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The purpose of this study was to analyze the Korean medicine treatment methods for Postherpetic Neuralgia (PHN) in Korea. There were 5 online databases searched (OASIS, NDSL, RISS, KISS and KMBASE) for studies which were related to PHN. A total of 12 studies were selected. Various treatments such as acupuncture, herbal medicine, and moxibustion were reported treatments for PHN, some of which included Western medicine and Korean medicine treatment. Korean herbal medicine was the most frequently used treatment method, followed by manual acupuncture. Sipjeondaebotanggami was the most frequently used prescription. Poria Sclerotium was the most frequently used principal herb, followed by Angelicae Gigantis Radix, Zingiberis Rhizoma, and Ginseng Radix. GB44, LI4, LR3 were the common acupoints used for the treatment of PHN. CV12 was the most frequently used moxibustion point, and gabapentin was the most frequently used concomitant Western drug. Additional research on Korean medicine treatment of PHN is expected in the future.

Objectives: This study is designed to statistically analyze data of outpatients visiting for recent 3 years. The purpose is to identify tendencies of patients who visit the hospitals before and after COVID-19. Methods: This study retrospectively analyzed the medical records of 452,487 patients who visited to the Daejeon·Cheonan·Cheongju Korean Medicine Hospital of Daejeon University from January 1, 2018 to August 31, 2020. The data is classified according to year, month, gender, age, and visit type. The statistical analysis was performed using IBM SPSS 25.0. Results: The total number of patients decreased in 2020 compared to before 2020, and the number of patients in each hospital also decreased from the previous year. According to the year of each hospital, the difference by year was not statistically significant at Daejeon Hospital, but Cheonan and Cheongju Hospital showed statistical difference. The change in monthly according to the year by hospital has continued to decrease from January to March in 2020, unlike the previous year, which recovered from a decline in March. In the analysis of patients by age, there was no statistically significant difference in the number of patients in the above 60s according to the year, while those under 60s have a tendency to significantly decrease.. Conclusion: We expect that the results of this study will be used as reference materials in analyzing effects of COVID-19 at health care utilization.

Background: The purpose of this study was to statistically analyze the treatment effect and patient satisfaction of traditional Korean medicine, including acupotomy treatment of cervical herniated intervertebral disc. Methods: This was a retrospective study of 22 patients who received traditional Korean medicine including acupotomy treatment amongst all patients diagnosed with cervical herniated intervertebral discs at the Korean Medicine hospital in Daejeon, Korean, from January 01, 2020 to April 30, 2021. The clinical data from patient medical records were statistically analyzed. Results: The Numeric Rating Scale, the European Quality of Life 5 Dimensions, and the European Quality of Life Visual Analogue Scale questionnaire scores were each compared before and after traditional Korean medicine treatment, including acupotomy, showed significantly improved scores after treatment (p < 0.001). Out of a total of 22 patients, 11 rated the treatment “very satisfactory” (50%), 5 “satisfactory” (22.7%), 5 “indifferent” (22.7%), 1 “unsatisfactory” (4.5%), and 0 “very unsatisfactory” (0%). Of the total 22 patients, 17 patients (77.3%) were willing to have further treatment, and 5 patients (22.7%) were not willing. Conclusion: Traditional Korean medicine treatment including acupotomy was an effective treatment for cervical herniated intervertebral discs. To determine the effect of an individual application (e.g., acupotomy) of traditional Korean medicine treatment for cervical herniated intervertebral disc, a prospective, controlled study is needed.

A patient diagnosed with Guillain-Barre syndrome (GBS) suffering from numbness in the toes and fingers, paralysis in the face, and back pain received intravenous immunoglobulin on December 28, 2019. Without an improvement in symptoms the patient was admitted to a Korean medicine hospital on January 1, 2020 to receive combined Korean medicine treatment including herbal medicine (Sipjeondaebo-tanggami and Hyangbujasunkipalmul-tang), acupuncture treatment, moxibustion, cupping treatment, and physical therapy. Treatment was administered over 51 days, of which 17 days were during hospitalization. Paralysis of facial muscle, and numbness in fingers and toes were evaluated using the Yanagihara score and numeric rating scale (NRS) score, respectively. Facial paralysis improved (21 to 40 based on Yanagihara score) and paresthesia of the hands and feet disappeared (NRS score 6-7 to NRS score 0). There were no side effects or sequela. This study suggested combined Korean medicine treatment may be effective for the treatment of GBS.

Background: This study was designed to statistically analyze the year, gender, age, insurance type, and condition/disease of patients who were admitted to the Department of Acupuncture and Moxibustion Medicine at DaeJeon Korean Medicine Hospital over a 5-year period (2015-2020).Methods: Patients who visited the Department of Acupuncture and Moxibustion Medicine at DaeJeon Korean Medicine Hospital were classified according to year, gender, age, insurance type, and condition/disease. The statistical analysis was performed using IBM SPSS 23.0.Results: There is an increasing number of patients attending the Department of Acupuncture and Moxibustion Medicine year-on-year over the 5-year period, with a higher frequency of females than males each year. The largest age groups represented in these patients were those aged in their 50s, followed by those aged in their 40s, and 60s. Furthermore, the number of patients using health insurance was greater than those using automobile insurance each year. Of the 5,061 patients, the most common group was the patients (n = 991) who reported sprain and strain of cervical spine, followed by lumbar spine, lumbar herniation of the intervertebral disc, and facial paralysis.Conclusion: The number of patients seeking traditional Korean medicine treatment continues to increase, particularly in the 40s to 60s age group, with a larger proportion using health insurance and sprain or strain of the cervical spine. The results of this study may be used as a local (Daejeon) reference to develop Korean medicine policies, such as setting up medical benefits for patients using Korean medicine hospitals.

Background: This study aims to statistically analyze and compare the curative effect and satisfaction level between typical traditional Korean medicine treatment and nonsurgical spinal decompression treatment.Methods: Of the patients who were diagnosed with the cervical or lumbar herniated intervertebral disc at the Department of Acupuncture and Moxibustion Medicine at the Daejeon Korean Medicine Hospital from April 14th to August 25th, 2019, this study retrospectively analyzed the medical records of 31 patients who underwent nonsurgical spinal decompression treatment and traditional Korean medicine (assigned to Group A) and another 31 patients who received typical traditional Korean medicine alone (assigned to Group B). The clinical data were analyzed using IBM SPSS Version 23.0.Results: No statistically significant differences appeared in terms of sociodemographic, condition, and therapeutic characteristics, except whether the patient received Western medicine treatment, before or after a treatment with traditional Korean medicine. Group A exhibited higher variations in numeric rating scale, EuroQol- 5 dimension and EuroQol visual analogue scale scores compared to Group B as determined by independent sample t test and analysis of covariance. In addition, the satisfaction score of Group A was higher than that of Group B The result of cross analysis revealed that desire for continued treatment in Group A was higher than that of Group B.Conclusion: This retrospective observational study showed that the patients with nonsurgical spinal decompression treatment reported a greater reduction in pain, improved quality of life and satisfaction than patients receiving typical traditional Korean medicine.

This case report describes a 60-year-old female patient diagnosed with intercostal neuropathy and vertebral compression fractures which occurred following an electric shock injury. The patient received acupuncture, pharmacopuncture, and herbal medicine administration between February 10th, 2020 and April 25th, 2020. The pain level in the thoracic and left intercostal areas was assessed using the Numerical Rating Scale. The Self-report of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale were used to diagnose neuropathic pain. The Neuropathic-Pain -Scale was used to evaluate the degree of neuropathic symptoms. The Oswestry Disability Index and the European Quality of Life-5 Dimensions were used to assess quality of life scales and functional disorder. Following combined Korean medicine treatment, the patient exhibited reduced levels of pain and significant improvement in functional disorder symptoms and quality of life.

Objectives Coronavirus Disease-19 (COVID-19) is a respiratory infection characterized by the main symptoms of pneumonia and fever. It is caused by the novel coronavirus severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), which is known to spread via respiratory droplets. We aimed to determine the rate and likelihood of SARS-CoV-2 transmission from COVID-19 patients through non-respiratory routes. Methods Serum, urine, and stool samples were collected from 74 hospitalized patients diagnosed with COVID-19 based on the detection of SARS-CoV-2 in respiratory samples. The SARS-CoV-2 RNA genome was extracted from each specimen and real-time reverse transcription polymerase chain reaction performed. CaCo-2 cells were inoculated with the specimens containing the SARS-COV-2 genome, and subcultured for virus isolation. After culturing, viral replication in the cell supernatant was assessed. Results Of the samples collected from 74 COVID-19 patients, SARS-CoV-2 was detected in 15 serum, urine, or stool samples. The virus detection rate in the serum, urine, and stool samples were 2.8% (9/323), 0.8% (2/247), and 10.1% (13/129), and the mean viral load was 1,210 ± 1,861, 79 ± 30, and 3,176 ± 7,208 copy/μL, respectively. However, the SARS-CoV-2 was not isolated by the culture method from the samples that tested positive for the SARS-CoV-2 gene. Conclusion While the virus remained detectable in the respiratory samples of COVID-19 patients for several days after hospitalization, its detection in the serum, urine, and stool samples was intermittent. Since the virus could not be isolated from the SARS-COV-2-positive samples, the risk of viral transmission via stool and urine is expected to be low.

OBJECTIVES To investigate registered nurses' awareness and implementation of oral health care in patients who are hospitalized in general wards or intensive care units (ICUs) in South Korea. METHODS This research was performed as a descriptive survey of 149 nurses working in nine general hospitals with at least 100 beds in major Korean cities. RESULTS Approximately half (40.9%) of the survey respondents reported providing oral health care for hospitalized patients but that relevant protocols were not available at most hospitals or wards (89.5%). Nurses working in an ICU were significantly more likely to provide oral health care than those working in general wards (83.9% vs 15.1%; P

Background: The purpose of this study was to analyze the medical dispute cases in Acupuncture and Moxibustion treatment, and present the guidelines of treatment to prevent medical disputes. Methods: Korean Acupuncture and Moxibustion Medicine Society medical dispute cases from January 2013 to September 2018 were collected and analyzed. Results: There were 80 cases, which included acupuncture treatment (54 cases), cupping treatment (7 cases), local infection / inflammation (17 cases), and neurological symptoms (13 cases). Analysis of the correlation between types of medical accidents and the treatment methods, showed that local infection and inflammation (12 cases) were the most reported in acupuncture treatment. Conclusion: This study was performed to analyze the current status of medical disputes in the field of acupuncture and moxibustion, and provide basic data for guidelines to prevent them. Further study preparing for clinical guidelines to prevent medical disputes in specific departments are warranted in the future. ©2019 Korean Acupuncture & Moxibustion Medicine Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This case report relates to a 40-year old male patient diagnosed with ankylosing spondylitis who was treated with acupotomy and traditional Korean medicine. He showed a significant improvement in joint range of motion (ROM) in cervical and lumbar vertebrae, and in pain and functional disorder symptoms. The patient received acupotomy, acupuncture, pharmacopuncture, herbal medicine and physical therapy (November 26, 2018 to December 17, 2018). Joint ROM for cervical and lumbar vertebrae was measured, and the pain level was assessed using a numerical rating scale. The functional disorder and quality of life scales were also assessed using the Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Disease Activity Index, Korean Health Assessment Questionnaire, and Modified Health Assessment Questionnaire. After applying acupotomy and traditional Korean medicine, the patient exhibited increased joint ROM and reduced pain, also in conjunction with improved responses in functional disorder and quality of life. ©2019 Korean Acupuncture & Moxibustion Medicine Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The aim of this study was to report on the resorption of herniated nucleus pulposus following acupotomy treatment. Two patients were treated with acupotomy which included integrative Korean Medicine treatment, for either cervical, or lumbar herniated nucleus pulposus. Magnetic Resonance Imaging was used to produce images before and after (several months) treatment. The Numerical Rating Scale scores and Range of Motion were used to assess the patients at admission and discharge. In both cases, substantial resorption of the respective herniated disc was observed in the magnetic resonance images, with a decrease in the Numerical Rating Scale score. Range of Motion improved in 1 case. This study shows that acupotomy treatment may be a clinically effective treatment for herniated nucleus pulposus resorption and pain relief.

Background: To investigate the role of CD47 in inflammatory responses in systemic lupus erythematosus (SLE). Methods: Expression of CD47 and signal regulatory protein alpha (SIRPα) by peripheral blood mononuclear cells (PBMCs) and changes in CD47 expression after exposure to SLE serum, healthy control (HC) serum, recombinant interferon (IFN)-α, or tumor necrosis factor (TNF)-α were examined. Human monocytes and THP1 cells were incubated with lipopolysaccharide (LPS), an anti-CD47 antibody, or both. TNF-α production was examined. Sera from SLE patients and HCs were screened to detect autoantibodies specific for CD47. Results: Twenty-five SLE patients and sixteen HCs were enrolled. CD47 expression by monocytes from SLE patients was higher than those from HCs (mean fluorescence intensity ± SD: 815.9 ± 269.4 vs. 511.5 ± 199.4, respectively, p &lt, 0.001). CD47 expression by monocytes correlated with SLE disease activity (Spearman’s rho = 0.467, p = 0.019). IFN-α but not TNF-α, increased CD47 expression. Exposing monocytes to an anti-CD47 antibody plus LPS increased TNF-α production by 21.0 ± 10.9-fold (compared with 7.3 ± 5.5-fold for LPS alone). Finally, levels of autoantibodies against CD47 were higher in SLE patients than in HCs (21.4 ± 7.1 ng/mL vs. 16.1 ± 3.1 ng/mL, respectively, p = 0.02). Anti-CD47 antibody levels did not correlate with disease activity (Spearman’s rho = −0.11, p = 0.759) or CD47 expression on CD14 monocytes (Spearman’s rho = 0.079, p = 0.838) in patients. Conclusions: CD47 expression by monocytes is upregulated in SLE and correlates with disease activity. CD47 contributes to augmented inflammatory responses in SLE. Targeting CD47 might be a novel treatment for SLE.

Supplemental Digital Content is available in the text, Background: Degenerative knee osteoarthritis (KOA) shows an increase in morbidity with improvement in the living conditions and extended lifespans. Treatment for degenerative KOA has been gaining attention since it significantly affects the life of the elderly population and is also associated with increased expenses for medical services and high socioeconomic costs. Treatments for degenerative KOA include nondrug therapy, drug therapy, and surgical treatment. For cases that show little response to conservative treatment but have not involved severe deformation of the knee, procedures such as arthroscopic surgery, autologous chondrocyte implantation, or autologous osteochondral transplantation can be performed. However, effective treatment is required for patients experiencing sustained knee pain after surgery. Although studies confirming the therapeutic effects of acupuncture or thread-embedding acupuncture (TEA) treatment for degenerative KOA have been reported, clinical studies on a combination of TEA and electroacupuncture (EA) in patients complaining of knee pain after arthroscopic surgery, autologous chondrocyte implantation, or autologous osteochondral transplantation have not yet been reported. Therefore, this study aimed to evaluate the effectiveness and safety of this combination treatment in patients with persistent knee pain after arthroscopic surgery, autologous chondrocyte implantation, or autologous osteochondral transplantation. Methods/design: This study has been designed as a 2-group, parallel, single-center, randomized, controlled, assessor-blinded trial. Thirty-six patients with degenerative KOA who complained of pain even after arthroscopic surgery, autologous chondrocyte implantation, or autologous osteochondral transplantation will be randomized to either the (TEA + EA + Usual care) group or the (Usual care only) group in a 1:1 ratio. The patients in the (TEA + EA + Usual care) group will receive TEA treatment once a week for 4 weeks for a total of 4 sessions and EA twice a week for a total of 8 sessions while continuing usual care. The (Usual care only) group will only receive usual care for 4 weeks. To assess the efficacy of the TEA and EA combination treatment, the visual analogue scale, the Korean version of the Western Ontario and McMaster Universities Osteoarthritis Index, the EuroQol 5-Dimension 5-Level, and the doses of the rescue drug taken will be evaluated at baseline (1W) and weeks 2 (2W), 4 (4W), 6 (6W), and 8 (8W). The primary efficacy endpoint is the mean change in visual analogue scale at week 4 (4W) compared to baseline. Adverse events will be assessed at every visit. Discussion: This study will provide useful data for evaluating the clinical efficacy and safety of TEA and electroacupuncture combination treatment for improving pain and quality of life after surgery for degenerative KOA. Trial registration: Clinical Research Information Service of Republic of Korea (CRIS- KCT0004804), March 6, 2020.

Stem cell–like memory T (Tscm) cells are a subset of memory T cells that have characteristics of stem cells. The characteristics of Tscm cells in patients with rheumatoid arthritis (RA) are not well known. The percentage of CD4+ and CD8+ Tscm cells in PBMCs and synovial fluid mononuclear cells was measured. After confirming the stem cell nature of Tscm cells, we examined their pathogenicity in RA patients and healthy controls (HCs) by assessing T cell activation markers and cytokine secretion after stimulation with anti-CD3/CD28 beads and/or IL-6. Finally, RNA transcriptome patterns in Tscm cells from RA patients were compared with those in HCs. In this study, the percentage of CD4+ and CD8+ Tscm cells in total T cells was significantly higher in RA patients than in HCs. Tscm cells self-proliferated and differentiated into memory and effector T cell subsets when stimulated. Compared with Tscm cells from HCs, Tscm cells from RA patients were more easily activated by anti-CD3/CD28 beads augmented by IL-6. Transcriptome analyses revealed that Tscm cells from RA patients showed a pattern distinct from those in HCs; RA-specific transcriptome patterns were not completely resolved in RA patients in complete clinical remission. In conclusion, Tscm cells from RA patients show a transcriptionally distinct pattern and are easily activated to produce inflammatory cytokines when stimulated by TCRs in the presence of IL-6. Tscm cells can be a continuous source of pathogenicity in RA.

Chlorine dioxide (ClO2) can be used as an alternative disinfectant for controlling fungal contamination during postharvest storage. In this study, we tested the in vitro and in vivo inhibitory effects of gaseous ClO2 against Diaporthe batatas SP-d1, the causal agent of sweetpotato dry rot. In in vitro tests, spore suspensions of SP-d1 spread on acidified potato dextrose agar were treated with various ClO2 concentrations (1-20 ppm) for 0-60 min. Fungal growth was significantly inhibited at 1 ppm of ClO2 treatment for 30 min, and completely inhibited at 20 ppm. In in vivo tests, spore suspensions were drop-inoculated onto sweetpotato slices, followed by ClO2 treatment with different concentrations and durations. Lesion diameters were not significantly different between the tested ClO2 concentrations; however, lesion diameters significantly decreased upon increasing the exposure time. Similarly, fungal populations decreased at the tested ClO2 concentrations over time. However, the sliced tissue itself hardened after 60-min ClO2 treatments, especially at 20 ppm of ClO2. When sweetpotato roots were dip-inoculated in spore suspensions for 10 min prior to treatment with 20 and 40 ppm of ClO2 for 0-60 min, fungal populations decreased with increasing ClO2 concentrations. Taken together, these results showed that gaseous ClO2 could significantly inhibit D. batatas growth and dry rot development in sweetpotato. Overall, gaseous ClO2 could be used to control this fungal disease during the postharvest storage of sweetpotato.

The aim of this report is to describe improved symptom changes in eye movement disorders and dizziness of a patient with Miller Fisher syndrome after receiving combined Korean medicine treatment (CKMT). A 24-year-old male was diagnosed with MFS accompanied by eye movement disorder, diplopia, and dizziness. For 6 weeks, the patient received acupuncture, electro-acupuncture, pharmacopuncture, herbal medicine, and physical therapy treatment. Visual analogue scale were checked and other outcomes (the range of eye movement, the distance that diplopia appears, diplopia questionnaire) were measured. Following CKMT, the movement of both eyes improved in both the horizontal and vertical direction. Also for diplopia and dizziness, there was a decrease in the visual analogue scale and the distance that diplopia appeared. The present case report suggests that CKMT may have a role in treating eye movement disorders and dizziness in patient diagnosed with MFS.

Docetaxel, an advanced taxoid, has been widely used as an anti-mitotic agent, but further augmentation of its properties is still required, including improvement in low aqueous solubility. Herein, we report the development of bio-eliminable low molecular weight methylcellulose-based surfactant-free injectable formulation for the delivery of docetaxel. Crude methylcellulose, a hydrophobically modified cellulose derivative, was hydrolyzed by an enzymatic degradation method to obtain low molecular weight methylcellulose (LMwMC). Docetaxel was successfully loaded in micelles with small particle sizes high drug loading and sustained release profile. The in vivo anti-cancer effects of intravenously injected nanoparticle systems in B16F10 melanoma xenograft mice were evaluated and demonstrated a significantly enhanced therapeutic effect with the docetaxel-LMwMC micellar aggregates compared to a commercially available docetaxel, Taxotere®. Surfactant-free solubilization of docetaxel could be a promising delivery method for effective insoluble drug delivery for anti-tumor efficacy.

Background/Aims: The signal transducer and activator of transcription 6 (STAT6) transcription factor mediates PPARγ-regulated gene expression in macrophages. However, it remains largely unknown how proximal membrane signaling events initiated by apoptotic cell recognition upregulate PPARγ expression and activate the lung homeostatic program. Methods: The STAT6 inhibitor AS1517499 was used to determine the role of STAT6 in mediating PPARγ activity, anti-inflammatory effects, and anti-fibrotic effects induced by apoptotic cell instillation after bleomycin treatment into C57BL/6 mice. Bronchoalveolar lavage fluid, alveolar macrophages and lungs were harvested at days 2, 7, and 14 and then analyzed by real-time PCR, immunoblotting, ELISA, immunocytochemistry and immunohistochemistry assays. Results: Our data demonstrate that apoptotic cell instillation after bleomycin results in prolonged enhancement of STAT6 phosphorylation in alveolar macrophages and lung. Co-administration of the STAT6 inhibitor, AS1517499, reversed the enhanced PPARγ expression and activity induced by apoptotic cell instillation after bleomycin treatment. By reducing the expression of PPARγ target genes, including CD36, macrophage mannose receptor, and arginase 1, AS1517499 inhibited efferocytosis and restored pro-inflammatory cytokine expression, neutrophil recruitment, protein levels, hydroxyproline content, and expression of fibrosis markers, including type 1 collagen α2, fibronectin, and α-smooth muscle actin. STAT6 inhibition reversed the expression profile of hepatocyte growth factor and interleukin-10. Conclusion: These results indicate that prolonged STAT6 activation following one-time apoptotic cell instillation facilitates continuous PPARγ activation, resulting in the resolution of bleomycin-induced lung inflammation and fibrosis.

Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation, which results in decreased bone mineral density. The MEF2C locus, which encodes the transcription factor MADS box transcription enhancer factor 2, polypeptide C (MEF2C), is strongly associated with adult osteoporosis and osteoporotic fractures. Although the role of MEF2C in bone and cartilage formation by osteoblasts, osteocytes, and chondrocytes has been studied, the role of MEF2C in osteoclasts, which mediate bone resorption, remains unclear. In this study, we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation. While decreased MEF2C expression resulted in diminished osteoclastogenesis, ectopic expression of MEF2C enhanced osteoclast generation. Using transcriptomic and bioinformatic approaches, we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1, which play a key role in osteoclastogenesis. Mechanistically, MEF2C binds to FOS regulatory regions to induce c-FOS expression, leading to the activation of NFATC1 and downstream osteoclastogenesis. Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis, a murine model of inflammatory arthritis. Our findings reveal direct regulation of osteoclasts by MEF2C, thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.

The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-&beta, 1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-&beta, 1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-&beta, 1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors.

Wild ginseng is known to contain additional physiologically and pharmacologically active substances than common ginseng. The utilization of this herb can be maximized by altering its composition via tissue culture generating adventitious roots. We enriched the content of specific ginsenosides and investigated their role in ameliorating memory impairment. Cultured wild ginseng root was subjected to extraction, steaming, and fermentation using Pediococcus pentosaceus HLJG0702 to enhance the levels of ginsenosides Rg5 /Rk1. The analysis of product, HLJG0701, confirmed target ginsenosides. We analyzed the inhibitory effect of ginsenoside Rg5/Rk1, HLJG0701 and the raw material on acetylcholinesterase. Further, we performed Morris water maze, Y-maze, and passive avoidance tasks with mice exhibiting memory deficit induced by scopolamine, and we analyzed the concentrations of acetylcholinesterase and acetylcholine in their brains. Studies showed that the levels of ginsenosides Rg5 /Rk1, not found in the raw material, were enhanced in HLJG0701. Ginsenosides and HLJG0701 significantly inhibited acetylcholinesterase unlike the raw material. In all behavioral tasks, HLJG0701 showed memory improvement. It reduced acetylcholinesterase, whereas, it preserved acetylcholine in brain. In conclusion, cultured wild ginseng root extract fermented by P. pentosaceus HLJG0702 contains the distinctive ginsenosides Rg5/Rk1, which may ameliorate memory impairment via inhibition of acetylcholinesterase resulting in increased acetylcholine levels in the brain.

Vulvar pain is a common complaint in women during reproductive and post-reproductive years. A 70-year-old woman experienced severe intractable vulvar pain after bladder cancer surgery and adjuvant radiation therapy. We performed five fluoroscopy-guided pudendal nerve blocks. Her numeric rating scale decreased from 10 to 3, and after 5 months, her pain was controlled only with oral medication. Pudendal nerve block might stop ongoing sensitization which lead acute nociceptive vulvar pain into chronic neuropathic vulvodynia by attenuating nociceptive stimulation and inflammation.

In this study, we generated recombinant virus-like particles (VLPs) against family Filoviridae, genus Ebolavirus, species Zaire ebolavirus, strain Makona (EBOV) in Drosophila melanogaster Schneider 2 (S2) cells using the EBOV Makona. S2 cells were cotransfected with four viral plasmids encoding EBOV Makona proteins and protein expression was analyzed by immunoblotting. We confirmed that EBOV Makona proteins were successfully expressed in S2 cells. Additionally, we further examined the formation of intracellular and extracellular VLPs by electron microscopy. eVLPs were produced by sucrose gradient ultracentrifugation of S2 cells transfected with EBOV Makona genes, and production of VLPs was confirmed by immunoblot analysis. Collectively, our findings showed that the S2 cell system could be a promising tool for efficient production of eVLPs.

Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits the TGFβ1-induced epithelial–mesenchymal transition (EMT), migration, and invasion of cancer cells. Apoptotic 344SQ (ApoSQ) cell-induced PPARγ activity in macrophages increased the levels of PTEN, which was secreted in exosomes. Exosomal PTEN was taken up by recipient lung cancer cells. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in 344SQ cells, restore cellular polarity, or exert anti-EMT and anti-invasive effects. The CM that was deficient in PPARγ ligands, including 15-HETE, lipoxin A4, and 15d-PGJ2, could not reverse the suppression of PPARγ activity or the PTEN increase in 344SQ cells and consequently failed to prevent the EMT process. Moreover, a single injection of ApoSQ cells inhibited lung metastasis in syngeneic immunocompetent mice with enhanced PPARγ/PTEN signaling both in tumor-associated macrophages and in tumor cells. PPARγ antagonist GW9662 reversed the signaling by PPARγ/PTEN; the reduction in EMT-activating transcription factors, such as Snai1 and Zeb1; and the antimetastatic effect of the ApoSQ injection. Thus, the injection of apoptotic lung cancer cells may offer a new strategy for the prevention of lung metastasis.

Backgrounds/Aims This study was conducted to verify and compare the safety and feasibility of single incision laparoscopic cholecystectomy (SILC) and conventional laparoscopic cholecystectomy (CLC). Methods A total of 2,080 patients underwent laparoscopic cholecystectomy in a single center, Konyang University Hospital, between 2010 and 2016. We retrospectively compared the demographics, perioperative outcome, and postoperative complication results between the CLC and SILC groups. Results Among the 2,080 patients who underwent laparoscopic cholecystectomy, 1,080 had CLC and 1,000 had SILC. When retrospectively reviewed, the SILC group had significantly higher percentages of patients who were aged under 80 years, who were women, and had the American Society of Anesthesiologist score of lower than 3 points compared to those of the CLC group. Furthermore, the CLC group had a higher percentage of patients with acute cholecystitis or empyema, whereas the SILC group had a higher percentage of patients with chronic cholecystitis. Preoperative percutaneous transhepatic gallbladder drainage insertion or H-vac insertion was more frequently conducted, bleeding loss was more common, and hospital stay was longer in the CLC group. Postoperative complications such as wound infection, biloma, bile duct injury, and duodenal perforation were not significantly different between the two groups. Conclusions In conclusion, if performed after preoperative patient selection such as in younger and female patients with no abdominal operation history at the time of benign gallbladder surgery, SILC can be considered feasible and safe without additional complications when compared with CLC.

Methotrexate (MTX) with its proven efficacy and safety profile remains as the anchor drug for the treatment of rheumatoid arthritis (RA).1 2 However, the impact of MTX alone or in conjunction with antitumour necrosis factor (anti-TNF) on humoral immune system and infection risk varies markedly among patients with RA, suggesting that other host factors influence the therapeutic response to MTX and/or anti-TNF treatment.3 A possible candidate is B-cell activating factor (BAFF), which promotes B-cell activation and differentiation for antibody production.4 When patients with RA received anti-TNF treatment, a high BAFF serum level prevented formation of antidrug antibody in patients taking MTX but not those who did not.5 Thus, in the presence of MTX, BAFF may exert a paradoxical anti-inflammatory effect. Here, we investigated whether high BAFF levels negatively impact vaccine response via the inhibitory BAFF–MTX interaction in patients with RA taking MTX. Patients with RA according to the revised 1987 American College of Rheumatology from the randomised controlled trial (ClinicalTrials.gov identifier: NCT02897011) that aimed to investigate the effects of a 2-week MTX discontinuation on vaccine response to seasonal influenza vaccination were included in this study.6 Patients with RA were randomised to continue MTX or to hold …

Objective Stem cell-like memory T (Tscm) cells are long-lived memory T cells that have multipotent capacity to differentiate into different subsets. However, the role of Tscm cells in autoimmune diseases remains unclear. Here, we performed phenotypic studies to identify Tscm cells in patients experiencing systemic lupus erythematosus (SLE). Methods CD4+ and CD8+ Tscm cells were identified in SLE patients and healthy controls (HCs). In in vitro culture systems, CD4+ Tscm cells were induced to differentiate into subsets of T cells, including follicular helper T (Tfh) cells, and cytokine production patterns were assessed after stimulation. After confirming induction of transcription factors for Tfh cells, the capacity of CD4+ Tscm-derived Tfh cells to help B cells was analyzed by measuring antibody secretion. Results The percentages of CD4+ and CD8+ Tscm cells among the naive CD4+/CD8+ or total CD4+ T cell populations were significantly higher in SLE patients than in HCs. Stimulated Tscm cells from SLE patients could replenish themselves and differentiate into other T lymphocyte subsets, including Tfh cells upon stimulation with T cell receptor. Production of T cell factor 1, which is an inducer of Tfh, was also increased. The differentiated Tfh cells increased antibody production by autologous B cells. Conclusion Taken together, these findings suggest that Tscm cells play a role in the pathogenesis of SLE by maintaining Tfh cells.

The alveolar bone process is the thickened ridge of bone that bears the teeth and is known to have dynamic functional interactions with surrounding tissues. However, the detailed morphological changes that occur during alveolar bone process development and the underlying molecular mechanisms behind this morphogenesis have not been elucidated. In this study, we examined the detailed morphological changes of the alveolar bone process during mouse development using HE and MTC staining. In addition, we evaluated the precise localization pattern of various signaling molecules involved in blood vessel formation including CD31, α-SMA, VEGF, periostin, and TGF-β. Innervation of the alveolar bone process was examined following injection of the nerve terminal dye AM1-43. The morphological and immunohistochemical data suggested that there is an intimate relationship between alveolar bone process development and blood vessel formation. To more closely examine the role of blood vessels in alveolar bone process formation, we microinjected mice with a clinically available anti-VEGF antibody, bevacizumab, at PN5 and analyzed the effects 5 days later. Compared to the control animals, anti-VEGF treated animals showed a disruption of the integration of bony tissues to form the alveolar bone process structures, which should contain the periodontal ligaments. Based on these data, we conclude that specific morphogenesis of the alveolar bone process is closely associated with blood vessel formation.

Teraspanin transmembrane protein, Perp (P53 apoptosis effector related to PMP22), which is found in the plasma membrane as a component of the desmosome, is reported to be involved in the morphogenesis of the epithelium and the enamel formation of the incisor. However, its expression pattern and signaling regulation during molar development have not been elucidated in detail. We have examined the precise expression patterns of Perp in developing lower molars and employed the knock-down of Perp by antisense oligodeoxynucleotide treatment during in vitro organ cultivation at embryonic day 13 to define the precise developmental function of Perp. Perp was expressed mainly in the dental lamina and stellate reticulum regions at the bud and cap stages. After Perp knock-down, the tooth germ showed disruption of the dental lamina and stellate reticulum with altered apoptosis and proliferation. The changed expression levels of related signaling molecules from the enamel knot and desmosome were evaluated by real-time quantitative polymerase chain reaction. A renal capsule transplantation method was employed to examine the effects of Perp knock-down on molar crown development. Ultrastructural observations revealed that enamel was deposited more densely in an irregular pattern in the cusp region, and that dentin was hypo-mineralized after Perp knock-down at the cap stage. Thus, Perp might play important roles in the formation and integration of stellate reticulum, dental lamina structure and enamel formation through signaling interactions with the enamel knot and desmosome-related signaling molecules at the cap stage of lower molar development.

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-&beta, 1-induced epithelial&ndash, mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-&beta, 1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a RhoA-targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-&beta, 1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-&beta, 1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cellsin vitroandin vivoorchestrate the interaction between COX-2/PGE2and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2production. Both NS-398 and COX-2-siRNA, as well as the PGE2receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2induction. Thein vivorelevance of the interaction between the COX-2/PGE2and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages followingin vivoexposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

Serine proteinase inhibitors play important and diverse roles in biological processes such as coagulation, defense mechanisms, and immune responses. Here, we identified and characterized a Kunitz-type proteinase inhibitor, designated FcKuSPI, of the BPTI/Kunitz family of serine proteinase inhibitors from the hemocyte cDNA library of the shrimp Fenneropenaeus chinensis. The deduced amino acid sequence of FcKuSPI comprises 80 residues with a putative signal peptide of 15 amino acids. The predicted molecular weight of the mature peptide is 7.66 kDa and its predicted isoelectric point is 8.84. FcKuSPI includes a Kunitz domain containing six conserved cysteine residues that are predicted to form three disulfide bonds. FcKuSPI shares 44-53% homology with BPTI/Kunitz family members from other species. FcKuSPI mRNA was expressed highly in the hemocytes and moderately in muscle in healthy shrimp. Recombinant FcKuSPI protein demonstrated anti-protease activity against trypsin and anticoagulant activity against citrated human plasma in a dose-dependent manner in in vitro assays.

Purpose To determine the reproducibility of MR elastography (MRE) and the reproducibility and repeatability of the stiffness measurement of MRE in the staging of liver fibrosis. Materials and Methods Ninety-four patients, who underwent liver MRE, were included in this study. The patients were classified into group 1 (n = 47) and group 2 (n = 47) according to our knowledge of their histologic hepatic fibrosis (HF) stage. To analyze the reproducibility of MRE, the group 1 patients underwent MRE twice. In addition, to evaluate the repeatability and reproducibility of the stiffness measurement of MRE, a single observer measured the stiffness values of the second MREs in group 1 twice, and two observers independently measured the stiffness values of MRE in group 2. A 95% Bland-Altman limits of agreement and intraclass correlation coefficients (ICCs) were used to evaluate the reproducibility and repeatability of MRE. Results In group I, there was no significant difference in the mean liver stiffness values of the first and second MRE examinations, i.e., 3.45 ± 0.25 kPa vs. 3.35 ± 0.23 kPa (p = 0.22). The reproducibility of the MRE examination and the reproducibility and repeatability of the stiffness measurement were high, i.e., the ICCs of each parameter were 0.945, 0.827, and 0.963, respectively, and the 95% limits of agreement were 25.3%, 35.35%, and 18.0%, respectively. Conclusion MRE is a promising tool for evaluating HF and has high reproducibility of the examination as well as reproducibility and repeatability of the stiffness measurements. J. Magn. Reson. Imaging 2014;39:326–331. © 2013 Wiley Periodicals, Inc.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis.

Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions, and provide a mechanism by which hypoxia augments inflammation and bone destruction.

Indeciduous Quercus species have been used in Korean folk medicine, having effects on various diseases such as dysentery, diarrhea, hemorrhagia and dermatitis. In this study, five Quercus species were used for determination of phenolic compounds. In particular,phenolic compounds content in Quercus salicina Blume was compared between its leaf and shoot. Results indicated that the concentration of phenolic compounds in the leaf (25702.13 μg g-1) was higher than in the shoot (16461.82 μg g-1). Among the five Quercusspecies, the average concentration of phenolic compounds in their leaves ranged from 900.91 to 25702.13 μg g-1, with the Q. salicina Blume leaf showing the highest concentration of total phenolic compounds. Quercus species have long been medicinally important, but there have been no previous reports about their functional ingredients. Key words: Quercus salicina Blume, Quercus acuta Thunberg, Quercus phillyraeoides A. Gray, Quercus glauca Thunberg, Quercus myrsinaefolia Blume, phenolic compounds.

Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment.

The receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. Study of the induction of HGF during the interaction of macrophages with apoptotic cells shows that only Mer is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway., The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a recombinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as activation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell–induced HGF mRNA and protein expression and did not inhibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, including extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in response to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expression. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apoptotic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway.

Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors.

Background Bruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis. Methods The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA). Results HM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA. Conclusions HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-0988-z) contains supplementary material, which is available to authorized users.

Different concentrations of estradiol (E2)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (E2-PLGA-NPs) were synthesized using the emulsion-diffusion method. Transmission electron microscopy results showed that the average particle size of E2-PLGA-NPs was 98 ± 1.9 nm when stabilized with polyvinyl alcohol and 103 ± 4.9 nm when stabilized with Tween-80. Fourier transform-infrared spectroscopy with diamond attenuated total reflectance was used to identify the presence or absence of E2 molecules in PLGA nanocapsules. Cell proliferation was assessed after treating SH-SY5Y neuroblastoma cells with 1 nM-1 μM of E2 and E2-PLGA-NPs. The neuroprotective efficacy against glutamate-induced excitotoxicity was also investigated in SH-SY5Y neuroblastoma cells. Neuroprotection was greater in E2-PLGA-NP-treated cells than in cells treated with the same concentration of E2. Furthermore, E2- and E2-PLGA-NP-treated cells expressed more p-ERK1/2 and p-CREB than cells treated with glutamate only. Moreover, the expression of p-ERK1/2 was higher than that of p-CREB. In this study, p-ERK1/2 had a greater influence on the neuroprotective effect of E2 and E2-PLGA-NPs than p-CREB.

The final aim of this study was to confirm the neuroprotective effects of recombinant human erythropoietin (rhEPO)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles stabilized by sodium cholate (rhEPO-Ch-NP) and compare their effects with those of rhEPO using an in vitro model of cerebral ischemia. Glutamate-induced excitotoxic damage on SH-SY5Y cells, a human neuroblastoma cell line, with or without rhEPO-Ch-NPs was quantitatively evaluated. The rhEPO-Ch-NPs were carefully prepared using a water-in-oil-in-water (w/o/w) emulsion solvent evaporation technique with PLGA, sodium cholate hydrate, and ethyl acetate. The rhEPO-Ch-NPs were fully characterized by both transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). In addition, significant intracellular uptake of these particles was monitored by confocal microscopy. Notably, the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and nuclear changes observed by 4',6-diamidino-2-phenylindole (DAPI) staining in SH-SY5Y cells demonstrated that rhEPO-Ch-NPs were safer at any concentration investigated and rescued more neuronal cells, while preserving normocytic features against glutamate-induced excitotoxic damages compared to rhEPO.

The receptor tyrosine kinase Mer plays a central role in inhibiting the inflammatory response of immune cells to pathogens. We aimed to understand the function of Mer signaling in the resolution of sterile inflammation in experiments with a Mer-neutralizing antibody or with Mer-deficient (Mer-/-) mice in a model of sterile, zymosan-induced acute inflammation. We found that inhibition or deficiency of Mer enhanced local and systemic inflammatory responses. The exacerbated inflammatory responses induced by the lack of Mer signaling were associated with reduced abundance of the transcription factors liver X receptor α (LXRα) and LXRβ and decreased expression of their target genes in peritoneal macrophages, spleens, and lungs. Similarly, treatment of mice with a Mer/Fc fusion protein, which prevents the Mer ligand Gas6 (growth arrest-specific protein 6) from binding to Mer, exacerbated the inflammatory response and decreased the abundance of LXR. Coadministration of the LXR agonist T0901317 with the Mer-neutralizing antibody inhibited the aggravating effects of the antibody on inflammation in mice. In vitro exposure of RAW264.7 cells or primary peritoneal macrophages to Gas6 increased LXR abundance in an Akt-dependent manner. Thus, we have elucidated a previously uncharacterized pathway involved in the resolution of acute sterile inflammation: Enhanced Mer signaling during the recovery phase increases the abundance and activity of LXR to inactivate the inflammatory response in macrophages.