous light-scattering nanogaps (corresponding to the porosity of up to ≈37.4 vol%) form at the interfaces of Al2O3 and the elastomers under stretching. This results in the gradual modulation of transmission from ≈90% to 16% at visible wavelengths and does not degrade with repeated stretching/releasing over more than 10 000 cycles. The underlying physics is precisely predicted by finite element analysis of the unit cells. As a proof of concept, a mobile-app-enabled smart window device for Internet of Things applications is realized using the proposed 3D nanocomposite with successful expansion to the 3 × 3 in. scale.

The Minimal Effect of Linker Length for Fatty Acid Conjugation to a Small Protein on the Serum Half-Life Extension.

Conjugation of serum albumin or one of its ligands (such as fatty acid) has been an effective strategy to prolong the serum half-lives of drugs via neonatal Fc receptor (FcRn)-mediated recycling of albumin. So far, fatty acid (FA) has been effective in prolonging the serum half-lives for therapeutic peptides and small proteins, but not for large therapeutic proteins. Very recently, it was reported a large protein conjugated to FA competes with the binding of FcRn with serum albumin, leading to limited serum half-life extension, because primary FA binding sites in serum albumin partially overlap with FcRn binding sites. In order to prevent such competition, longer linkers between FA and the large proteins were required. Herein, we hypothesized that small proteins do not cause substantial competition for FcRn binding to albumin, resulting in the extended serum half-life. Using a small protein (28 kDa), we investigated whether the intramolecular distance in FA-protein conjugate affects the FcRn binding with albumin and serum half-life using linkers with varying lengths. Unlike with the FA-conjugated large protein, all FA-conjugated small proteins with different linkers exhibited comparable the FcRn binding to albumin and extended serum half-life.

Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide.

The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A "clickable" non-natural amino acid-p-azido-l-phenylalanine (AzF)-was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide-alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.

Intramolecular distance in the conjugate of urate oxidase and fatty acid governs FcRn binding and serum half-life in vivo.

Therapeutic proteins are indispensable for treatment of various human diseases. However, intrinsic short serum half-lives of proteins are still big hurdles for developing new therapeutic proteins or expanding applications of existing ones. Urate oxidase (Uox) is a therapeutic protein clinically used for treatment of hyperuricemia. Due to its short half-life, its application for gout treatment requires prolonging the half-life in vivo. Conjugation of a fatty acid (FA), a serum albumin (SA) ligand, to therapeutic proteins/peptides is an emerging strategy to prolong serum half-life presumably via neonatal Fc receptor (FcRn)-mediated recycling. FA conjugation was proven effective for peptides and small proteins (less than 28 kDa), but not for Uox (140 kDa). We hypothesized that the intramolecular distance in the conjugate of FA and Uox is a critical factor for effective FcRn-mediated recycling. In order to control the intramolecular distance in the conjugate, we varied linker lengths between Uox and palmitic acid (PA). There was a linear correlation between the linker length and serum half-life of PA-conjugated Uox (Uox-PA) conjugates. The longer linker led to about 7-fold greater extension of serum half-life of Uox in mice than the unmodified Uox. The trend in serum half-life extension matched well with that in the tertiary structure formation of FcRn/SA/Uox-PA in vitro. These results demonstrate that the intramolecular distance in the conjugate of Uox and FA governs the stable formation of FcRn/SA/FA-conjugated protein and serum half-life extension in vivo. These findings would also contribute to development of effective FAconjugated therapeutic proteins.

An NMR-Based Similarity Metric for Higher Order Structure Quality Assessment Among U.S. Marketed Insulin Therapeutics.

Protein or peptide higher order structure (HOS) is a quality attribute that could affect therapeutic efficacy and safety. Where appropriate, the HOS similarity between a proposed follow-on product and the reference listed drug should be demonstrated during regulatory assessment. Establishing quantitative HOS similarity for 2 drug substances, manufactured by different processes, has been challenging. Herein, HOS differences among U.S. marketed insulin drug products (DPs) were quantified using nuclear magnetic resonance spectra and principal component analysis (PCA). Then, the unitless Mahalanobis distance (DM) in PCA space was calculated between insulin analog reference listed drugs and their recently approved follow-on products, and all DM values were 3.29 or less. By contrast, a larger DM value of 20.5 was obtained between the 2 insulin human DPs independently approved. However, upon mass-balanced and reversible dialysis of the 2 insulin human DPs against the same buffers, the DM value was reduced to 1.19 or less. Thus, the observed range of nuclear magnetic resonance-PCA-derived DM values can be used as a robust and sensitive measure of HOS similarity. Overall, the DM values of 3.3 for DP and 1.2 for drug substances using insulin therapeutics represented realistic and achievable similarity metrics for developing generic or biosimilar drugs, quality assurance, or control.

Ghrelin in Alzheimer's disease: Pathologic roles and therapeutic implications.

Ghrelin, which has many important physiological roles, such as stimulating food intake, regulating energy homeostasis, and releasing insulin, has recently been studied for its roles in a diverse range of neurological disorders. Despite the several functions of ghrelin in the central nervous system, whether it works as a therapeutic agent for neurological dysfunction has been unclear. Altered levels and various roles of ghrelin have been reported in Alzheimer's disease (AD), which is characterized by the accumulation of misfolded proteins resulting in synaptic loss and cognitive decline. Interestingly, treatment with ghrelin or with the agonist of ghrelin receptor showed attenuation in several cases of AD-related pathology. These findings suggest the potential therapeutic implications of ghrelin in the pathogenesis of AD. In the present review, we summarized the roles of ghrelin in AD pathogenesis, amyloid beta (Aß) homeostasis, tau hyperphosphorylation, neuroinflammation, mitochondrial deficit, synaptic dysfunction and cognitive impairment. The findings from this review suggest that ghrelin has a novel therapeutic potential for AD treatment. Thus, rigorously designed studies are needed to establish an effective AD-modifying strategy.

Traditional Oriental Medicines and Alzheimer's Disease.

Alzheimer's disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as ß-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.

Co-delivery of therapeutic protein and catalase-mimic nanoparticle using a biocompatible nanocarrier for enhanced therapeutic effect.

Therapeutic proteins are indispensable in the treatment of various human diseases. Despite the many benefits of therapeutic proteins, they also exhibit diverse side effects. Therefore, reducing unwanted side effects of therapeutic proteins as well as enhancing their therapeutic efficacy are very important in developing therapeutic proteins. Urate oxidase (UOX) is a therapeutic enzyme that catalyzes the conversion of uric acid (UA) into a soluble metabolite, and it is used clinically for the treatment of hyperuricemia. Since UA degradation by UOX generates H2O2 (a cytotoxic side product), UOX was co-delivered with catalase-mimic nanoparticles (AuNPs) using biocompatible pluronic-based nanocarriers (NCs) to effectively reduce H2O2-associated toxicity in cultured cells and to enhance UA degradation efficiency in vivo. Simple temperature-dependent size changes of NCs allowed co-encapsulation of both UOX and AuNPs at a high loading efficiency without compromising critical properties, resulting in efficient modulation of a mixing ratio of UOX and AuNPs encapsulated in NCs. Co-localizing UOX and AuNPs in the NCs led to enhanced UA degradation and H2O2 removal in vitro, leading to a great reduction in H2O2-associated cytotoxicity compared with UOX alone or a free mixture of UOX and AuNPs. Furthermore, we demonstrated that co-delivery of UOX and AuNPs using NCs significantly improves in vivo UA degradation compared to simple co-injection of free UOX and AuNPs. More broadly, we showed that biocompatible pluronic-based nanocarriers can be used to deliver a target therapeutic protein along with its toxicity-eliminating agent in order to reduce side effects and enhance efficacy.

Strategies to improve the photocatalytic activity of TiO2: 3D nanostructuring and heterostructuring with graphitic carbon nanomaterials.

TiO2-based photocatalysis has been considered to be one of the most promising avenues for environmental remediation including water purification. However, several technical issues such as the limited surface area of bulk TiO2, the large band gap of TiO2, and rapid charge recombination still limit the practical application of TiO2 photocatalysts. Therefore, here we focus on two structural design strategies: (i) monolithic three-dimensional (3D) nanostructuring, and (ii) heterostructuring with graphitic carbon nanomaterials. A monolithic 3D nanostructure enables maximal surface area in a given volume and efficient reuse of the photocatalyst without recollection. Heterostructuring with carbon nanomaterials helps achieve maximal utilization of the solar spectrum and charge separation and provides efficient TiO2 photocatalysts. In this review, recent progress on TiO2 photocatalysts toward the abovementioned strategies will be summarized. Further discussion and direction will provide insights into the rational design of highly efficient TiO2 photocatalysts, and help develop advanced photocatalyst models.

Multifunctional Hierarchically-Assembled Hydrogel Particles with Pollen Grains via Pickering Suspension Polymerization.

Hierarchical assembly of heterogeneous particles is of great importance to interface and colloid science. In this work, a facile but powerful approach for the large-scale production of multifunctional hydrogel particles armored with biological colloidal species is developed by combining Pickering stabilization and photopolymerization. Biocompatible hollow pollen grains extracted from naturally occurring pollen species with an average diameter of ∼32 µm serve as universal solid emulsifiers dispersed in an oil phase and are self-assembled at the interface between an oil phase and a photo-cross-linkable hydrogel to make water-in-oil (W/O) emulsion droplets. While droplets are solidified into hydrogel particles by UV-induced free-radical polymerization, self-assembled hollow pollen grains are transformed to a robust shell on hydrogel particles with supracolloidal structures. The physically adsorbed hollow pollen grains on the hydrogel core can be released by a hydration-induced swelling of hollow pollen grains, leading to a transient floating behavior of core-shell particles. The size of the resultant core-shell particles is easily controlled by tailoring the process parameters such as a liquid volume or a loading mass of hollow pollen grains. The incorporation of magnetic or upconverting luminescent nanoparticles into a hydrogel core successfully expands the functionality of core-shell particles that can provide new design opportunities for floating drug delivery or ecofriendly proppants.

Multifunctional Polymer Nanocomposites Reinforced by 3D Continuous Ceramic Nanofillers.

Polymer nanocomposites with inclusion of ceramic nanofillers have relatively high yield strength, elastic moduli, and toughness that therefore are widely used as functional coating and films for optoelectronic applications. Although the mechanical properties are enhanced with increasing the fraction of nanofiller inclusion, there generally is an upper limit on the amount of nanofiller inclusion because the aggregation of the fillers in the polymer matrix, which typically occurs, degrades the mechanical and/or optical performances above 5 vol % of inclusions. Here, we demonstrate an unconventional polymer nanocomposite composed of a uniformly distributed three-dimensional (3D) continuous ceramic nanofillers, which allows for extremely high loading (∼19 vol %) in the polymer matrix without any concern of aggregation and loss in transparency. The fabrication strategy involves conformal deposition of Al2O3 nanolayer with a precise control in thickness that ranges from 12 to 84 nm on a 3D nanostructured porous polymer matrix followed by filling the pores with the same type of polymer. The 3D continuous Al2O3 nanolayers embedded in the matrix with extremely high filler rate of 19.17 vol % improve compressive strength by 142% compared to the pure epoxy without Al2O3 filler, and this value is in agreement with theoretically predicted strength through the rule of mixture. These 3D nanocomposites show superb transparency in the visible (>85% at 600 nm) and near-IR (>90% at 1 µm) regions and improved heat dissipation beyond that of conventional Al2O3 dispersed nanocomposites with similar filler loading of 15.11 vol % due to the existence of a continuous thermal conduction path through the oxide network.