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Background: Spatial and functional hepatic zonation, established by the heterogeneous tissue along the portal-central axis of the liver, is important for ensuring optimal liver function. Researchers have attempted to develop reliable hepatic models to mimic the liver microenvironment and analyze liver function using hepatocytes cultured in the developed systems. However, mimicking the liver microenvironment in vitro remains a great challenge owing to the lack of perfusable vascular networks in the model systems and the limitation in maintaining hepatocyte function over time. Methods: In this study, we established a microphysiological system that operated under continuous flush medium flow, thereby allowing the supply of nutrients and oxygen to liver organoids and the removal of waste and release of cytokines therefrom, similar to the function of blood vessels. Results: The application of microphysiological system to organoid culture was advantageous for reducing the differentiation time and enhancing the functional maturity of human liver organoid. Conclusion: Hence, our microphysiological culture system might open the possibility of the miniaturized liver model system into a single device to enable more rational in vitro assays of liver response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Byeon, Jung, Han, Son and Jeong.)

Vascular smooth muscle cell (VSMC) proliferation and migration play critical roles in arterial remodeling. Citropten, a natural organic compound belonging to coumarin and its derivative classes, exhibits various biological activities. However, mechanisms by which citropten protects against vascular remodeling remain unknown. Therefore, in this study, we investigated the inhibitory effects of citropten on VSMC proliferation and migration under high-glucose (HG) stimulation. Citropten abolished the proliferation and migration of rat vascular smooth muscle cells (RVSMCs) in a concentration-dependent manner. Also, citropten inhibited the expression of proliferation-related proteins, including proliferating cell nuclear antigen (PCNA), cyclin E1, cyclin D1, and migration-related markers such as matrix metalloproteinase (MMP), MMP2 and MMP9, in a concentration-dependent manner. In addition, citropten inhibited the phosphorylation of ERK and AKT, as well as hypoxia-inducible factor-1α (HIF-1α) expression, mediated to the Krüppel-like factor 4 (KLF4) transcription factor. Using pharmacological inhibitors of ERK, AKT, and HIF-1α also strongly blocked the expression of MMP9, PCNA, and cyclin D1, as well as migration and the proliferation rate. Finally, molecular docking suggested that citropten docked onto the binding site of transient receptor potential vanilloid 1 (TRPV1), like epigallocatechin gallate (EGCG), a well-known agonist of TRPV1. These data suggest that citropten inhibits VSMC proliferation and migration by activating the TRPV1 channel., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Human iPSC-derived cardiac organoids (hiPSC-COs) for cardiotoxicity drug testing via the variety of cell lines and unestablished protocols may lead to differences in response results due to a lack of criteria for generation period and size. To ensure reliable drug testing, it is important for researchers to set optimal generation period and size of COs according to the cell line and protocol applied in their studies. Hence, we sought to propose a process to establish minimum criteria for the generation duration and size of hiPSC-COs for cardiotoxic drug testing. We generated hiPSC-COs of different sizes based on our protocol and continuously monitored organoids until they indicated a minimal beating rate change as a control that could lead to more accurate beating rate changes on drug testing. Calcium transients and physiological tests to assess the functionality of hiPSC-COs on selected generation period, which showed regular cardiac beating, and immunostaining assays to compare characteristics were performed. We explained the generation period and size that exhibited and maintained regular beating rate changes on hiPSC-COs, and lead to reliable response results to cardiotoxicity drugs. We anticipate that this study will offer valuable insights into considering the appropriate generation period and size of hiPSC-COs ensuring reliable outcomes in cardiotoxicity drug testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hinokitiol (HKT) is one of the essential oil components found in the heartwood of Cupressaceae plants, and has been reported to have various bioactive effects, including anti-inflammatory effects. However, the improving effect of HKT on periodontitis, which is characterized by periodontal tissue inflammation and alveolar bone loss, has not been clearly revealed. Therefore, we investigated the periodontitis-alleviating effect of HKT and the related molecular mechanisms in human periodontal ligament cells. According to the study results, HKT downregulated SIRT1 and NOX4, which were increased by Porphyromonas gingivalis Lipopolysaccharide (PG-LPS) stimulation and were found to regulate pro-inflammatory mediators and oxidative stress through SIRT1/NOX4 signals. Additionally, by increasing the expression of osteogenic makers such as alkaline phosphatase, osteogenic induction of human periodontal ligament (HPDL) cells, which had been reduced by PG-LPS, was restored. Furthermore, we confirmed that NOX4 expression was regulated through regulation of SIRT1 expression with HKT. The in vitro effect of HKT on improving periodontitis was proven using the periodontal inflammation model, which induces periodontal inflammation using ligature, a representative in vivo model. According to in vivo results, HKT alleviated periodontal inflammation and restored damaged alveolar bone in a concentration-dependent manner in the periodontal inflammation model. Through this experiment, the positive effects of HKT on relieving periodontal tissue inflammation and recovering damaged alveolar bone, which are important treatment strategies for periodontitis, were confirmed. Therefore, these results suggest that HKT has potential in the treatment of periodontitis.

For centuries, natural products are regarded as vital medicines for human survival. Clematis terniflora var. mandshurica (Rupr.) Ohwi is an ingredient of the herbal medicine, Wei Ling Xian, which has been used in Chinese medicine to alleviate pain, fever, and inflammation. In particular, C. terniflora leaves have been used to cure various inflammatory diseases, including tonsillitis, cholelithiasis, and conjunctivitis. Based on these properties, this study aimed to scientifically investigate the anti-inflammatory effect of an ethanol extract of leaves of C. terniflora (EELCT) using activated macrophages that play central roles in inflammatory response. In this study, EELCT inhibited the essential inflammatory mediators, such as nitric oxide, cyclooxygenase-2, tumor necrosis factor- α , interleukin- (IL-) 6, IL-1 β , and inducible nitric oxide synthase, by suppressing the nuclear factor- κ B and mitogen-activated protein kinase activation in macrophages. Acute lung injury (ALI) is a fatal respiratory disease accompanied by serious inflammation. With high mortality rate, the disease has no effective treatments. Therefore, new therapeutic agents must be developed for ALI. We expected that EELCT can be a promising therapeutic agent for ALI by reducing inflammatory responses and evaluated its action in a lipopolysaccharide- (LPS-) induced ALI model. EELCT alleviated histological changes, immune cell infiltration, inflammatory mediator production, and protein-rich pulmonary edema during ALI. Collectively, our results may explain the traditional usage of C. terniflora in inflammatory diseases and suggest the promising potential of EELCT as therapeutic candidate for ALI., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Ji-Yeong Park et al.)

Atopic dermatitis (AD) is an allergic disorder characterized by skin inflammation. It is well known that the activation of various inflammatory cells and the generation of inflammatory molecules are closely linked to the development of AD. There is accumulating evidence demonstrating the beneficial effects of herbal extracts (HEs) on the regulation of inflammatory response in both in vitro and in vivo studies of AD. This review summarizes the anti-atopic effects of HEs and its associated underlying mechanisms, with a brief introduction of in vitro and in vivo experiment models of AD based on previous and recent studies. Thus, this review confirms the utility of HEs for AD therapy.

Periodontal disease is a chronic disease with a high prevalence, and in order to secure natural materials to prevent oral diseases, new materials that protect periodontal tissue from inflammation are being sought. Genes were identified using real-time quantitative polymerase chain reaction (RT-qPCR), and proteins were confirmed using Western blot. Dichlorodihydrofluorescein diacetate (DCF-DA) analysis was used, and the antibacterial effects were confirmed through Minimum Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) analysis. To confirm this effect in vivo, Sprague-Dawley rats, in which periodontitis was induced using ligation or Lipopolysaccharide of Porphyromonas gingivalis (PG-LPS), were used. In vitro experiments using human periodontal ligament (HPDL) cells stimulated with PG-LPS showed that Ginsenoside Rg6 (G-Rg6) had anti-inflammatory, antibacterial, antioxidant, and osteoblast differentiation properties. In vivo, G-Rg6 was effective in Sprague-Dawley rats in which periodontitis was induced using ligation or PG-LPS. Therefore, Ginsenoside Rg6 shows potential effectiveness in alleviating periodontitis.

The possibility of inducing skin sensitization reactions following exposure to various chemicals can lead to skin diseases, and the evaluation of skin sensitivity to such substances is very important. However, as animal tests for skin sensitization are prohibited, the OECD Test Guideline 442 C was designated as part of an alternative testing method. Therefore, in this study, the reactivity of cysteine and lysine peptides to nanoparticle substrates was identified through HPLC-DAD analysis according to the skin sensitization animal replacement test method specified in the OECD Test Guideline 442 C. In this study, all criteria for skin sensitization experiments specified in OECD Test Guideline 442 C were satisfied. As a result of analyzing the disappearance rates of cysteine and lysine peptides for the five types of nanoparticle substrates (TiO 2 , CeO 2 , Co 3 O 4 , NiO, and Fe 2 O 3 ) using the established analytical method, all were identified as positive. Therefore, our findings suggest that basic data from this technique can contribute to skin sensitization studies by providing the depletion percentage of cysteine and lysine peptides for nanoparticle materials that have not yet been tested for skin sensitization., Competing Interests: Conflict of interestThe authors have declared that there is no conflict of interest., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Osteoporosis is a systemic skeletal disorder where osteoclasts are prevalent among osteoblasts. Oxidative stress is one of the main causes of osteoporosis, and nuclear factor erythroid-2-related factor 2 (Nrf2) is the master regulator of antioxidant responses. Phytol, a diterpene isolated from Stevia rebaudiana leaves, has many biological effects, including antimicrobial, antioxidant, and anti-inflammatory effects. This study investigated the crosstalk between Nrf2 and osteoclast differentiation in the presence of phytol. Phytol inhibited osteoclast differentiation through TRAP-positive and F-actin formation. The expression of anti-nuclear factor of activated T cells-c1 (NFATc1) and c-Fos was suppressed by phytol, as shown using Western blot and RT-PCR analysis. Phytol inhibited oxidative stress by suppressing reactive oxidant species (ROS) accumulation while recovering antioxidant enzymes, including superoxide dismutase and catalase. Additionally, phytol ameliorated osteoclast-specific differentiation, function, and oxidative stress through Nrf2 regulation by siRNA transfection. In conclusion, these data demonstrate the inhibitory effect of phytol on osteoclast differentiation through Nrf2 regulation, suggesting its potential use in oxidative stress-related osteoporosis and bone diseases.

Background: Atopic dermatitis (AD) is multifactorial disease that is highly involved in the activity of T cells from the skin lesion. Seeds of Helianthus annuus extract have been traditionally used as anti-inflammatory reagent but few studies have been reported on leaf of H. annuus that are discarded uselessly as an immunomodulator., Purpose: Therefore, here, the regulatory effect of Helianthus annuus extract (HAE) on AD via suppression of T cell activity was investigated., Methods: The efficacy of HAE was evaluated in T cells stimulated with CD3/CD28 antibody and PMA/A23187. And demonstration of the alleviating effect of HAE on AD in the ears of Balb/c female mice stimulated with mite extract and DNCB., Results: Pre-treatment with HAE abrogates IL-2 production from activated T cells. It was also found that HAE suppresses the expression of surface molecules in activated T cells. Cell viability results demonstrated that HAE is not associated with cytotoxicity in resting and activated T cells. Besides, we exhibited that regulated phosphorylation of MAPK through TAK1-IKKα-NFκB by pre-treatment with HAE leads to the suppressive effect of HAE on T cell activation. Oral administration of HAE attenuates manifestations of AD including reduced thickness of dermis and epidermis, decreased IgE level in serum, and declined mRNA levels of atopic cytokines on ear tissues. The ameliorative effect of HAE on AD was found to be associated with suppressed activity of T cells from draining lymph nodes., Conclusion: Therefore, our results provide that HAE alleviates AD symptoms via modulation of T cell activity. In addition, these results suggest the immunomodulatory effect of HAE on T-cell mediated diseases., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Atopic dermatitis (AD) is a highly recurrent chronic inflammatory skin disease, characterized by severe itching, immune imbalance, and skin barrier dysfunction. Damage to the skin barrier function is known to be the main cause of Th1/Th2 immune imbalance, due to the Th2-mediated immune response, and pro-inflammatory cytokines, including IL-4, IL-5, IL-13 and IL-31 and it plays an important role in further eliciting the environment of AD through stimulation. Currently, the most widely used drugs for the treatment of AD are corticosteroids, antihistamines and immunosuppressants (used by more than 60% of patients), which are reported to exhibit various side effects when taken for a long time. Therefore, interest in the physiological activity of safer plant-derived natural extracts is increasing. Callicarpa dichotoma is traditionally used in oriental medicine for bruises, habitual pain, gastric and postpartum hemorrhage. Recent studies have reported that it exhibits antioxidant anti-inflammatory and anti-hepatotoxic activity, but the role and activity of C. dichotoma in AD have not yet been studied. Therefore, in this study, the new physiological activity of C. dichotoma in the AD environment was investigated, suggesting its potential as a natural therapeutic agent.

Periodontitis is an infectious inflammatory disease of the tissues around the tooth that destroys connective tissue and is characterized by loss of periodontal ligaments and alveolar bone. Currently, surgical methods for the treatment of periodontitis have limitations and new treatment strategies are needed. Therefore, this study evaluated the efficacy of the compound betulin isolated from bark of Betula platyphylla on the inhibition of periodontitis in vitro and in vivo periodontitis induction models. In the study, betulin inhibited pro-inflammatory mediators, such as tumor necrosis factor, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2, in human periodontal ligament cells stimulated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS). In addition, it showed an anti-inflammatory effect by down-regulating 11β-hydroxysteroid dehydrogenase type 1 and transcription factor C/EBP β produced by PG-LPS. Moreover, PG-LPS inhibited the osteogenic induction of human periodontal ligament cells. The protein and mRNA levels of osteogenic markers, such as inhibited osteopontin (OPN) and runt-related transcription factor 2 (RUNX2), were regulated by betulin. In addition, the efficacy of betulin was demonstrated in a typical in vivo model of periodontitis induced by PG-LPS, and the results showed through hematoxylin & eosin staining and micro-computed tomography that the administration of betulin alleviated alveolar bone loss and periodontal inflammation caused by PG-LPS. Therefore, this study proved the efficacy of the compound betulin isolated from B. platyphylla in the inhibition of periodontitis and alveolar bone loss, two important strategies for the treatment of periodontitis, suggesting the potential as a new treatment for periodontitis.

In recent decades, dopant-free Si-based solar cells with a transition metal oxide layer have gained noticeable research interest as promising candidates for next-generation solar cells with both low manufacturing cost and high power conversion efficiency. Here, we report the effect of the substrate temperature for the deposition of vanadium oxide (V 2 O 5-x , 0 ≤ X ≤ 5) thin films (TFs) for enhanced Si surface passivation. The effectiveness of SiO x formation at the Si/V 2 O 5-x interface for Si surface passivation was investigated by comparing the results of minority carrier lifetime measurements, X-ray photoelectron spectroscopy, and atomic force microscopy. We successfully demonstrated that the deposition temperature of V 2 O 5-x has a decisive effect on the surface passivation performance. The results confirmed that the aspect ratio of the V 2 O 5-x islands that are initially deposited is a crucial factor to facilitate the transport of oxygen atoms originating from the V 2 O 5-x being deposited to the Si surface. In addition, the stoichiometry of V 2 O 5-x TFs can be notably altered by substrate temperature during deposition. As a result, experimentation with the fabricated Si/V 2 O 5-x heterojunction solar cells confirmed that the power conversion efficiency is the highest at a V 2 O 5-x deposition temperature of 75 °C.

Citropten is a coumarin that is mainly found in fruits of Rutaceae trees, but its anti-inflammatory activities in colitis is still unknown. In this study, we investigated its attenuating effect of citropten isolated from Citrus aurantifolia extract on DSS-induced colitis through the modulation of the activity of T cells and intestinal epithelial cells. We found that pre-treatment with citropten downregulates the activity of T cells and intestinal epithelial cells without a negative effect on the viability of Jurkat and HT-29 cells. The results from the Western blot analysis revealed that pre-treatment with citropten reduces the NFκB and MAPK signaling pathway in activated T cells and intestinal epithelial cells. We elucidated that the oral administration of citropten alleviates the colonic inflammation and activity of effector T cells in DSS-induced colitis by measuring changes in body weight, histological scoring from H&E-stained sections, mRNA levels of pro-inflammatory cytokines and the phosphorylation level of the MAPK signaling pathway.

Background/aims: The optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains to be determined., Methods: A retrospective review was conducted on 77 NSCLC patients with synchronous BM who underwent first-line EGFR-tyrosine kinase inhibitor (TKI) Tx. The outcomes of patients were analyzed according to the clinicopathological characteristics including local Tx modalities., Results: Fifty-nine patients underwent local Tx for BM (gamma knife surgery [GKS], 37; whole brain radiotherapy [WBRT], 18; others, four) concurrently or sequentially with EGFR-TKI. Patients treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all patients were 9 and 19 months, respectively. In 60 patients with follow-up brain imaging, the median time to CNS progression was 15 months. Patients with EGFR exon 19 deletion had a significantly longer median OS than those with other mutations including L858R (23 months vs. 17 months). Other clinical characteristics, including CNS symptoms, number of BM, and the use of local Tx were not associated with OS, as well as PFS. In terms of the local optimal Tx modality, no difference was found between GKS and WBRT in the OS and PFS., Conclusion: This study suggests that EGFR-TKI may result in a favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Bone diseases such as osteoporosis are the result of osteoclast over-activation. There are many therapeutic agents from natural compounds inhibiting the formation of osteoclast that have been reported and are continuously being interested. Amygdalin (AD) is isolated from seeds of Prunus armeniaca L. which has many pharmaceutical effects; however, the effect of AD on osteoclast formation and function remains unknown. Therefore, the underlying mechanism of AD on RANKL-induced osteoclast in RAW 264.7 cells was investigated. Molecular docking simulation revealed that AD can bind to the active sites of RANKL with negative binding affinities. Through TRAP activity, bone resorption, and migration, AD effectively inhibited osteoclast differentiation and function. Expression of transcription factors, such as NFATc1, c-fos, and osteospecific genes (including dcstamp , acp5 , ATP6v0d2 , and ctsk results) showed an osteoclast differentiated inhibitory effect by AD treatment. In addition, RANKL-induced activation of MAPK, ER stress, and ROS levels in RANKL-induced osteoclast was significantly inhibited while antioxidant enzymes were recovered in the presence of AD. These results suggest that AD may be a potential candidate derived from natural sources for the treatment of osteoclast bone-related diseases.

In the last decades, the conductive polymer PEDOT:PSS has been introduced in Si-based hybrid solar cells, gaining noticeable research interest and being considered a promising candidate for next generation solar cells which can achieve both of low manufacturing cost and high power conversion efficiency. This study succeeded in improving the electrical conductivity of PEDOT:PSS to 937 S/cm through a simple process of adding hydroquinone (HQ) to the pristine PEDOT:PSS solution. The results also showed that the addition of HQ to PEDOT:PSS(HQ-PEDOT:PSS) could not only dramatically improve the conductivity but also well-sustain the work function characteristics of PEDOT:PSS by promoting the formation of more continuous conductive-PEDOT channels without removing the insulating PSS. In this report, we reveal that the application of the HQ-PEDOT:PSS to the Si/PEDOT:PSS HSC could significantly improve the short-circuit current and open-circuit voltage characteristics to increase the power conversion efficiency of the HSCs compared to the conventional approaches. Moreover, we also treated the Si surface with the organic monomer, benzoquinone (BQ) to (1) passivate the excess Si surface defect states and (2) to improve the properties of the Si/PEDOT:PSS interface. We show that BQ treatment is able to dramatically increase the minority carrier lifetime induced by effective chemical and field-effect passivation in addition to enhancing the wettability of the Si surface with the PEDOT:PSS solution. As a result, the power conversion efficiency was increased by 10.6% by introducing HQ and BQ into the fabrication process of the Si/PEDOT:PSS HSC.

Using 126 endogenous lichen fungus (ELF) extracts, inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) were evaluated. Among them, extract ELF29 of the endogenous fungus Diaporthe mahothocarpus of the lichen Cladonia symphycarpia showed the highest inhibitory activity against hMAO-A. Compounds alternariol (AT), 5'-hydroxy-alternariol (HAT), and mycoepoxydiene (MED), isolated from the extract, had potent inhibitory activities against hMAO-A with IC 50 values of 0.020, 0.31, and 8.68 µM, respectively. AT, HAT, and MED are reversible competitive inhibitors of hMAO-A with K i values of 0.0075, 0.116, and 3.76 µM, respectively. The molecular docking studies suggested that AT, HAT, and MED had higher binding affinities for hMAO-A (-9.1, -6.9, and -5.6 kcal/mol, respectively) than for hMAO-B (-6.3, -5.2, and -3.7 kcal/mol, respectively). The relative tight binding might result from a hydrogen bond interaction of the three compounds with a Tyr444 residue in hMAO-A, whereas no hydrogen bond interaction was proposed in hMAO-B. In silico pharmacokinetics, the three compounds showed high gastrointestinal absorption without violating Lipinski's five rules, but only MED showed high probability to cross the blood-brain barrier. These results suggest that AT, HAT, and MED are candidates for treating neuropsychiatric disorders, such as depression and cardiovascular disease.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata ( C. tricuspidata ) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1β, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Two novel esterase genes, est 8L and est 13L, were isolated and identified from a compost metagenomic library. The encoded Est8L and Est13L had molecular masses of 33,181 and 44,913 Da consisting of 314 and 411 amino acids, respectively, without signal peptides. Est8L showed the highest identity (32.9%) to a hyper-thermophilic carboxylesterase AFEST from Archaeoglobus   fulgidus compared to other esterases reported and was classified to be a novel member of family IV esterases with conserved regions such as HGGG, DY, GXSXG, DPL, and GXIH. Est13L showed the highest identity (98.5%) to the family VIII esterase Est7K from the metagenome library. Est8L and Est13L had the highest activities for p -nitrophenyl butyrate (C4) and p -nitrophenyl caproate (C6), respectively, and Est13L showed a broad substrate specificity for p -nitrophenyl substrates. Est8L and Est13L effectively hydrolyzed glyceryl tributyrate. The optimum temperatures for activities of Est8L and Est13L were identical (40 °C), and the optimum pH values were 9.0 and 10.0, respectively. Est13L showed higher thermostability than Est8L. Sephacryl S-200 HR chromatography showed that the native form of Est8L was a dimer. Interestingly, Est13L was found to be a tetramer, contrary to other family VIII esterases reported. Est8L was inhibited by 30% isopropanol, methanol, and acetonitrile; however, Est13L was activated to 182.9% and 356.1%, respectively, by 30% isopropanol and methanol. Est8L showed enantioselectivity for the S -form, but Est13L showed no enantioselectivity. These results show that intracellular Est8L and/or Est13L are oligomeric in terms of native forms and can be used for pharmaceutical and industrial applications with organic solvents under alkaline conditions.

The extracts of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) have various therapeutic effects, including inflammation and allergy. In this study, gomisin M2 (GM2) was isolated from S. chinensis and its beneficial effects were assessed against atopic dermatitis (AD). We evaluated the therapeutic effects of GM2 on 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE)-induced AD-like skin lesions with BALB/c mice ears and within the tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated keratinocytes. The oral administration of GM2 resulted in reduced epidermal and dermal thickness, infiltration of tissue eosinophils, mast cells, and helper T cells in AD-like lesions. GM2 suppressed the expression of IL-1β, IL-4, IL-5, IL-6, IL-12a, and TSLP in ear tissue and the expression of IFN-γ, IL-4, and IL-17A in auricular lymph nodes. GM2 also inhibited STAT1 and NF-κB phosphorylation in DNCB/DFE-induced AD-like lesions. The oral administration of GM2 reduced levels of IgE (DFE-specific and total) and IgG2a in the mice sera, as well as protein levels of IL-4, IL-6, and TSLP in ear tissues. In TNF-α/IFN-γ-stimulated keratinocytes, GM2 significantly inhibited IL-1β, IL-6, CXCL8, and CCL22 through the suppression of STAT1 phosphorylation and the nuclear translocation of NF-κB. Taken together, these results indicate that GM2 is a biologically active compound that exhibits inhibitory effects on skin inflammation and suggests that GM2 might serve as a remedy in inflammatory skin diseases, specifically on AD.

Currently, periodontitis treatment relies on surgical operations, anti-inflammatory agents, or antibiotics. However, these treatments cause pain and side effects, resulting in a poor prognosis. Therefore, in this study, we evaluated the impact of the compound epiloliolide isolated from Sargassum horneri on the recovery of inflammatory inhibitors and loss of periodontal ligaments, which are essential treatment strategies for periodontitis. Here, human periodontal ligament cells stimulated with PG-LPS were treated with the compound epiloliolide, isolated from S. horneri. In the results of this study, epiloliolide proved the anti-inflammatory effect, cell proliferation capacity, and differentiation potential of periodontal ligament cells into osteoblasts, through the regulation of the PKA/CREB signaling pathway. Epiloliolide effectively increased the proliferation and migration of human periodontal ligament cells without cytotoxicity and suppressed the protein expression of proinflammatory mediators and cytokines, such as iNOS, COX-2, TNF-α, IL-6, and IL-1β, by downregulating NLRP3 activated by PG-LPS. Epiloliolide also upregulated the phosphorylation of PKA/CREB proteins, which play an important role in cell growth and proliferation. It was confirmed that the anti-inflammatory effect in PG-LPS-stimulated large cells was due to the regulation of PKA/CREB signaling. We suggest that epiloliolide could serve as a potential novel therapeutic agent for periodontitis by inhibiting inflammation and restoring the loss of periodontal tissue.

Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4'-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases.

Periodontitis is a set of chronic inflammatory diseases caused by the accumulation of Gram-negative bacteria on teeth, resulting in gingivitis, pocket formation, alveolar bone loss, tissue destruction, and tooth loss. In this study, the contents of ginsenosides isolated from Panax ginseng fruit extract were quantitatively analyzed, and the anti-inflammatory effects were evaluated in human periodontal ligament cells. The major ginsenosides, Re, Ra8, and Rf, present in ginseng fruit were simultaneously analyzed by a validated method using high-performance liquid chromatography with a diode-array detector; Re, Ra8, and Rf content per 1 g of P. ginseng fruit extract was 1.01 ± 0.03, 0.33 ± 0.01, and 0.55 ± 0.04 mg, respectively. Ginsenosides-Re, -Ra8, and -Rf inhibited the production of pro-inflammatory factors and the expression of important cytokines in periodontitis by inducing the expression of heme oxygenase 1 (HO-1), promoting osteoblast differentiation of periodontal ligament cells, suppressing alveolar bone loss, and promoting the expression of osteoblast-specific genes, such as alp , opn , and runx2 . An inhibitory effect of these ginsenosides on periodontitis and alveolar bone loss was observed via the regulation of HO-1 and subsequent epidermal growth factor receptor (EGFR) signaling. Silencing EGFR with EGFR siRNA confirmed that the effect of ginsenosides on HO-1 is mediated by EGFR. In conclusion, this study evaluated the contents of ginsenosides-Re, -Ra8, and -Rf isolated from P. ginseng fruit extract. Therefore, these results provide important basic data for future P. ginseng fruit component studies and suggest that ginsenosides Re, Ra8, and Rf have potential as future treatment options for periodontitis.

Background and Purpose: Kaempferol is a natural flavonoid widely investigated in various fields due to its antioxidant, anti-cancer, and anti-inflammatory activities, but few studies have shown its inhibitory effect on T cell activation. This study examined the therapeutic potential of kaempferol in atopic dermatitis by modulating T cell activation., Experimental Approach: Effects of kaempferol on T cell activation and the underlying mechanisms were investigated in Jurkat cells and mouse CD4 + T cells. A model of atopic dermatitis in mice was used to determine its therapeutic potential on T cell-mediated conditions in vivo. Western blots, RT-PCR, pulldown assays and ELISA were used, along with histological analysis of skin., Key Results: Pretreatment with kaempferol reduced CD69 expression and production of inflammatory cytokines including IL-2 from activated Jurkat cells and murine CD4 + T cells without cytotoxicity. Pulldown assays revealed that kaempferol physically binds to MRP-1 in T cells, inhibiting the action of MRP-1. In activated T cells, kaempferol suppressed JNK phosphorylation and the TAK1-IKKα mediated NF-κB pathway. Oral administration of kaempferol to mice showed improved manifestation of atopic dermatitis, a T cell-mediated condition. Western blot results showed that, as in the in vitro studies, decreased phosphorylation of JNK was associated with down-regulated MRP-1 activity in vivo, in the kaempferol-treated mice in the atopic dermatitis model., Conclusion and Implications: Kaempferol regulates T cell activation by inhibiting MRP-1 activity in activated T cells, thus showing protective effects against T cell mediated disease in vivo., (© 2021 The British Pharmacological Society.)

Background: Since the results of the ToGA trial were published, trastuzumab-based chemotherapy has been used as the standard first-line treatment for HER2-positive recurrent or primary metastatic gastric cancer (RPMGC). However, the real-world data has been rarely reported. Therefore, we investigated the outcomes of trastuzumab-based chemotherapy in a single center., Methods: This study analyzed the real-world data of 47 patients with HER2-positive RPMGC treated with trastuzumab-based chemotherapy in a single institution., Results: With the median follow-up duration of 18.8 months in survivors, the median overall survival (OS) and progression-free survival were 12.8 and 6.9 months, respectively, and the overall response rate was 64%. Eastern Cooperative Oncology Group performance status 2 and massive amount of ascites were independent poor prognostic factors for OS, while surgical resection before or after chemotherapy was associated with favorable OS, in multivariate analysis. In addition, 5 patients who underwent conversion surgery after chemotherapy demonstrated an encouraging median OS of 30.8 months, all with R0 resection., Conclusions: Trastuzumab-based chemotherapy in patients with HER2-positive RPMGC in the real world demonstrated outcomes almost comparable to those of the ToGA trial. Moreover, conversion surgery can be actively considered in fit patients with a favorable response after trastuzumab-based chemotherapy.

Osteoblasts and osteoclasts play a pivotal role in maintaining bone homeostasis, of which excessive bone resorption by osteoclasts can cause osteoporosis and various bone diseases. However, current osteoporosis treatments have many side effects, and research on new treatments that can replace these treatments is ongoing. Therefore, in this study, the roles of ligustroside (LGS) and oleoside dimethylester (ODE), a natural product-derived compound isolated from Syringa oblata subsp. dilatata as a novel, natural product-derived osteoporosis treatments were investigated. In the results of this study, LGS and ODE inhibited the differentiation of receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced RAW264.7 cells into osteoclasts without cytotoxicity, and down-regulated the activity of TRAP, a specific biomarker of osteoclasts. In addition, it inhibited bone resorption and actin ring formation, which are important functions and features of osteoclasts. Also, the effects of LGS and ODE on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and phosphoinositide 3-kinases (PI3K)/ protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathways that play important roles in osteoclast differentiation were evaluated. In the results, LGS and ODE downregulated the phosphorylation of RANKL-induced MAPK and PI3K/Akt/mTOR proteins in a concentration-dependent manner, translocation of NF-κB into the nucleus was inhibited. As a result, the compounds LGS and ODE isolated from S. oblate subsp. dilatata effectively regulated the differentiation of RANKL-induced osteoclasts and inhibited the phosphorylation of signaling pathways that play a pivotal role in osteoclast differentiation. Therefore, these results suggest the possibility of LGS and ODE as new natural product treatments for bone diseases caused by excessive osteoclasts.

Inflammatory bowel disease (IBD) is an immune disorder that develops due to chronic inflammation in several cells. It is known that colorectal and T cells are mainly involved in the pathogenesis of IBD. Chrysophanol is an anthraquinone family member that possesses several bioactivities, including anti-diabetic, anti-tumor, and inhibitory effects on T cell activation. However, it is unknown whether chrysophanol suppresses the activity of colorectal cells. In this study, we found that chrysophanol did not induce cytotoxicity in HT-29 colorectal cells. Pre-treatment with chrysophanol inhibited the mRNA levels of pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated HT-29 cells. Western blot analysis revealed that pre-treatment with chrysophanol mitigates p65 translocation and the mitogen-activated protein kinase (MAPK) pathway in activated HT-29 cells. Results from the in vivo experiment confirmed that oral administration of chrysophanol protects mice from dextran sulfate sodium (DSS)-induced IBD. Chrysophanol administration attenuates the expression of pro-inflammatory cytokines in colon tissues of the DSS-induced IBD model. In addition, we found that oral administration of chrysophanol systemically decreased the expression of effector cytokines from mesenteric lymph nodes. Therefore, these data suggest that chrysophanol has a potent modulatory effect on colorectal cells as well as exhibiting a beneficial potential for curing IBD in vivo.

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus , has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.

Since hypoxia-induced neurotoxicity is one of the major causes of neurodegenerative disorders, including the Alzheimer's disease, continuous efforts to find a novel antioxidant from natural products are required for public health. 6,7,4'-trihydroxyflavanone (THF), isolated from Dalbergia odorifera , has been shown to inhibit osteoclast formation and have an antibacterial activity. However, no evidence has reported whether THF has a protective role against hypoxia-induced neurotoxicity. In this study, we found that THF is not cytotoxic, but pre-treatment with THF has a cytoprotective effect on CoCl 2 -induced hypoxia by restoring the expression of anti-apoptotic proteins in SH-SY5y cells. In addition, pre-treatment with THF suppressed CoCl 2 -induced hypoxia-related genes including HIF1α , p53 , VEGF , and GLUT1 at the mRNA and protein levels. Pre-treatment with THF also attenuated the oxidative stress occurred by CoCl 2 -induced hypoxia by preserving antioxidant proteins, including SOD and CAT. We revealed that treatment with THF promotes HO-1 expression through Nrf2 nuclear translocation. An inhibitor assay using tin protoporphyrin IX (SnPP) confirmed that the enhancement of HO-1 by pre-treatment with THF protects SH-SY5y cells from CoCl 2 -induced neurotoxicity under hypoxic conditions. Our results demonstrate the advantageous effects of THF against hypoxia-induced neurotoxicity through the HO-1/Nrf2 signaling pathway and provide a therapeutic insight for neurodegenerative disorders.

Colitis is a multifactorial disorder that mostly occurs in the gastrointestinal tract. Despite improvements in mucosal inflammation research, little is known regarding the small bioactive molecules that are beneficial for regulating T cells and colon cell activity. 6,7,4'-trihydroxyflavanone (THF) is a flavanone that possesses anti-osteoclastogenesis activity and exerts protective effects against methamphetamine-induced immunotoxicity. Whether THF mitigates intestinal inflammation by regulating T cells and colon cell activity remains unknown. In the present study, Jurkat and HT-29 cells were used for in vitro experiments, and dextran sulfate sodium (DSS)-induced colitis model in mice was used for in vivo experiment. We observed that THF did not have a negative effect on the viability of Jurkat and HT-29 cells. Quantitative PCR and Western blot analysis revealed that THF regulates the activity of Jurkat cells and HT-29 cells via the NFκB and MAPK pathways under stimulated conditions. In the DSS-induced colitis model, oral administration of THF attenuated the manifestations of DSS-induced colitis, including a reduction in body weight, shrinkage of the colon, and enhanced expression of pro-inflammatory cytokines in the colon and mesenteric lymph nodes. These data suggest that THF alleviates DSS-induced colitis by modulating the activity of T cells and colon cells in vivo.

Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion. Interestingly, the cellular heterogeneity of organoids is reflected in their differential response to cisplatin or etoposide. We propose to utilize the organoids as small cell lung cancer patient avatar models that would be ideal for investigating the mechanisms underlying tumor recurrence after chemotherapy, and would ultimately help to develop personalized medicine.

Inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) and antioxidant activity were evaluated for 195 extracts from Ukraine-derived endogenous lichen fungi (ELF). Among them, an ELF13 (identified as Daldinia fissa ) extract showed the highest inhibitory activity against MAO-B, and 5-hydroxy-2-methyl-chroman-4-one (HMC) was isolated as a ~ 4-fold selective inhibitor of MAO-B (IC 50 = 3.23 µM) compared to MAO-A (IC 50 = 13.97 µM). HMC is a reversible competitive inhibitor with a K i value of 0.896 µM. No cytotoxicity was observed in normal and cancer cells at 50 µM of HMC. HMC showed blood-brain barrier permeability and high gastrointestinal absorption in silico pharmacokinetics. The docking simulation results showed that the binding affinity of HMC for MAO-B (-7.3 kcal/mol) was higher than that of MAO-A (-6.1 kcal/mol) and that HMC formed a hydrogen bond interaction with Cys172 of MAO-B (distance: 3.656 Å), whereas no hydrogen bonding was predicted with MAO-A. These results suggest that HMC can be considered a candidate for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

In this report, we present a process for the fabrication and tapering of a silicon (Si) nanopillar (NP) array on a large Si surface area wafer (2-inch diameter) to provide enhanced light harvesting for Si solar cell application. From our N , N -dimethyl-formamide (DMF) solvent-controlled spin-coating method, silica nanosphere (SNS in 310 nm diameter) coating on the Si surface was demonstrated successfully with improved monolayer coverage (>95%) and uniformity. After combining this method with a reactive ion etching (RIE) technique, a high-density Si NP array was produced, and we revealed that controlled tapering of Si NPs could be achieved after introducing a two-step RIE process using (1) CHF 3 /Ar gases for SNS selective etching over Si and (2) Cl 2 gas for Si vertical etching. From our experimental and computational study, we show that an effectively tapered Si NP (i.e., an Si nanotip (NT)) structure could offer a highly effective omnidirectional and broadband antireflection effect for high-efficiency Si solar cell application.

Cudratricusxanthone A (CTXA) is a natural bioactive compound extracted from the roots of Cudrania tricuspidata Bureau and has been shown to possess anti-inflammatory, anti-proliferative, and hepatoprotective activities. However, at present, anti-adipogenic and anti-inflammatory effects of CTXA on adipocytes remain unclear. In this study, we investigated the effects of CTXA on lipid accumulation and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, two known inflammatory enzymes, in 3T3-L1 preadipocytes. Strikingly, CTXA at 10 µM markedly inhibited lipid accumulation and reduced triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. On mechanistic levels, CTXA at 10 µM suppressed not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A, but also phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) and STAT-5 during 3T3-L1 preadipocyte differentiation. In addition, CTXA at 10 µM up-regulated phosphorylation levels of cAMP-activated protein kinase (AMPK) while down-regulating expression and phosphorylation levels of acetyl-CoA carboxylase (ACC) during 3T3-L1 preadipocyte differentiation. Moreover, CTXA at 10 µM greatly attenuated tumor necrosis factor (TNF)-α-induced expression of iNOS, but not COX-2, in 3T3-L1 preadipocytes. These results collectively demonstrate that CTXA has strong anti-adipogenic and anti-inflammatory effects on 3T3-L1 cells through control of the expression and phosphorylation levels of C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, STAT-3/5, AMPK, and iNOS.

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2 R )-4-(4-hydroxyphenyl)-2-butanol 2- O -β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin β3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κβ translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

Periodontitis is an infectious inflammatory disease of tissues around teeth that destroys connective tissues and is characterized by the loss of periodontal ligaments and alveolar bone. A new treatment strategy is needed owing to the limitations of the current surgical treatment method and the side effects of anti-inflammatory drugs. Therefore, here, we assessed whether Panax ginseng fruit extract (PGFE) is a new therapeutic agent for periodontitis in vitro and in vivo. According to the results, PGFE suppressed pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and pro-inflammatory mediators such as inducible nitric oxide synthase and cyclooxygenase-2 through heme oxygenase-1 expression in human periodontal ligament cells stimulated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS). In addition, the osteogenic induction of human periodontal ligament cells was inhibited by PG-LPS, and protein and mRNA levels of osteogenic markers such as alkaline phosphatase, collagen type 1 (COL1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2) were increased. The efficacy of PGFE for inhibiting periodontitis in vitro was demonstrated in a representative in vitro model of periodontitis induced by ligature and PG-LPS. Subsequently, hematoxylin and eosin staining and micro-computed tomography of the euthanized experimental animal model confirmed suppressed periodontal inflammation, which is an important strategy for treating periodontitis and for recovering the resulting alveolar bone loss. Therefore, PGFE is a potential, novel therapeutic agent for periodontal diseases.

Background: Three-dimensional (3D) cell cultures with architectural and biomechanical properties similar to those of natural tissue have been the focus for generating liver tissue. Microarchitectural organization is believed to be crucial to hepatic function, and 3D cell culture technologies have enabled the construction of tissue-like microenvironments, thereby leading to remarkable progress in vitro models of human tissue and organs. Recently, to recapitulate the 3D architecture of tissues, spheroids and organoids have become widely accepted as new practical tools for 3D organ modeling. Moreover, the combination of bioengineering approach offers the promise to more accurately model the tissue microenvironment of human organs. Indeed, the employment of sophisticated bioengineered liver models show long-term viability and functional enhancements in biochemical parameters and disease-orient outcome., Results: Various 3D in vitro liver models have been proposed as a new generation of liver medicine. Likewise, new biomedical engineering approaches and platforms are available to more accurately replicate the in vivo 3D microarchitectures and functions of living organs. This review aims to highlight the recent 3D in vitro liver model systems, including micropatterning, spheroids, and organoids that are either scaffold-based or scaffold-free systems. Finally, we discuss a number of challenges that will need to be addressed moving forward in the field of liver tissue engineering for biomedical applications., Conclusion: The ongoing development of biomedical engineering holds great promise for generating a 3D biomimetic liver model that recapitulates the physiological and pathological properties of the liver and has biomedical applications.

In immunological responses, controlling excessive T cell activity is critical for immunological homeostasis maintenance. Diketoacetonylphenalenone, derived from Hawaiian volcanic soil-associated fungus Penicillium herquei FT729, possesses moderate anti-inflammatory activity in RAW 264.7 cells but its immunosuppressive effect on T cell activation is unknown. In the present study, diketoacetonylphenalenone (up to 40 μM) did not show cytotoxicity in T cells. Western blot analysis showed treatment with diketoacetonylphenalenone did not alter the expression of anti-apoptotic proteins. Pretreatment with diketoacetonylphenalenone suppressed the interleukin-2 production in activated T cells induced by T cell receptor-mediated stimulation and PMA/A23187. The CFSE-proliferation assay revealed the inhibitory effect of diketoacetonylphenalenone on the proliferation of T cells. The expression of surface molecules on activated T cells was also reduced. We discovered the suppression of the TAK1-IKKα-NF-κB pathway by pretreatment with diketoacetonylphenalenone abrogated mitogen-activated protein kinase (MAPK) signaling in activated T cells. These results suggest that diketoacetonylphenalenone effectively downregulates T cell activity via the MAPK pathway and provides insight into the therapeutic potential of immunosuppressive reagents.

The appropriate regulation of T cell activity under inflammatory conditions is crucial for maintaining immune homeostasis. Salinosporamide A discovered as a self-resistance product from the marine bacterium Salinospora tropica , has been used as a potent proteasome inhibitor (PI). Although PIs have been developed as novel therapeutics for autoimmune diseases, due to their immunosuppressive effect, whether salinosporamide A inhibits T cell activation remains unknown. The current study finds that salinosporamide A is not cytotoxic, but controls T cell proliferation. Results from our cell cycle arrest analysis revealed that salinosporamide A leads to cell cycle arrest and regulates the expression of cyclin-dependent kinases. Under activated conditions, salinosporamide A abrogated T cell activation by T cell receptor-mediated stimulation, in which the production of cytokines was inhibited by pretreatment with salinosporamide A. Furthermore, we demonstrated that the regulation of T cell activation by salinosporamide A is mediated by suppressing the MAPK pathway. Therefore, our results suggest that salinosporamide A effectively suppresses T cell activation through regulating T cell proliferation and the cell cycle and provides great insight into the development of novel therapeutics for autoimmune diseases or graft-versus-host disease.

The objective of this study was to assess the inhibitory effect of the flavonoid aromadendrin on T cell activity to identify a non-cytotoxic immunosuppressive reagent. Conventional and qualitative PCR, MTT assays, flow cytometry and Western blotting were used to evaluate the effect of aromadendrin on the activity, cell viability and confluency, and proximal signal transduction of activated T cells. Aromadendrin effectively regulated IL-2 and IFNγ production in vitro from activated Jurkat T cells without cytotoxicity. Pre-treatment with aromadendrin also suppressed the expression levels of surface molecules CD69, CD25, and CD40L. Reduced calcium (Ca 2+ ) influx in activated T cells pre-treated with aromadendrin was observed. Western blotting revealed that aromadendrin blocked the dephosphorylation of nuclear factor of activated T (NFAT) cells and its nuclear translocation. Involvement of the NFκB and MAPK pathways in the inhibitory effect of aromadendrin was also demonstrated. Results obtained demonstrated the suppressive effect of aromadendrin on T cell activation by Ca 2+ influx regulation through NFAT activity suppression of the activated T cells.

Purpose: For unresectable or initially metastatic gastric cancer, conversion surgery (CVS), after systemic chemotherapy, has received attention as a treatment strategy. This study evaluated the prognostic value of ypTNM stage and the oncologic outcomes in patients receiving CVS., Materials and Methods: A retrospective review of clinicopathologic findings and oncologic outcomes of 116 patients who underwent CVS with curative intent, after combination chemotherapy, between January 2000 and December 2015, has been reported here., Results: Twenty-six patients (22.4%) underwent combined resection of another organ and 12 patients received para-aortic lymphadenectomy (10.3%). Pathologic complete remission (CR) was confirmed in 11 cases (9.5%). The median overall survival (OS) and disease-free survival (DFS) times were 35.0 and 21.3 months, respectively. In multivariate analysis, ypTNM stage was the sole independent prognostic factor for DFS (P=0.042). Tumors invading an adjacent organ or involving distant lymph nodes showed better survival than those with peritoneal seeding or solid organ metastasis (P=0.084). Kaplan-Meier curves showed that the 3-year OS rate of patients with pathologic CR and those with CR of the primary tumor but residual node metastasis was 81.8% and 80.0%, respectively. OS was 65.8% for stage 1 patients, 49.8% for those at stage 2, and 36.3% for those at stage 3., Conclusions: The ypTNM staging is a significant prognostic factor in patients who underwent CVS for localized unresectable or stage IV gastric cancers. Patients with locally advanced but unresectable lesions or with tumors with distant nodal metastasis may be good candidates for CVS., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Korean Gastric Cancer Association.)

Psoralea corylifolia is a medicinal herb that provides advantageous pharmacological effects against vitiligo and skin rash. Former studies have shown that bakuchicin, a furanocoumarin compound from the fruits of P. corylifolia, has therapeutic effects against inflammation, and infection. This study aimed to define the pharmacological effects of bakuchicin on inflammatory responses and lichenification, the major symptoms of atopic dermatitis (AD). To induce AD-like skin inflammation, we exposed the ears of female BALB/c mice to 2, 4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae (house dust mite) extract (DFE) for 4 weeks. Intragastric administration of bakuchicin attenuated the symptoms of AD-like skin inflammation, as evident by reductions in ear thickness, erythema, and keratosis. Bakuchicin also reversed increases in auricular epidermal and dermal layer thicknesses, and attenuated eosinophil and mast cell infiltration in AD-induced mice. It also suppressed T h 2 gene expression as well as that of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-4, IL-13, IL-31, IL-1β, IL-6, CXCL-1, and CCL-17 in the ear tissue. The levels of total and DFE-specific immunoglobulin (Ig)E, and IgG2a in the mice sera were reduced by the bakuchicin. To investigate the effect of bakuchicin on keratinocytes, experiments were performed using HaCaT cells, the representative cell type used in skin disease studies. Tumor necrosis factor-α and interferon-γ were used to activate keratinocytes. Bakuchicin suppressed T h 2 gene expression and that of pro-inflammatory cytokines and chemokines; it also suppressed STAT-1 phosphorylation and the nuclear translocation of NF-κB in activated keratinocytes. These results suggest that bakuchicin attenuated AD symptoms, thus suggesting it as a potential therapeutic agent for the treatment of AD., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC 50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC 50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC 50 = 0.098 µM) and MAO-A (IC 50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a K i value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a K i value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (-7.8 kcal/mol) was greater than its affinity for AChE (-7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (-8.8 kcal/mol) was greater than its affinity for MAO-A (-7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer's disease with multi-targeting activities.

Since T lymphocytes act as mediators between innate and acquired immunity, playing a crucial role in chronic inflammation, regulation of T cell activation to suitable levels is important. Chrysophanol, a member of the anthraquinone family, is known to possess several bioactivities, including anti-microbial, anti-cancer, and hepatoprotective activities, however, little information is available on the inhibitory effects of chrysophanol on T cell activation. To elucidate whether chrysophanol regulates the activity of T cells, IL-2 expression in activated Jurkat T cells pretreated with chrysophanol was assessed. We showed that chrysophanol is not cytotoxic to Jurkat T cells under culture conditions using RPMI (Rosewell Park Memorial Institute) medium. Pretreatment with chrysophanol inhibited IL-2 production in T cells stimulated by CD3/28 antibodies or SEE-loaded Raji B cells. We also demonstrated that chrysophanol suppressed the expression of the CD40 ligand (CD40L) in activated T cells, and uncontrolled conjugation between B cells by pretreatment with chrysophanol reduced T cell activation. Besides, treatment with chrysophanol of Jurkat T cells blocked the NFκB signaling pathway, resulting in the abrogation of MAPK (mitogen-activated protein kinase) in activated T cells. These results provide novel insights into the suppressive effect of chrysophanol on T cell activation through the regulation of CD40L expression in T cell receptor-mediated stimulation conditions.

Osteoarthritis (OA) is a common joint degenerative disease induced by oxidative stress in chondrocytes. Although induced-heme oxygenase-1 (HO-1) has been found to protect cells against oxygen radical damage, little information is available regarding the use of bioactive compounds from natural sources for regulating the HO-1 pathway to treat OA. In this study, we explored the inhibitory effects of cudratricusxanthone O (CTO) isolated from the Maclura tricuspidata Bureau ( Moraceae ) on H 2 O 2 -induced damage of SW1353 chondrocytes via regulation of the HO-1 pathway. CTO promoted HO-1 expression by enhancing the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus without inducing toxicity. Pretreatment with CTO-regulated reactive oxygen species (ROS) production by inducing expression of antioxidant enzymes in H 2 O 2 -treated cells and maintained the functions of H 2 O 2 -damaged chondrocytes. Furthermore, CTO prevented H 2 O 2 -induced apoptosis by regulating the expression of anti-apoptotic proteins. Treatment with the HO-1 inhibitor tin-protoporphyrin IX revealed that these protective effects were exerted due to an increase in HO-1 expression induced by CTO. In conclusion, CTO protects chondrocytes from H 2 O 2 -induced damages-including ROS accumulation, dysfunction, and apoptosis through activation of the Nrf2/HO-1 signaling pathway in chondrocytes and, therefore, is a potential therapeutic agent for OA treatment.

Cudratrixanthone U (CTU) is a prenylated xanthone compound isolated from Maclura tricuspidata Bureau (Moraceae). Prenylated xanthones have been reported to exhibit a variety of biological activities. However, the effects of prenylated xanthone on osteoclast differentiation and function are still unclear. Excessive bone resorption by osteoclasts is considered a major cause of diseases such as osteoporosis. Accordingly, suppression of excessive osteoclast formation and function is one of strategies for treating osteoclast related bone diseases. In this study, CTU inhibited osteoclast differentiation and function in RAW264.7 macrophages and BMM cells induced by receptor activator of nuclear factor-κB ligand (RANKL). CTU regulated the formation of TRAF6-TAK1 complex in RANKL-induced RAW264.7 macrophages and BMM cells. Osteoclast-specific genes including those encoding matrix metallopeptidase 9 (MMP-9), dendritic cell-specific transmembrane proteins (DC-STAMP), cathepsin K (CTSK) and chemokine CC motif ligand 4 (CCL4) play an important role in bone resorption and migration, and were effectively regulated by CTU. These results suggest that CTU is a potential therapeutic agent in osteoporosis., (Copyright © 2020 Kim, Kwon, Lee, Lee, Lee and Jeong.)