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Woo-Jin Jeon,1,* Hong-Ki Lee,2,3,* Young-Guk Na,1 Minwoo Jung,1 Su-Cheol Han,2 Jeong Ho Hwang,2 Eunhye Jung,4 Dasom Hwang,4 Jin Soo Shin,4 Cheong-Weon Cho1 1College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, Republic of Korea; 2Center for Companion Animal New Drug Development, Jeonbuk Branch, Korea Institute of Toxicology (KIT), Jeongeup, Jeollabuk-do, 53212, Republic of Korea; 3Human Health Risk Assessment Center, Jeonbuk Branch, Korea Institute of Toxicology (KIT), Jeongeup, Jeollabuk-do, 53212, Republic of Korea; 4Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea*These authors contributed equally to this workCorrespondence: Jin Soo Shin, Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea, Email jsshin@krict.re.kr Cheong-Weon Cho, College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea, Email chocw@cnu.ac.krIntroduction: The ongoing SARS-CoV-2 pandemic has affected public health, the economy, and society. This study reported a nanotechnology-based strategy to enhance the antiviral efficacy of the antiviral agent remdesivir (RDS).Results: We developed a nanosized spherical RDS-NLC in which the RDS was encapsulated in an amorphous form. The RDS-NLC significantly potentiated the antiviral efficacy of RDS against SARS-CoV-2 and its variants (alpha, beta, and delta). Our study revealed that NLC technology improved the antiviral effect of RDS against SARS-CoV-2 by enhancing the cellular uptake of RDS and reducing SARS-CoV-2 entry in cells. These improvements resulted in a 211% increase in the bioavailability of RDS.Conclusion: Thus, the application of NLC against SARS-CoV-2 may be a beneficial strategy to improve the antiviral effects of antiviral agents.Keywords: remdesivir, nanostructured lipid carrier, antiviral effect, SARS-CoV-2, virus entry

Ticagrelor (TCG), an antiplatelet agent, has low solubility and permeability; thus, there are many trials to apply the pharmaceutical technology for the enhancement of TCG solubility and permeability. Herein, we have developed the TCG high-loaded nanostructured lipid carrier (HL-NLC) and solidified the HL-NLC to develop the oral tablet. The HL-NLC was successfully fabricated and optimized with a particle size of 164.5 nm, a PDI of 0.199, an encapsulation efficiency of 98.5%, and a drug loading of 16.4%. For the solidification of HL-NLC (S-HL-NLC), the adsorbent was determined based on the physical properties of the S-HL-NLC, such as bulk density, tap density, angle of repose, Hausner ratio, Carr's index, and drug content. Florite R was chosen because of its excellent adsorption capacity, excellent physical properties, and solubility of the powder after manufacturing. Using an S-HL-NLC, the S-HL-NLC tablet with HPMC 4 K was prepared, which is showed a released extent of more than 90% at 24 h. Thus, we have developed the sustained release tablet containing the TCG-loaded HL-NLC. Moreover, the formulations have exhibited no cytotoxicity against Caco-2 cells and improved the cellular uptake of TCG. In pharmacokinetic study, compared with raw TCG, the bioavailability of HL-NLC and S-HL-NLC was increased by 293% and 323%, respectively. In conclusion, we successfully developed the TCG high-loaded NLC tablet, that exhibited a sustained release profile and enhanced oral bioavailability.

A size-controlled high-quality sulphide solid electrolyte for all-solid-state Li batteries was prepared by a novel polar-to-nonpolar solvent exchange process.

Na3ZnGaS4 is a new class of Na+-conducting solid electrolytes. Herein, vacancies are introduced into Na(2) sites by adjusting the Zn/Ga ratio. The conductivity of vacancy-incorporated Na2.8Zn0.8Ga1.2S4 is increased by more than two orders of magnitude.

Objectives: Ssanghwa-tang (SHT) is a traditional herbal formula comprising nine medicinal herbs, and it is used for reducing fatigue in Korea. SHT exerts various effects such as anti-inflammatory, antioxidant, and anti-aging activities, and protection against acute hepatotoxicity. However, the genotoxicity of SHT has not yet been established.Methods: Ten components were identified in SHT water extract by using high-performance liquid chromatography analysis. We assessed the genotoxicity of SHT by using bacterial reverse mutation (Ames test), chromosome aberration, and in vivo micronucleus tests.Results: The contents of paeoniflorin, glycyrrhizin, and liquiritin apioside in SHT were 15.57, 6.94, and 3.48 mg/g extract, respectively. SHT did not increase the revertant colonies of Salmonella typhimurium and Escherichia coli strains in the presence or absence of metabolic activity. Although SHT did not induce structurally abnormal chromosomes in Chinese hamster lung (CHL) cells in the presence of metabolic activity, the number of structurally aberrated chromosomes increased dose-dependently in the absence of metabolic activity. In the in vivo micronucleus test, SHT did not affect the formation of micronuclei compared with the vehicle control.Conclusions: Genotoxicity of SHT was not observed in the Ames test and in vivo micronucleus test. However, based on the results of chromosome aberration test, it can be presumed that SHT has the potential to induce genotoxicity because it induced structurally abnormal chromosomes in the absence of metabolic activity.

Stroke research in non-human primates (NHPs) with gyrencephalic brains is a critical step in overcoming the translational barrier that limits the development of new pharmaceutical and rehabilitative strategies for stroke. White-matter stroke (WMS) has a unique pathophysiology from gray-matter stroke and is not well understood because of a lack of pertinent animal models. To create a precise capsular infarct model in the cynomolgus macaque, we first used electrical stimulation to map hand movements, followed by viral tracing of the hand motor fibers (hMFs). This enabled us to identify stereotactic targets in the posterior limb of the internal capsule (PLIC). Neural tracing showed that hMFs occupy the full width of the PLIC, owing to overlap with the motor fibers for the leg. Furthermore, the hMFs were distributed in an oblique shape, requiring coronal tilting of the target probe. We used the photothrombotic infarct lesioning technique to precisely destroy the hMFs within the internal capsule. Double-point infarct lesioning that fully compromised the hMFs resulted in persistent hand motor and walking deficits whereas single-point lesioning did not. Minor deviations in targeting failed to produce persistent motor deficits. Accurate stereotactic targeting with thorough involvement of motor fibers is critical for the production of a capsular infarct model with persistent motor deficits. In conclusion, the precision capsular infarct model can be translated to the NHP system to show persistent motor deficits and may be useful to investigate the mechanism of post-stroke recovery as well as to develop new therapeutic strategies for the WMS.

Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01097-4.

Highlights • Four-week repeated-dose toxicity of intramuscular DSS was studied in minipigs. • DSS administration at ≥10 mg/kg/day causes toxicity and injection-site reaction. • The NOAEL of DSS after 4-week administration was 2 mg/kg/day in minipigs., Diclofenac sodium salt (DSS) is a widely used nonsteroidal anti-inflammatory drug. The present study was performed under good laboratory practice (GLP) regulations to investigate the toxicity of DSS after 4 weeks of repeated intramuscular administration at doses of 0, 2, 10, or 20 mg/kg/day in 32 minipigs and to evaluate the DSS effect following a 2-week recovery period. Dose-related clinical signs and alterations of hematological or clinical chemistry parameters, organ weight, and macroscopic as well as histopathological findings in hepatic, renal, gastrointestinal, skin and injection sites were observed in both sexes’ animals of the 10 or 20 mg/kg/day group. With the exception of the skin-related findings, most symptoms showed a tendency to resolve after the 2-week recovery period. The systemic exposure (AUClast) of DSS in plasma showed similar pattern to the increase rate of the dose and similar values between males and females except for the female 20 mg/kg dose group (56 %) on Day1. The systemic exposure showed a decreasing trend in the 10 or 20 mg/kg group after 4-week of repeated administration compared to Day1. The no-observed-adverse-effect level of DSS in this study was considered to be 2 mg/kg/day in both male and female minipigs.

The energy densities (EDs) of lithium-ion batteries have improved remarkably mostly via increases in the capacity of cathode materials, which suggests that the next quantum leap will require the simultaneous implementation of high-voltage cathodes and Li metal anodes for high-voltage operations. Herein, we describe for the first time that the compatibility of Li metal in adiponitrile (ADN) is ensured via the utilization of porous Li2O-coated Li (Li/Li2O). The optimal Li2O layer is constructed simply by immersing Li metal in ADN containing nitronium tetrafluoroborate (NO2BF4). When cycled in LiBF4/ADN, porous Li2O facilitates the formation of a stable LiF-enriched interfacial layer, which enables reversible Li plating/stripping during extended cycles with no dendrite formation. The sequential formation of LiF within the pores of Li2O is crucial, because massive formation of LiF precipitates is unavoidable without Li2O. Li/Li2O is also operable in LiTFSI/ADN (TFSI = bis(trifluoromethane)sulfonimide) with the addition of LiBF4. Finally, as a proof-of-concept experiment, we show the charge/discharge behaviors of LiNi0.5Mn1.5O4 when coupled with Li/Li2O in LiBF4:LiTFSI/ADN, which proves that a Li metal cell can be charged to 6.0 V. We hope that this work will expedite the development of Li metal batteries with a high level of ED in the dinitrile family.

Oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) and polyhexamethyleneguanidine phosphate (PHMG-P) are cationic biocides containing a guanidine group. Direct exposure of the lungs to PHMG-P is known to induce pulmonary inflammation and fibrotic changes. Few studies have assessed the pulmonary toxicity of PGH, another member of the guanidine family. In this study, we assessed the acute and repeated toxicity of PGH and PHMG-P to compare the pathological progression induced by both chemicals. PGH (1.5 mg/kg) or PHMG (0.6 mg/kg) was instilled intratracheally to mice once or three times every 4 days; subsequently, cytokine levels were quantified and a histopathological examination was performed. To verify the toxic mechanism of PGH, we quantified cell viability and cytokine production induced by PGH or PHMG-P in the presence or absence of anionic material in cells. Instillation of PGH and PHMG-P into the mouse lung increased cytokine production, immune cell infiltration, and pulmonary fibrotic changes. These pathological changes were exacerbated over time in the single- and the repeated-dose PHMG-P groups, but were resolved over time in the PGH groups. PGH or PHMG-P showed cytotoxic effects, IL-1β secretion, and ROS production in a dose-dependent manner in human cell lines. However, the co-treatment of anionic materials with PGH or PHMG-P significantly reduced these toxic responses, which confirmed that the cation of PGH disrupted the plasma membrane via ionic interaction, as observed for PHMG-P. In addition, we suggest the disruption of plasma membrane as a molecular initiating event of cationic chemicals-induced adverse outcomes when exposed directly to the lungs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s43188-020-00058-x) contains supplementary material, which is available to authorized users.

In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 – as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 μg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.

The development of high-performance Mg-alloyable anodes operable in conventional electrolytes could be a critical breakthrough for the viability of magnesium-ion batteries (MIBs). Herein, we show that 3Mg/Mg2Sn can be used as an anode with unprecedented high performance in conventional electrolytes. The as-made 3Mg/Mg2Sn consists of crystalline Mg-rich (c-Mg), amorphous Mg-rich (a-Mg), and intermetallic Mg2Sn phases. During the 1st de-magnesiation of 3Mg/Mg2Sn in Mg(HMDS)2 : MgCl2 (HMDS = hexamethyldisilazide), c-Mg is first dealloyed. After the complete dissolution of c-Mg, a-Mg and intermetallic Mg2Sn are then de-magnesiated at slightly higher voltages, resulting in a capacity of 1243 mA h g−1 (3.9 Mg2+) at 100 mA g−1. Subsequent charge/discharge reversibly delivers ca. 805 mA h g−1 (2.5 Mg2+) with no re-formation of c-Mg, which indicates that the reversibility comes mostly from Mg2Sn (Mg2Sn ⇆ Sn) with an additional contribution from a-Mg (0.5 Mg2+). Though not involved in the reversible process, the dissolution of c-Mg generates micro-to-macropores, which contribute to the excellent rate-capability and cyclability of 3Mg/Mg2Sn. The Mg2+ ions, irreversibly released from 3Mg/Mg2Sn, also compensate for a decrease in the Mg2+ concentration, which can occur when a full-cell is constructed with a Mg2+-trapping Mo6S8 cathode. Furthermore, once dealloyed in Mg(HMDS)2 : MgCl2, the 3Mg/Mg2Sn becomes compatible with various conventional electrolytes.

Cathode materials in potassium ion batteries (KIBs) generally exhibit low charge storage capabilities when compared with cathode materials implemented in lithium or sodium ion batteries. In this work, K0.78Fe1.60S2 is described as a high capacity KIB cathode that exhibits mixed anion/cation redox behaviors during charge/discharge (C/D). When charged to 3.2 V vs. K/K+, K+ extraction occurs along with simultaneous oxidations of S2− to S22− and Fe(II) to Fe(III). During subsequent discharge to 1.5 V, this process is reversed, in addition to a further reduction of Fe(II) to Fe(I). After a few C/D cycles, K0.78Fe1.60S2 reversibly delivers 0.69 K+ with a capacity of 100.5 mA h g−1 (i.e., K0.20Fe1.60S2 ⇆ K0.89Fe1.60S2). The evolution of S2− and Fe(II) valence states along with a lack of discernable changes in crystallographic dimensions clearly confirms the concomitant redox of anions and cations with C/D. Density functional theory calculations also validate the possibility of mixed redox reactions in K0.78Fe1.60S2. Unique structural features of K0.78Fe1.60S2 (layers consisting of edge-shared FeS4 tetrahedra with partial Fe vacancies) result in high K+ diffusion coefficients that are unprecedented (ca. 10−9 cm2 s−1), which contributes to an excellent rate capability (56.3 mA h g−1 at 1000 mA g−1vs. 100.5 mA h g−1 at 20 mA g−1). Nudged elastic band calculations also reveal that the diffusion preferentially occurs along [100] directions with a low activation energy barrier of 0.41 eV.

NaCrO2 with high rate-capability is an attractive cathode material for sodium-ion batteries (NIBs). However, the amount of reversibly extractable Na+ ions is restricted by half, which results in relatively low energy density for practical NIB cathodes. Herein, we describe aliovalent-doped O3–Na0.9[Cr0.9Sn0.1]O2 (NCSnO) and O3–Na0.8[Cr0.9Sb0.1]O2 (NCSbO), both of which show high-voltage characteristics that translate to an increase in energy density. In contrast to NaCrO2, NCSnO and NCSbO can be reversibly charged to 3.80 and 3.95 V, respectively, delivering 0.5 Na+ along with Cr3+/4+ redox alone. The reversible chargeability to Na0.4[Cr0.9Sn0.1]O2 and Na0.3[Cr0.9Sb0.1]O2 is not associated with the suppression of Cr6+ formation. Both compounds show concentrations of Cr6+ that are higher than that of Na0.3CrO2, with an absence of O3′ phases. This implies that aliovalent-doping contributes to a suppression of the Cr6+ migration into tetrahedral sites in the interslab space, which reduces the possibility of irreversible comproportionation. NCSnO and NCSbO deliver capacities comparable to that of NaCrO2, but show a higher average discharge voltage (2.94 V for NaCrO2; 3.14 V for NCSnO; 3.21 V for NCSbO), which leads to a noticeable increase in energy densities. The high-voltage characteristics of NCSnO and NCSbO are also validated via density-functional-theory calculations.

Zaltoprofen is a nonsteroidal anti-inflammatory drug with poor oral bioavailability. S(+)-zaltoprofen (SZPF)-loaded nanostructured lipid carriers (NLCs) were prepared to enhance oral bioavailability. SZPF-loaded NLCs (NLC-SZPF) were prepared using the hot-melting homogenization method and optimized using the Box-Behnken design. The characterization of optimized NLC-SZPF, in vitro release, cytotoxicity, cellular uptake, ex vivo permeability, and pharmacokinetic parameters were evaluated to confirm the advantages of NLC formulation. NLC-SZPF with a diameter of 105.5 ± 1.2 nm had a high encapsulation efficiency of 99.84 ± 0.01%. NLC-SZPF showed a sustained-release profile, high biocompatibility, and high permeability across the intestinal tract. The relative bioavailability of NLC-SZPF was 431.3% compared with that of SZPF after oral administration to experimental rats. NLC-SZPF was successfully optimized using experimental designs to enhance the oral bioavailability of SZPF. Hence, NLC-SZPF could be a promising approach to overcome the poor oral bioavailability of SZPF.

Background Telemetry is a wireless implanted device that measures biological signals in conscious animals and usually requires surgery for its removal when the study is finished. After removing the device, the animals are either used for other studies or euthanatized. Case presentation Herein, we report the case of a living cynomolgus monkey (Macaca fascicularis) that was used for the entire experimental period, instead of euthanasia, after surgical removal of an implanted telemetry system. Radiography was used to determine the status of the implanted telemetry, following which, a repair surgery was performed for removing the system; clinical signs were used to preserve the life of the cynomolgus monkey. Postoperative clinical signs, food consumption, hematology, and serum biochemistry were examined during the 12-month observational period. No abnormal readings or conditions were observed in the subject after implant removal. Conclusions This study may be a useful case report for living cynomolgus monkeys in telemetry implantations used throughout the study period. We suggest minimizing the suffering and improving the welfare of these animals.

Sodium dichloroisocyanurate-96% (NaDCC) is commonly used to treat drinking water, industrial water, and wastewater. However, exposure to NaDCC by inhalation can have toxic pulmonary effects in humans. In the present study, we evaluated the potential toxicity of NaDCC following a 90-day inhalation toxicity study in Sprague-Dawley/Crl:CD (SD) rats. The animals were exposed to 0.4, 2.0, or 10.0 mg/m

KFeO2 is presented as a new type of cathode material for potassium-ion batteries. In contrast to LiFeO2 and NaFeO2, KFeO2 has tetrahedrally coordinated Fe3+ ions linked by three-dimensional corner-sharing. When chemically oxidized, KFeO2 releases ca. 0.3 K+ (K0.7FeO2) and shows no apparent changes in X-ray diffraction patterns. Rietveld refinement of KFeO2 and K0.7FeO2 reveals negligible variation in the unit cell dimension and in the basic structure, but noticeable differences in FeO4 volumes and inter-tetrahedra angles due to the Jahn-Teller active Fe4+ (eg2t2g2) in K0.7FeO2. The refinement also shows no preferential extraction of K+ from two possible sites (K1 and K2), which coincides with the results from density-functional-theory calculation. In accordance with the compositional and structural analysis, KFeO2 delivers a reversible capacity of 60 mAh g−1 (ca. 0.28 K+) during the initial charge/discharge (C/D), showing a plateau-like voltage response at 3.43 V vs. K/K+. In-operando diffraction studies also show no distinctive signs of pattern evolution, which is likely due to the structural similarities of KFeO2 and K0.7FeO2. With repeated cycling, however, the reversible capacity of KFeO2 continuously decreases and falls to 30 mAh g−1 after 50 C/D cycles. The repeated changes in the FeO4 tetrahedra geometry appear to cause a decrease in the crystallinity of KFeO2, which eventually aggravates the facile K+ transport. The results of this study show that the practicality of KFeO2 can be realized via improvements of cyclability by mitigating the Jahn-Teller effect (for example, isovalent doping with Al3+or Ga3+).

O3–KCrO2 is the only known stoichiometric layered transition metal oxide with a layered structure, which enables efficient coupling with a graphite anode for K+-shuttling batteries. O3–KCrO2, however, shows low Coulombic efficiency during 1st charge/discharge cycle and continuous capacity fading during subsequent cycles. Here, we present a slightly K+-deficient compound P′3-K0.8CrO2, synthesized from a commercially available K2CrO4, as a stable cathode in potassium ion batteries. During the 1st charge, K0·8CrO2 mostly retains its P′3-phase with a short P3 region and finally returns to a P′3-phase (K0·48CrO2). Subsequent discharge shows reversible phase transitions, but ultimately yielded a new O′3-K0.9CrO2 phase. Absence of an O3-phase and persistence of a P′3-phase during charge/discharge, result in negligible volume changes (1.08%) and facile K+-diffusion through the spacious-prismatic sites (D = 10−11 - 10−10 cm2 s−1). This eventually contributes to a significant improvement in cyclic stability (99% retention after 300 cycles at 1 C) and rate capability (52 mAh·g−1 at 2 C), respectively. We believe that the use of slightly K+-deficient chromium oxides synthesized via a simple protocol should enhance the commercial viability of KxCrO2 in potassium ion batteries.

Ssanghwa-tang (SHT), a traditional herbal formula, has been widely used to recover fatigue or consumptive disease after an illness. Along with much attention to herbal formula, the concerns about the safety and toxicity have arisen. To establish the safety information, SHT was administrated in Crl:CD Sprague Dawley rats at a daily dose of 0, 1000, 2000, and 5000 mg/kg for 4 weeks. During the test periods, we examined the mortality, clinical observation, body weight change, food consumption, organ weights, hematology, serum biochemistry, and urinalysis parameters. No changes of mortality and necropsy findings occurred in any of the groups during the experimental period. In either sex of rats treated with SHT at 5000 mg/kg/day, changes were observed in food intake, reticulocyte, total bilirubin, some urinalysis parameters, and relative organ weights. The results indicated that SHT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. This dosage was considered no observed adverse effect level (NOAEL) and was appropriate for a 13-week subchronic toxicity study.

Ethnopharmacological relevance Traditional herbal medicines have diverse efficacy and are increasingly used worldwide. However, some of these herbal medicines have toxicities or side effects, but the scientific understanding of traditional herbal medicine toxicity has not yet been established. Asiasari Radix et Rhizoma (ARE) is known as a herbal medicine used to relieve pain, and recent studies have shown that ARE has anticancer and antimelanogenesis efficacy. Aim of the study Current study was conducted to assess the potential genotoxicity of an ethanolic extract of ARE. Materials and methods The genotoxixity of ARE was confirmed by the bacterial reverse mutation assay (Ames test), a mammalian chromosomal aberration test, and a micronucleus test in vivo using ICR mice and comet assay using Sprague-Dawley rats. Results ARE showed no genotoxicity in a micronucleus test up to 2000 mg/kg body weight in vivo. By contrast, the chromosomal aberration test showed that ARE induced an increase in the number of chromosomal aberrations after treatment for 6 h with a metabolic activation system and for 6 and 22 h without the metabolic activation system when compared with vehicle control. In the Ames test, all strains except TA1535, with or without a metabolic activation system, showed an increase in the number of revertant mutant colonies in the ARE-treated group. In comet assay, DNA damage was observed in the stomach when ARE was administered. Conclusion ARE potentially shows genotoxicity by inducing DNA damage.

Repeated charge/discharge in aqueous zinc-ion batteries (ZIBs) commonly results in surface corrosion/passivation and dendrite formation on zinc anodes, which is a major challenge for the commercialization of zinc-based batteries. In this work, metallic Zn modified by self-assembled monolayers is described as a viable anode for ZIBs. ω-mercaptoundecanoic acid that is spontaneously adsorbed on Zn (MUDA/Zn) contributes to the simultaneous suppression of side reactions and dendrite formation in ZIBs. Though one-molecular-thick, densely packed alkyl chains prohibit H

Glufosinate-ammonium (GLA) is a broad-spectrum herbicide for agricultural weed control and crop desiccation. Due to many GLA-resistant crops being developed to effectively control weeds and increase harvest yields, herbicide usage and the residual GLA in food has increased significantly. Though perinatal exposure by the residual GLA in food might affect brain development, the developmental neurotoxicity of GLA is still unclear. Therefore, this study aimed to investigate the effects of perinatal exposure to GLA on cortical development. The analysis revealed that perinatal GLA exposure altered behavioral changes in offspring, especially motor functional behavior. Moreover, perinatal GLA exposure affected cortical development, particularly by disrupting interneuron migration. These results provide new evidence that early life exposure to GLA alters cortical development.

BACKGROUND: Since primates have more biological similarities to humans than do other animals, they are a valuable resource in various field of research, including biomedicine, regenerative medicine, and drug discovery. However, there remain limitations to maintenance and expansion of primary hepatocytes derived from nonhuman primates. To overcome these limitations, we developed a novel culture system for primate cells. METHODS: Primary hepatocytes from Macaca fascicularis (mf-PHs) were isolated from hepatectomized liver. To generate chemically derived hepatic progenitor cells (mf-CdHs), mf-PHs were cultured with reprogramming medium containing A83-01, CHIR99021, and hepatocyte growth factor (HGF). The bi-potent differentiation capacity of mf-CdHs into hepatocytes and biliary epithelial cells was confirmed by treatment with hepatic differentiation medium (HDM) and cholangiocytic differentiation medium (CDM), respectively. RESULTS: mf-PHs cultured with reprogramming medium showed rapid proliferation capacity in vitro and expressed progenitor-specific markers. Moreover, when cultured in HDM, these progenitor cells stably differentiated into hepatocyte-like cells expressing the mature hepatic markers. On the other hand, when cultured in CDM, the differentiated biliary epithelial cells expressed mature cholangiocyte characteristics. CONCLUSION: The results of the present study demonstrate that we successfully induced the formation of hepatic progenitor cells from mf-PHs by culturing them with a combination of small molecules, including growth factors. These results offer a means of expanding nonhuman primate hepatocytes without genetic manipulation for cellular resource, preclinical applications and regenerative medicine for the liver.

NaCrO

Background and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.Experimental ApproachWe designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.Representative SchematicWhat is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis.What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

Ginseng (Panax ginseng) is commonly used in Asia as a medicinal herb. In particular, fermented ginseng, GBCK25, has been recently developed to increase ginsenoside absorption. It also has other beneficial biological effects such as hemodynamic and anti-inflammation functions. Here, we investigated the potential toxicity of GBCK25 in Sprague–Dawley rats following 13 weeks of GBCK25 treatment by oral gavage at doses of 250, 500, or 1000 mg/kg/day and reversible toxic effects over a 4-week recovery phase. Ten male and female rats per group were randomly allocated to the main toxicology groups and five male and female rats per group were allocated to the 0 and 1000 mg/kg/day recovery groups, respectively. There was no mortality; significant clinical toxicity or microscopic findings; and changes in body weight, food consumption, hematological parameters, serum biochemistry, or absolute and relative organ weights in any of the groups. In conclusion, there were no toxicological changes upon repeated oral gavage of GBCK25 at doses of 250, 500, or 1000 mg/kg/day in Sprague–Dawley rats over 13 weeks. The no-observed-adverse-effect level of GBCK25 was 1000 mg/kg/day in both sexes of Sprague–Dawley rat.

High-dose radiation-induced tissue damage is a major limiting factor in the medical application of nuclear technology. Herein, we tested 28-day repeated-dose toxicity of KMRC011, an agonist of toll-like receptor (TLR) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. KMRC011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional 2-week recovery period. There were no dose-related toxicological changes in mortality, clinical observations, body weight, food consumption, ophthalmological findings, electrocardiographs, coagulation, serum chemistry, organ weights, or urinalysis and urine chemistry. Although treatment-related changes, such as increased white blood cells, increased absolute and relative neutrophils, decreased relative lymphocytes and inflammatory lesions, were noted in the maximum dose group, these findings were not observed after the 2-week recovery period. Further, we considered that the kidneys and heart may be target organs of TLR5 agonists, as well as the spleen, and that autophagic signals can be triggered in tissue damage and the repair process. Importantly, accumulation of p62 protein, an indicator of autophagy, and a decrease of caveolin-1 protein, a regulator of TLR5 protein half-life, were found in both tissues from the highest dose group. Therefore, we conclude that the no-observed-adverse-effect level for KMRC011 may be greater than 0.04 mg/kg/day in male and female monkeys. Additionally, we propose that further studies are needed to identify the molecular signals, which are related to KMRC011-induced adverse effects.

P′3-type Na0.52CrO2 is proposed as a viable cathode material for potassium-ion batteries (KIBs). The in-situ-generated title compound during the first charge of O3-NaCrO2 in K+-containing electrolytes can reversibly accommodate 0.35 K+-ions with no interference with Na+. In addition to the sequential interlayer slippage that occurs with Na+-insertion, K+-insertion into Na0.52CrO2 induces a sudden phase separation, which ultimately results in a biphasic structure when fully discharged (K+-free O3-NaCrO2 and K+-rich P3-K0.6Na0.17CrO2). A reversible transition between monophasic (Na0.52CrO2) and biphasic states during repeated K+-insertion/deinsertion is also maintained, which contributes to superior electrochemical properties of the title compound when used as a KIB cathode. Na0.52CrO2 delivers a specific capacity of 88 mA h g–1 with an average discharge potential of 2.95 V versus K/K+. This high level of energy density (260 W h kg–1 at 0.05C) is not substantially decreased at fast C-rates (195 W h kg–1 at ...

Herein is the first use of a CoSn(OH)6/graphene composites as a high-performance anode in lithium ion batteries (LIBs). CoSn(OH)6 alone is found to be electrochemically active and to possess electrochemical properties that are superior to those displayed in its dehydrated form (CoSnO3). In contrast to the formation of 3Li2O in CoSnO3 during the first discharge (CoSnO3 + 6Li+ + 6e− → Co + Sn + 3Li2O), the production of 6 mol of LiOH in CoSn(OH)6 (CoSn(OH)6 + 6Li+ + 6e− → Co + Sn + 6LiOH) seems to provide nanometric Co/Sn particles with more efficient reversibility for the subsequent Li+-insertion/de-insertion via conversion/alloy reactions. The electrochemical performance of CoSn(OH)6 is further improved when composited with graphenes. This is accomplished by electrostatically combining negatively charged Co2+/Sn2+-anchored graphene oxide (GO) with positively charged amine-functionalized graphene (GN) in a solution. The subsequent hydrothermal reaction produces CoSn(OH)6 nanocubes that are tightly held by graphene sheets (GO/CS/GN). The GO/CS/GN delivers unprecedentedly high capacity and excellent cyclability (discharge capacities of 1475 mAh·g−1 for the 100th charge/discharge (C/D) cycles at a 0.1 A·g−1). In contrast to the comparison materials (CoSnO3/graphene composites) the rate performance is also remarkable, delivering a capacity of 650 mAh·g−1 at 2.0 A·g−1. Keywords: CoSn(OH)6, Graphene, Lithium ion battery, Anode, Self-assembly

For the first time we report that hard-wood (oak) can spontaneously create interconnected channels of μm to nm in diameter during carbonization at an optimized temperature (1100°C). These microstructural features have never been found in other hard-carbons without the use of additives. When compared with sucrose-based hard-carbon (SHC), oak-based hard-carbon (OHC) shows much higher charge-storage capability (ca. 223 vs. 112 mAhg−1 at 20 mAg−1) and excellent stability (fading rate of 0.04 vs. 0.08%cycle−1) as an anode in potassium-ion batteries. The high performance of OHC mainly results from interwoven nanoporous channels, which lead to facile charge transfer and fast K+-diffusion.

This paper describes a study and experimental demonstration on a magnetron operating at 2.45 GHz. We checked the characteristics of the 1 kW magnetron. There were two noise sources of magnetron at frequencies of 0.5 Hz and 75 kHz. In order to suppress these noises, we used an external injection locking method. Measurement results showed that the frequency noise suppression was down up to 30 dBc and the phase fluctuation is reduced to 4 degrees when injection input power was 7 W. Power combining experiments were performed using two identical magnetrons. An initial result showed an output power of 2 kW, corresponding to combining efficiency $\pmb{ > 93\%}$ .

Despite extensive effort during the past few decades, a comprehensive understanding of the key variables governing the electrochemical properties of cathode materials in Li-ion batteries is still far from complete. To elucidate the critical parameters affecting energy density (ED) and capacity (Q) retention in layer and spinel cathodes, we data-mine the existing experimental data via confirmatory factor analysis (CFA) based on a structural equation model (SEM), which is a proven, versatile tool in understanding complex problems in the social science. The data sets are composed of 18 and 15 parameters extracted from 38 layer and 33 spinel compounds, respectively. CFA reveals the irrelevance of Q retention to all the parameters we adopt, but it also reveals the sensitive variations of ED with specific parameters. We validate the usefulness of CFA in material science and pinpointed critical parameters for high-ED cathodes, hoping to suggest a new insight in materials design.

Many researchers are using viruses to deliver genes of interest into the brains of laboratory animals. However, certain target brain cells are not easily infected by viruses. Moreover, the differential tropism of different viruses in monkey brain is not well established. We investigated the cellular tropism of lentivirus and adeno-associated virus (AAV) toward neuron and glia in the brain of cynomolgus monkeys (Macaca fascularis). Lentivirus and AAV were injected into putamen of the monkey brain. One month after injection, monkeys were sacrificed, and then the presence of viral infection by expression of reporter fluorescence proteins was examined. Tissues were sectioned and stained with NeuN and GFAP antibodies for identifying neuronal cells or astrocytes, respectively, and viral reporter GFP-expressing cells were counted. We found that while lentivirus infected mostly astrocytes, AAV infected neurons at a higher rate than astrocytes. Moreover, astrocytes showed reactiveness when cells were infected by virus, likely due to virus-mediated neuroinflammation. The Sholl analysis was done to compare the hypertrophy of infected and uninfected astrocytes by virus. The lentivirus infected astrocytes showed negligible hypertrophy whereas AAV infected astrocytes showed significant changes in morphology, compared to uninfected astrocytes. In the brain of cynomolgus monkey, lentivirus shows tropism for astrocytes over neurons without much reactivity in astrocytes, whereas AAV shows tropism for neurons over glial cells with a significant reactivity in astrocytes. We conclude that AAV is best-suited for gene delivery to neurons, whereas lentivirus is the best choice for gene delivery to astrocytes in the brain of cynomolgus monkeys.

Repeated dose oral toxicity and toxicokinetic of KDS2010, a new drug for Parkinson's disease, was investigated after 4-week repeated oral administration at 30, 50, 75, or 100 mg/kg/day in rats. Body weight and body weight gain decreased in rats of both sexes in the 75 and 100 mg/kg groups, and food consumption was reduced in male rats of the 75 and 100 mg/kg male groups. Histological alterations were observed in the kidney (urothelial hyperplasia, inflammatory cell infiltration in the renal pelvis, tubular vacuolation/degeneration, basophilic tubules, and hyaline droplets in the proximal tubules) of the 75 and 100 mg/kg male groups and the 50 and 100 mg/kg female groups. The 75 and 100 mg/kg male groups showed adverse effect in the testes (degeneration/exfoliation of germ cells, seminiferous tubules atrophy) and epididymis (cellular debris, oligospermia). These changes were partially recovered after a 2-week recovery period. However, basophilic tubules and hyaline droplets in the proximal tubules in the kidney and germ cell degeneration/exfoliation in the testis were not recovered. In toxicokinetics study, systemic exposure to KDS2010 increased proportionally in both sexes by in a dose -dependent manner. In addition, repeated administration for 4 weeks led to increased tendency of systemic exposure in both sexes compared with that in Day 1. In conclusion, KDS2010 was shown to target the kidney and testis with a no-observed-adverse-effect level of 50 and 30 mg/kg/day for males and females, respectively.

KCrS

High-dose radiation-induced tissue damage is a major limiting factor in the medical application of nuclear technology. Herein, we tested 28-day repeated-dose toxicity of KMRC011, an agonist of toll-like receptor (TLR) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. KMRC011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional 2-week recovery period. There were no dose-related toxicological changes in mortality, clinical observations, body weight, food consumption, ophthalmological findings, electrocardiographs, coagulation, serum chemistry, organ weights, or urinalysis and urine chemistry. Although treatment-related changes, such as increased white blood cells, increased absolute and relative neutrophils, decreased relative lymphocytes and inflammatory lesions, were noted in the maximum dose group, these findings were not observed after the 2-week recovery period. Further, we considered that the kidneys and heart may be target organs of TLR5 agonists, as well as the spleen, and that autophagic signals can be triggered in tissue damage and the repair process. Importantly, accumulation of p62 protein, an indicator of autophagy, and a decrease of caveolin-1 protein, a regulator of TLR5 protein half-life, were found in both tissues from the highest dose group. Therefore, we conclude that the no-observed-adverse-effect level for KMRC011 may be greater than 0.04 mg/kg/day in male and female monkeys. Additionally, we propose that further studies are needed to identify the molecular signals, which are related to KMRC011-induced adverse effects.