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Background/aim: Flammulina velutipes (FV), also known as the golden needle mushroom, is an edible and medicinal fungus that contains bioactive substances regulating various physiological functions. While the fruiting bodies of FV are commonly consumed, their stipes are often discarded despite containing polysaccharides. In this study, the biological functions of FV stipes (FV-S) were investigated to reduce waste and pollution while increasing their value., Materials and Methods: The antioxidant activity of FV was evaluated using three methods: the DPPH radical-scavenging capacity assay, ferrous ion chelating assay, and reducing power analysis. The anti-cancer potential was assessed through MTT viability and immunoblotting analyses., Results: Results showed that FV-S had higher polysaccharide and total phenolic contents and greater antioxidant abilities, particularly in ethanolic extracts. FV-S also exhibited significant anticancer properties, specifically in hot water extracts with high polysaccharide contents, and suppressed prostate cancer cell viability by inhibiting androgen receptor and PCa-specific antigen mRNA expression while inducing caspase-3/7 activation., Conclusion: FV-S is rich in bioactive components, possesses higher antioxidant and anticancer abilities, and has potential as an anticancer agent, which could enhance the value of FV., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Air pollution has led to an increased exposure of all living organisms to fine dust. Therefore, research efforts are being made to devise preventive and therapeutic remedies against fine dust-induced chronic diseases., Methods: Research of the respiratory protective effects of KRG extract in a particulate matter (PM; aerodynamic diameter of <4 μm) plus diesel exhaust particle (DEP) (PM4+D)-induced airway inflammation model. Nitric oxide production, expression of pro-inflammatory mediators and cytokines, and IRAK-1, TAK-1, and MAPK pathways were examined in PM4-stimulated MH-S cells. BALB/c mice exposed to PM4+D mixture by intranasal tracheal injection three times a day for 12 days at 3 day intervals and KRGE were administered orally for 12 days. Histological of lung and trachea, and immune cell subtype analyses were performed. Expression of pro-inflammatory mediators and cytokines in bronchoalveolar lavage fluid (BALF) and lung were measured. Immunohistofluorescence staining for IRAK-1 localization in lung were also evaluated., Results: KRGE inhibited the production of nitric oxide, the expression of pro-inflammatory mediators and cytokines, and expression and phosphorylation of all downstream factors of NF-κB, including IRAK-1 and MAPK/AP1 pathway in PM4-stimulated MH-S cells. KRGE suppressed inflammatory cell infiltration and number of immune cells, histopathologic damage, and inflammatory symptoms in the BALF and lungs induced by PM4+D; these included increased alveolar wall thickness, accumulation of collagen fibers, and TNF-α, MIP2, CXCL-1, IL-1α, and IL-17 cytokine release. Moreover, PM4 participates induce alveolar macrophage death and interleukin-1α release by associating with IRAK-1 localization was also potently inhibited by KRGE in the lungs of PM4+D-induced airway inflammation model. KRGE suppresses airway inflammatory responses, including granulocyte infiltration into the airway, by regulating the expression of chemokines and inflammatory cytokines via inhibition of IRAK-1 and MAPK pathway. Conclusion : Our results indicate the potential of KRGE to serve as an effective therapeutic agent against airway inflammation and respiratory diseases., (© 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: Although many studies have evaluated the efficacy and pharmacokinetics of Korean Red Ginseng (KRG) components (Rg1, Rb1, Rg3, Rd, etc.), few have examined the in vivo pharmacokinetics of the radiolabeled components. This study investigated the pharmacokinetics of ginsenosides and their metabolite compound K (CK), 20(s)-protopanaxadiol (PPD), and 20(s)-protopanaxatriol (PPT) using radioisotopes in rat oral administration., Methods: Sprague-Dawley rats were dosed orally once with 10 mg/kg of the tritium(3H) radiolabeled samples, and then the blood was collected from the tail vein after 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 96, and 168 h. Radioactivity in the organs, feces, urine, and carcass was determined using a liquid scintillation counter (LSC) and a bio-imaging analyzer system (BAS)., Results and Conclusion: After oral administration, as the 3 H-labeled ginsenosides were converted to metabolites, C max and half-life increased, and T max decreased. Interestingly, Rb1 and CK showed similar values, and after a single oral administration of components, the cumulative excretion ratio of urine and feces was 88.9%-92.4%. Although most KRG components were excreted within 96-168 h of administration, small amounts of components were detected in almost all tissues and mainly distributed to the liver except for the digestive tract when observed through autoradiography. This study demonstrated that KRG components were distributed to various organs in the rats. Further studies could be conducted to prove the bioavailability and transmission of KRG components to confirm the mechanism of KRG efficacy., Competing Interests: The authors declare no conflict of interest., (© 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: Although Korean Red Ginseng (KRG) is safe, this finding was only evaluated in 3-mo-long studies. Its safety was verified through a 6-mo KRG administration clinical study, but long-term studies beyond 6 mo are insufficient. This study investigated the safety and efficacy of 12-mo KRG administration., Methods: In this study, 300 mg/kg of KRG was administered to male and female Sprague Dawley rats for 4, 8, and 12 mo to evaluate its efficacy and safety. Clinical signs, including pathological examination and haematological analyses, were observed. Flow cytometric analyses were utilised to analyse spleen and thymus immune cell counts after 12 mo. Proteomic analysis of the sera was performed using a nanospray-interfaced mass spectrometer with an 11-plex Tandem Mass Tag (TMT) labelling system. Bioinformatic analysis was then performed using Ingenuity Pathway Analysis and PANTHER. Data are available via ProteomeXchange with identifier PXD032036., Results: No significant body and organ weight changes were observed, and haematological and serum biochemical analyses did not show clinical significance. The effectiveness of long-term KRG administration was confirmed through increased immune cell distribution and activity. Changes in proteins correlated with viral infection reduction were confirmed through proteomic analysis., Conclusion: The results suggested that 12-mo KRG intake is safe, improves immune system activity, and reduces viral infections with no significant changes in toxicological aspects., (© 2022. The Author(s).)

The study aims to identify the safety profile of a mixed extract (KGC-02-PS) from two traditional medicinal herbs, Puerariae radix and Hizikia fusiforme . In a subacute oral toxicity study, KGC-02-PS was administered orally for 28 days by gavage to Sprague Dawley rats (both sexes) at a daily dose of 0, 500, 1000, and 2000 mg/kg body weight. Bodyweight, food consumption, and clinical signs were monitored during the experimental period. After administering the final dose, this study conducted hematology, serum biochemistry, and pathological evaluations. In addition, the study performed a bacterial reverse mutation test with varying concentrations of KGC-02-PS (312.5 μg - 5,000 μg/plate) following OECD guideline No. 471, before testing five bacterial strains ( Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2) in the presence or absence of metabolic activation. The preclinical evaluation of KGC-02-PS's subacute oral toxicity yielded no associated toxicological effects or any changes in clinical signs, body weight, and food consumption. Moreover, examining KGC-02-PS's hematological and serum biochemical characteristics and pathology yielded no toxicological changes in terms of organ weight measurements and gross or histopathological findings. KGC-02-PS neither increased the number of revertant colonies in all bacterial strains used in the bacterial reverse mutation test, nor did it induce genotoxicity related to bacterial reverse mutations under the study's conditions. Also, KGC-02-PS's no-observed-adverse-effect level was greater than 2000 mg/kg.

Background: Few studies reported the therapeutic effect of Korean Red Ginseng (KRG) in lung inflammatory diseases. However, the anti-inflammatory role and underlying molecular in cadmium-induced lung injury have been poorly understood, directly linked to chronic lung diseases (CLDs): chronic obstructive pulmonary disease (COPD), cancer etc. Therefore, in this study we aim to investigate the therapeutic activities of water extract of KRG (KRG-WE) in mouse cadmium-induced lung injury model., Method: The anti-inflammatory roles and underlying mechanisms of KRG-WE were evaluated in vitro under cadmium-stimulated lung epithelial cells (A549) and HEK293T cell line and in vivo in cadmium-induced lung injury mouse model using semi-quantitative polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), luciferase assay, immunoblotting, and FACS., Results: KRG-WE strongly ameliorated the symptoms of CdSO 4 -induced lung injury in mice according to total cell number in bronchoalveolar lavage fluid (BALF) and severity scores as well as cytokine levels. KRG-WE significantly suppressed the upregulation of inflammatory signaling comprising mitogen-activated protein kinases (MAPK) and their upstream enzymes. In in vitro study, KRG-WE suppressed expression of interleukin (IL)-6, matrix metalloproteinase (MMP)-2, and IL-8 while promoting recovery in CdSO 4 -treated A549 cells. Similarly, KRG-WE reduced phosphorylation of MAPK and c-Jun/c-Fos in cadmium-exposed A549 cells., Conclusion: KRG-WE was found to attenuate symptoms of cadmium-induced lung injury and reduce the expression of inflammatory genes by suppression of MAPK/AP-1-mediated pathway., Competing Interests: The authors declare no conflict of interest., (© 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: Various treatments are used to relieve menopausal symptoms for women. However, herbal substances are frequently used as complementary and alternative therapies as other treatments can increase ovarian and breast cancer risk. While the herbal substances' therapeutic effect is essential, the safety of their use is considered more important. This study aims to confirm the safety of red ginseng and herb extract complex (RHC), which are used to relieve menopausal symptoms., Methods: This randomized, double-blind, placebo-controlled clinical study recruited and divided 120 women experiencing menopausal symptoms into the RHC and placebo groups (60 women per group). Subjects were administered with 2 g RHC or placebo daily for 12 wk. Adverse reactions, female hormonal changes, and uterine thickness were observed and recorded on wk 0, 6, and 12. Hematologic and blood chemistry tests were also conducted., Results: The reactions of the subjects who received RHC or placebo at least once were analyzed. A total of six adverse reactions occurred in the RHC group, while nine occurred in the placebo group; common reactions observed in both groups were genital, subcutaneous tissue, and vascular disorders. However, there was no statistically significant difference between the administration groups (p = 0.5695), and no severe adverse reactions occurred in both groups., Conclusion: This study confirms the safety of daily intake of 2 g of RHC for 12 wk by menopausal women., (© 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Objectives: The aim of this study was to describe an alternative landmark for screw insertion into the body of the ilium with bilateral sacroiliac luxation in cats., Methods: Seven cat cadavers with artificially induced bilateral sacroiliac luxation were used. The screw insertion point was determined using the caudal iliac crest and cranial acetabular rim. These two points make the first guideline; a second guideline ran perpendicular to the caudal iliac crest point. The screw insertion point was halfway along the second guideline across the ilium body. Surgery was performed in a minimally invasive manner using fluoroscopy., Results: Postoperative radiographs and CT were performed. In the postoperative evaluation, the sacroiliac joint reduction percentage was almost 90% and there was no significant difference in pelvic canal diameter ratio before and after surgery. Screw depth/sacral width was >60% in all cadavers. On CT, the angle between the screw and sacrum wing was within the normal range of 96.24° to the left and 98.65° to the right, except in one case., Conclusions and Relevance: In previous studies, surgical repair was based on having an intact contralateral ilium. However, this method is not applicable to patients with bilateral sacroiliac luxation and is mostly performed using open reduction methods. The screw insertion point suggested in this study offers a potential alternative repair technique for patients with bilateral sacroiliac luxation.

Rheumatoid arthritis (RA) is an autoimmune disorder that is characterized by increasing levels of proinflammatory cytokines. The ubiquitous enzyme dipeptidyl peptidase-4 (DPP4, also known as CD26) regulates different immune disorders, although the effects of DPP4 in RA are uncertain. Here, we found lower levels of DPP4 in RA synovial tissues compared with normal tissues. DPP4 levels were also lower in a rat collagen-induced arthritis model than in control (healthy) rats. Overexpression of DPP4 or exogenous treatment of RA synovial fibroblasts with DPP4 reduced levels of proinflammatory interleukin (IL)-1β, IL-6, and IL-13, and increased anti-inflammatory IL-10 synthesis, while DPP4 inhibitors sitagliptin and vildagliptin increased proinflammatory cytokine production, indicating an enhanced risk of RA development. The evidence suggests that increasing DPP4 expression is a novel strategy for RA disease., (© 2021 Wiley Periodicals LLC.)

Background: Korean Red Ginseng (KRG) is a traditional herb that has several beneficial properties including anti-aging, anti-inflammatory, and autophagy regulatory effects. However, the mechanisms of these effects are not well understood. In this report, the underlying mechanisms of anti-inflammatory and autophagy-promoting effects were investigated in aged mice treated with KRG-water extract (WE) over a long period., Methods: The mechanisms of anti-inflammatory and autophagy-promoting activities of KRG-WE were evaluated in kidney, lung, liver, stomach, and colon of aged mice using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR), and western blot analysis., Results: KRG-WE significantly suppressed the mRNA expression levels of inflammation-related genes such as interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 ( MCP-1), and IL-6 in kidney, lung, liver, stomach, and colon of the aged mice. Furthermore, KRG-WE downregulated the expression of transcription factors and their protein levels associated with inflammation in lung and kidney of aged mice. KRG-WE also increased the expression of autophagy-related genes and their protein levels in colon, liver, and stomach., Conclusion: The results suggest that KRG can suppress inflammatory responses and recover autophagy activity in aged mice., Competing Interests: The authors declare no conflicts of interest. All authors listed have read and approved the submitted manuscript. This manuscript has not been submitted to or published in any journal and is not being considered for publication elsewhere., (© 2021 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by synovial inflammation. Interleukin-6 (IL-6) is a key proinflammatory cytokine in OA progression. Particulate matter 2.5 (PM2.5) exposure increases the risk of different diseases, including OA. Up until now, no studies have described any association between PM2.5 and IL-6 expression in human OA synovial fibroblasts (OASFs). Here, our data show that PM2.5 concentration- and time-dependently promoted IL-6 synthesis in human OASFs. We also found that reactive oxygen species (ROS) generation potentiated the effects of PM2.5 on IL-6 production. ASK1, ERK, p38, and JNK inhibitors reduced PM2.5-induced increases of IL-6 expression. Treatment of OASFs with PM2.5 promoted phosphorylation of these signaling cascades. We also found that PM2.5 enhanced c-Jun phosphorylation and its translocation into the nucleus. Thus, PM2.5 increases IL-6 production in human OASFs via the ROS, ASK1, ERK, p38, JNK, and AP-1 signaling pathways. Our evidence links PM2.5 with OA progression., (© 2020 Wiley Periodicals LLC.)

Biological aging provokes morbidity and several functional declines, causing older adults more susceptible to a variety of diseases than younger adults. In particular, aging is a major risk factor contributing to non-communicable diseases, such as neurodegenerative disorders. Alzheimer's disease (AD) is an aging-related neurodegenerative disease that is characterized by cognitive deficits and the formation of amyloid plaques formed by the accumulation of amyloid-β (Aβ) peptides. Non-saponin fraction with rich polysaccharide (NFP) from red ginseng, the largest fraction of the components of red ginseng, perform many biological activities. However, it has not been clarified whether the NFP from Korean red ginseng (KRG) has beneficial effects in the aging and AD. First, proteomics analysis was performed in aged brain to identify the effect of NFP on protein changes, and we confirmed that NFP induced changes in proteins related to the neuroprotective- and neurogenic-effects. Next, we investigated (1) the effects of NFP on AD pathologies, such as Aβ deposition, neuroinflammation, neurodegeneration, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN), in 5XFAD transgenic mouse model of AD using immunostaining; (2) the effect of NFP on Aβ-mediated mitochondrial respiration deficiency in HT22 mouse hippocampal neuronal cells (HT22) using Seahorse XFp analysis; (3) the effect of NFP on cell proliferation using WST-1 analysis; and (4) the effect of NFP on Aβ-induced cognitive dysfunction in 5XFAD mouse model of AD using Y-maze test. Histological analysis indicated that NFP significantly alleviated the accumulation of Aβ, neuroinflammation, neuronal loss, and mitochondrial dysfunction in the subiculum of 5XFAD mouse model of AD. In addition, NFP treatment ameliorated mitochondrial deficits in Aβ-treated HT22 cells. Moreover, NFP treatment significantly increased the AHN and neuritogenesis of neural stem cells in both healthy and AD brains. Furthermore, NFP significantly increased cell proliferation in the HT22 cells. Finally, NFP administration significantly enhanced and restored the cognitive function of healthy and AD mice, respectively. Taken together, NFP treatment demonstrated changes in proteins involved in central nervous system organization/maintenance in aged brain and ameliorates AD pathology. Collectively, our findings suggest that NFP from KRG could be a potential therapeutic candidate for aging and AD treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Insulin-like growth factor (IGF) signaling has been documented in several human malignancies and is thought to contribute to cellular differentiation and migration, as well as malignant progression. A major binding molecule of IGF, IGF-binding protein 3 (IGFBP-3), regulates multiple IGF effects. Here, we focused on the effect of IGFBP-3 in the motility of osteosarcoma cells and examined signaling regulation., Materials and Methods: Using a human osteosarcoma tissue array, immunohistochemical staining determined levels of IGFBP-3 expression in osteosarcoma tissue and in normal tissue. The wound healing migration assay, Transwell migration assay, luciferase reporter assay, immunofluorescence staining, Western blot and real-time quantitative PCR were performed to examine whether IGFBP-3 facilitates VCAM-1-dependent migration of osteosarcoma cells., Key Findings: In this study, we found significantly higher IGFBP-3 levels in osteosarcoma tissue compared with normal healthy tissue. IGFBP-3 treatment of two human osteosarcoma cell lines promoted cell migration and upregulated levels of VCAM-1 expression via PI3K/Akt and AP-1 signaling., Significance: IGFBP-3 appears to be a novel therapeutic target in metastatic osteosarcoma., (Copyright © 2020. Published by Elsevier Inc.)

Background: Abnormal chloride (Cl - ) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl - secretion in nasal epithelium., Methods: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR -/- ], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl - transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis., Results: RGAE (at 30μg/mL of ginsenosides) significantly increased Cl - transport [measured as change in short-circuit current (ΔI SC  = μA/cm 2 )] when compared with control in WT and CFTR -/- MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR -/-  = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔI SC attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 μ m vs control, 3.9+/-0.09 μ m; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz; p  < 0.0001) in MNSE., Conclusion: RGAE augments ASL depth and CBF by stimulating Cl - secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis., (© 2019 The Korean Society of Ginseng, Published by Elsevier Korea LLC.)

Background: Most clinical studies of immune responses activated by Korean Red Ginseng (KRG) have been conducted exclusively in patients. However, there is still a lack of clinical research on immune-boosting benefits of KRG for healthy persons. This study aims to confirm how KRG boosts the immune system of healthy subjects., Methods: A total of 100 healthy adult subjects were randomly divided into two groups that took either a 2 g KRG tablet or a placebo per day for 8 weeks. The primary efficacy evaluation variables included changes in T cells, B cells, and white blood cells (WBCs) before and after eight weeks of KRG ingestion. Cytokines (TNF-α, INF-γ, IL-2 and IL-4), WBC differential count, and incidence of colds were measured in the secondary efficacy evaluation variables. Safety evaluation variables were used to identify changes in laboratory test results that incorporated adverse reactions, vital signs, hematological tests, blood chemistry tests, and urinalysis., Results: Compared to the placebo group, the KRG intake group showed a significant increase in the number of T cells (CD3) and its subtypes (CD4 and CD8), B cells, and the WBC count before and after eight weeks of the intake. There were no clinically significant adverse reactions or other notable results in the safety evaluation factors observed., Conclusion: This study has proven through its eight-week intake test and subsequent analysis that KRG boosts the immune system through an increase in T cells, B cells, and WBCs, and that it is safe according to the study's safety evaluation., Competing Interests: The authors declare no conflict of interest., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

A wide range of studies have steadily pointed out the relation of oxidative stress to the primary and secondary causes of human disease and aging. As such, there have been multiple misconceptions about oxidative stress. Most of reactive oxygen species (ROS) generated from chronic diseases cause oxidative damage to cell membrane lipids and proteins. ROS production is increased by abnormal stimulation inside and outside in the body, and even though ROS are generated in cells in response to abnormal metabolic processes such as disease, it does not mean that they directly contribute to the pathogenesis of a disease. Therefore, the focus of treatment should not be on ROS production itself but on the prevention and treatment of diseases linked to ROS production, including types 1 and 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer's disease. In this regard, Korean Red Ginseng (KRG) has been traditionally utilized to help prevent and treat diseases such as diabetes, cancer, inflammation, nervous system diseases, cardiovascular disease, and hyperlipidemia. Therefore, this review was intended to summarize in vivo animal and human clinical studies on the antioxidant activities of KRG and its components, ginsenosides., Competing Interests: The authors have declared no conflict of interest, (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Traditional medicinal practices have used natural products such as adaptogens to treat inflammatory, autoimmune, neurodegenerative, bacterial, and viral diseases since the early days of civilization. Panax ginseng Myer is a common herb used in East Asian countries for millennia, especially in Korea, China, and Japan. Numerous studies indicate that ginseng can modulate the immune system and thereby prevent diseases. Although the human immune system comprises many different types of cells, multiple studies suggest that each type of immune cell can be controlled or stimulated by ginseng or its derivatives. Provisional lists of ginseng's potential for use against viruses, bacteria, and other microorganisms suggest it may prove to be a valuable pharmaceutical resource, particularly if higher-quality evidence can be found. Here, we reviewed the role of ginseng as an immune-modulating agent in attempt to provide a valuable starting point for future studies on the herb and the human immune system., Competing Interests: The authors declare no conflict of interest., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Osteosarcoma is the most common primary tumor of the skeletal system and is well-known to have an aggressive clinical outcome and high metastatic potential. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers. However, the effect of CXCL13 in the motility of osteosarcoma cells remains uncertain. Here, we found that CXCL13 increases the migration and invasion potential of three osteosarcoma cell lines. In addition, CXCL13 expression was upregulated in migration-prone MG-63 cells. Vascular cell adhesion molecule 1 (VCAM-1) siRNA and antibody demonstrated that CXCL13 promotes migration via increasing VCAM-1 production. We also show that CXCR5 receptor controls CXCL13-mediated VCAM-1 expression and cell migration. Our study identified that CXCL13/CXCR5 axis facilitate VCAM-1 production and cell migration in human osteosarcoma via the phospholipase C beta (PLCβ), protein kinase C α (PKCα), c-Src, and nuclear factor-κB (NF-κB) signaling pathways. CXCL13 and CXCR5 appear to be a novel therapeutic target in metastatic osteosarcoma.

Coal fly dust (CFD)-induced asthma model is used as an ambient particulate matter model of serious pulmonary damage. We aimed to evaluate the effects of a combination of ginseng and Salvia plebeia R. Br extract (KGC-03-PS; KG3P) and its individual components (hispidulin, nepetin and rosmarinic acid) in a CFD-induced mouse model of airway inflammation (asthma). We also evaluated signal transduction by KG3P and its individual components in the alveolar macrophage cell line, MH-S cells. In vitro, KG3P and its individual components inhibited nitric oxide production and expression of pro-inflammatory mediators and cytokines (iNOS, COX-2, IL-1β, IL-6 and TNF-α) through the NF-κB and MAPK pathways in coal fly ash (CFA)-induced inflammation in MH-S cells. Moreover, in the CFD-induced asthma model in mice, KG3P and its predominant individual component, nepetin, inhibited Asymmetric Dimethyl arginine (ADMA) and Symmetric Dimethyl arginine (SDMA) in serum, and decreased the histopathologic score in the lungs. A significant reduction in the neutrophils and immune cells in BALF and lung tissue was demonstrated, with significant reduction in the expression of the pro-inflammatory cytokines. Finally, IRAK-1 localization was also potently inhibited by KG3P and nepetin. Thus, KG3P extract can be considered as a potent candidate for amelioration of airway inflammation.

Korean red ginseng (KRG)'s pharmacological efficacy and popular immunomodulatory effects have already been proven in many studies; however, the component of KRG that is effective in immune activity has not been studied before. Therefore, this study extracted and separated KRG for an immune activity comparison. In the water fraction obtained by extracting KRG powder with water, a red ginseng neutral polysaccharide (RGNP) fraction and a red ginseng acidic polysaccharide (RGAP) fraction were obtained. Each fraction was orally administered for 10 days to mice with reduced immunity, and the number of IgM antibody-forming cells (AFCs) in splenocytes was measured to compare the immune activity of the water fractions. The results showed that the RGAP fraction has the greatest number of AFCs. To set the optimal dose of the RGAP fraction, which had the highest immune activity, the AFCs, macrophage activity, and splenocyte subtype in the mice were analyzed. As a result, the number of AFCs was significantly increased in the RGAP fraction compared to RGNP. The intraperitoneal macrophage phagocytosis activity and the number of T cells, B cells, and macrophages in the spleen increased significantly. It can, therefore, be confirmed that immune activity increases by a fraction containing higher RGAP content, and we hypothesize that RGAP activates immune activity.

Panax ginseng , a medicinal plant, has been used as a blood-nourishing tonic for thousands of years in Asia, including Korea and China. P. ginseng  exhibits adaptogen activity that maintains homeostasis by restoring general biological functions and non-specifically enhancing the body's resistance to external stress. Several P. ginseng  effects have been reported. Korean Red Ginseng, in particular, has been reported in both basic and clinical studies to possess diverse effects such as enhanced immunity, fatigue relief, memory, blood circulation, and anti-oxidation. Moreover, it also protects against menopausal symptoms, cancer, cardiac diseases, and neurological disorders. The active components found in most Korean Red Ginseng varieties are known to include ginsenosides, polysaccharides, peptides, alkaloids, polyacetylene, and phenolic compounds. In this review, the identity and bioactivity of the non-saponin components of Korean Red Ginseng discovered to date are evaluated and the components are classified into polysaccharide and nitrogen compounds (protein, peptide, amino acid, nucleic acid, and alkaloid), as well as fat-soluble components such as polyacetylene, phenols, essential oils, and phytosterols. The distinct bioactivity of Korean Red Ginseng was found to originate from both saponin and non-saponin components rather than from only one or two specific components. Therefore, it is important to consider saponin and non-saponin elements together., Competing Interests: All authors have no conflicts of interest to declare., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Much has been written on the physiological benefits of Korean Red Ginseng (KRG). Among its various components, ginsenosides have been widely investigated for their various pharmacological effects. However, polysaccharides are a major KRG component that has not received scrutiny similar to that of ginsenosides. The present study aims to fill that gap in the existing literature and to investigate the possible functions of polysaccharide in KRG. The researchers evaluated proteomic changes in non-saponin fractions with rich polysaccharides (NFP) in KRG. Based on the serum analysis, proteomics analysis of the liver and the spleen was additionally conducted to identify related functions. We validated the suggested functions of NFP with the galactosamine-induced liver injury model and the cyclophosphamide-induced immunosuppression model. Then, we evaluated the antimetastatic potential of NFP in the lungs. Further proteomics analysis of the spleen and liver after ingestion confirmed functions related to immunity, cancer, hepatoprotection, and others. Then, we validated the suggested corresponding functions of the NFP in vivo model. NFP showed immune-enhancing effects, inhibited melanoma cell metastasis in the lung, and decreased liver damage. The results show that using the proteomic approach uncovers the potential effects of polysaccharides in KRG, which include enhancing the immune system and protecting the liver.

Cardiovascular diseases are a rapidly growing epidemic with high morbidity and mortality. There is an urgent need to develop nutraceutical-based therapy with minimum side effects to reduce cardiovascular risk. Panax ginseng occupies a prominent status in herbal medicine for its various therapeutic effects against inflammation, allergy, diabetes, cardiovascular diseases, and even cancer, with positive, beneficial, and restorative effects. The active components found in most P. ginseng varieties are known to include ginsenosides, polysaccharides, peptides, alkaloids, polyacetylene, and phenolic compounds, which are considered to be the main pharmacologically active constituents in ginseng. P. ginseng is an adaptogen. That is, it supports living organisms to maintain optimal homeostasis by exerting effects that counteract physiological changes caused by physical, chemical, or biological stressors. P. ginseng possesses immunomodulatory (including both immunostimulatory and immunosuppressive), neuromodulatory, and cardioprotective effects; suppresses anxiety; and balances vascular tone. P. ginseng has an antihypertensive effect that has been explained by its vasorelaxant action, and paradoxically, it is also known to increase blood pressure by vasoconstriction and help maintain cardiovascular health. Here, we discuss the potential adaptogenic effects of P. ginseng on the cardiovascular system and outline a future research perspective in this area., Competing Interests: All authors have no conflict of interest to declare., (© 2020 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Chondrosarcomas are well known for their resistance to chemotherapeutic agents, including cisplatin, which is commonly used in chondrosarcomas. Amphiregulin (AR), a ligand of epidermal growth factor receptor (EGFR), plays an important role in drug resistance. We therefore sought to determine the role of AR in cisplatin chemoresistance. We found that AR inhibits cisplatin-induced cell apoptosis and promotes ATP-binding cassette subfamily B member 1 (ABCB1) expression, while knockdown of ABCB1 by small interfering RNA (siRNA) reverses these effects. High phosphoinositide 3-kinase (PI3K), Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation levels were observed in cisplatin-resistant cells. Pretreating chondrosarcoma cells with PI3K, Akt and NF-κB inhibitors or transfecting the cells with p85, Akt and p65 siRNAs potentiated cisplatin-induced cytotoxicity. In a mouse xenograft model, knockdown of AR expression in chondrosarcoma cells increased the cytotoxic effects of cisplatin and also decreased tumor volume and weight. These results indicate that AR upregulates ABCB1 expression through the PI3K/Akt/NF-κB signaling pathway and thus contributes to cisplatin resistance in chondrosarcoma.

Over the last two decades, there have been no significant changes in patient outcomes in relation to the treatment of osteosarcoma, an aggressive malignant neoplasm. It is known that vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and in osteosarcoma. Moreover, VEGF-A expression correlates with clinical stages of osteosarcoma. The adipokine resistin exhibits proinflammatory, proangiogenic and metastatic properties, and evidence suggests that resistin may serve as a prognostic biomarker linking obesity and inflammation to cancer. However, whether resistin has a role in osteosarcoma angiogenesis is unclear. This investigation shows that resistin promotes VEGF-A expression in human osteosarcoma cells and activates the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 signaling pathways, while ERK, JNK, and p38 inhibitors or their small interfering RNAs (siRNAs) inhibit resistin-induced VEGF-A expression as well as endothelial progenitor cell (EPC) migration and tube formation. We also found that resistin upregulates VEGF-A expression by enhancing activation of the transcription factor nuclear factor-kappa B (NF-κB). Finally, resistin promotes angiogenesis in the chick chorioallantoic membrane (CAM) model. Resistin appears to be a promising target for human osteosarcoma.

Background: The roots of Korean red ginseng (Panax ginseng C.A.Mey.; KGC) have been used as an herbal supplement to enhance vital energy and immune capacity. Salvia plebeia R.Br. has been used to treat inflammatory diseases., Purpose: The aim of this study was to examine the anti-asthmatic effects of a mixture of Korean red ginseng and Salvia plebeia R.Br. (KGC3P), its component nepetin, and their modes of action in alleviating ovalbumin (OVA)-induced asthma in mice., Method: BALB/c mice were sensitized with OVA then subjected to intratracheal, intraperitoneal, and aerosol challenges. KGC3P and nepetin were administered orally for four weeks. Airway hyperresponsiveness (AHR), OVA-specific IgE levels, and Th2 cytokine- and gene expression levels in bronchoalveolar lavage fluid (BALF) and splenocytes were measured. Histological and immune cell subtype analyses were performed. PTEN and Akt phosphorylation levels were also evaluated., Results: KGC3P reduced OVA-induced AHR, serum IgE levels, histological changes, and eosinophils infiltration but also the absolute number of immune cell subtypes including CD3 + /CD4 + , CD3 + /CD8 + , CD4 + /CD69 + , and Gr-1 + /CD11b + in the lungs, BALF, and mesenteric lymph nodes (MLN). KGC3P also lowered the Th2 cytokines IL-4, IL-5, and IL-13 in the BALF and splenocytes and downregulated the IL-4, IL-13, IL-17, TNF-α, and MUC5AC genes in the lung. KGC3P upregulated the peroxisome proliferator-activated receptor (PPAR)γ gene but downregulated the p-Akt and p-PTEN phosphorylation. Similar results were obtained with nepetin treatment., Conclusion: KGC3P and nepetin are anti-asthmatic because they reduce various immune cells such as eosinophils and Th2 cell as well as Th2 cytokines. These mechanisms may be accompanied by the regulation of PPARγ expression and the PTEN pathway. Taken together, our results indicate that KGC3P and nepetin may potentially prevent and treat asthma., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Hyperkalemia is often associated with cardiac dysfunction. In this study an earthworm extract (dilong) was prepared from dried Pheretima aspergillum powder and its effect against high-KCl challenge was determined in H9c2 cardiomyoblast cells. H9c2 cells pre-treated with dilong (31.25, 62.5, 125, and 250 mg/mL) for 24 hours, where challenged with different doses of KCl treatment for 3 hours to determine the protective mechanisms of dilong against cardiac fibrosis. High-KCl administration induced mitochondrial injury and elevated the levels of pro-apoptotic proteins. The mediators of fibrosis such as ERK, uPA, SP1, and CTGF were also found to be upregulated in high-KCl condition. However, dilong treatment enhanced IGF1R/PI3k/Akt activation which is associated with cell survival. In addition, dilong also reversed high-KCl induced cardiac fibrosis related events in H9c2 cells and displayed a strong cardio-protective effect. Therefore, dilong is a potential agent to overcome cardiac events associated with high-KCl toxicity., (© 2019 Wiley Periodicals, Inc.)

Objective: Long non-coding RNA (LncRNA) has been reported to play an important role in type 2 diabetes (T2D). We investigated the role of LncRNA maternally expressed gene 3 (MEG3) and its potential interaction with miR-185-5p in palmitate-induced hepatocyte insulin resistance., Patients and Methods: High-fat diet (HFD) mice and insulin resistant hepatocyte were employed. Relative mRNA expressions of MEG3, miR-185-5p, and early growth response proteins-2 (Egr2) were measured by qRT-PCR. Western blot was performed to evaluate Egr2 protein expression levels. Glycogen contents and plasma insulin levels were tested by the corresponding assay., Results: MEG3 and Egr2 were upregulated, but miR-185-5p was downregulated in palmitate-treated insulin resistance hepatocytes and HFD mice. MEG3 knockdown alleviated the influence of palmitate on insulin resistance in vitro and in vivo. miR-185-5p expression was upregulated upon MEG3 knockdown. Expression of Egr2 was positively correlated with MEG3 knockdown or overexpression, which could be negatively managed by abnormal expression of miR-185-5p., Conclusions: Our data demonstrated that LncRNA MEG3 aggravated palmitate-induced insulin resistance by regulating miR-185-5p/Egr2 axis, providing new insights into T2D therapeutic strategies.

Myocardial fibrosis is a critical event during septic shock. Upregulation in the fibrosis signaling cascade proteins such as fibroblast growth factor (FGF), urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and activation of matrix metalloproteinases (MMPs) are widely associated with the development of myocardial infarction, dilated cardiomyopathy, cardiac fibrosis and heart failure. However, evidences suggest that the common upstream mediators of fibrosis cascade play little role in cardiac fibrosis induced by LPS; further, it is unknown if LPS directly triggers the expressions and/or activity of FGF-2, uPA, tPA, MMP-2 and MMP-9 in cardiac fibroblasts. In the present study, we treated primary cultures of cardiac fibroblasts with LPS to explore whether LPS upregulates FGF-2, uPA, tPA, MMP-2, MMP-9 and enhance cellular migration. Further the precise molecular and cellular mechanisms behind these LPS induced responses were identified. Inhibition assays on MAPKs using U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor) and QNZ (NFκB inhibitor) show that LPS-induced upregulation of FGF-2, uPA, MMP-2 and MMP-9 in cardiac fibroblasts was mediated through ERK1/2 signaling. Collectively, our results provide a link between LPS-induced cardiac dysfunction and ERK1/2 signaling pathway and thereby implies ERK1/2 as a possible target to regulate LPS induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Excessive stress causes varied physiological and psychological disorders including male reproductive problems. Here, we attempted to investigate the protective effects of Korean Red Ginseng ( Panax ginseng Meyer; KRG) against sub-acute immobilization stress-induced testicular damage in experimental rats., Methods: Male rats (age, 4 wk; weight, 60-70 g) were divided into four groups ( n  = 8 in each group): normal control group, immobilization control group, immobilization group treated with 100 mg/kg of KRG daily, and immobilization group treated with 200 mg/kg of KRG daily. Normal control and immobilization control groups received vehicle only. KRG (100 mg/kg and 200 mg/kg) was mixed in the standard diet powder and fed daily for 6 mo. Parameters such as organ weight, blood chemistry, sperm kinematic values, and expression levels of testicular-related molecules were measured using commercially available kits, Western blotting, and reverse transcription polymerase chain reaction., Results: Data revealed that KRG restored the altered testis and epididymis weight in immobilization stress-induced rats significantly ( p  < 0.05). Further, KRG ameliorated the altered blood chemistry and sperm kinematic values when compared with the immobilization control group and attenuated the altered expression levels of spermatogenesis-related proteins (nectin-2, cAMP responsive element binding protein 1, and inhibin-⍺), sex hormone receptors (androgen receptor, luteinizing hormone receptor, and follicle-stimulating hormone receptor), and antioxidant-related enzymes (glutathione S-transferase m5, peroxiredoxin-4, and glutathione peroxidase 4) significantly in the testes of immobilization stress-induced rats., Conclusion: KRG protected immobilization stress-induced testicular damage and fertility factors in rats, thereby indicating its potential in the treatment of stress-related male sterility.

Ginseng has been traditionally used for several millennia in Asian countries, including Korea, China, and Japan, not only as a nourishing and tonifying agent but also as a therapeutic agent for a variety of diseases. In recent years, the various effects of red ginseng including immunity improvement, fatigue relief, memory improvement, blood circulation improvement, antioxidation, mitigation of menopausal women's symptoms, and anticancer an effect have been reported in clinical as well as basic research. Around the world, there is a trend of the rising consumption of health functional foods on the level of disease prevention along with increased interest in maintaining health because of population aging and the awareness of lifestyle diseases and chronic diseases. Red ginseng occupies an important position as a health functional food. But till now, international ginseng monographs including those of the World Health Organization have been based on data on white ginseng and have mentioned red ginseng only partly. Therefore, the red ginseng monograph is needed for component of red ginseng, functionality certified as a health functional food in the Korea Food and Drug Administration, major efficacy, action mechanism, and safety. The present red ginseng monograph will contribute to providing accurate information on red ginseng to agencies, businesses, and consumers both in South Korea and abroad.

The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ER&alpha;) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ER&alpha; regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ER&alpha; in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ER&alpha;/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ER&alpha;/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ER&alpha; reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ER&alpha; binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ER&alpha; attenuated the activity of the BNIP3 promoter by binding to SP-1 or NF&kappa;B sites.

Regulatory T cells play an important role in autoimmunity and have been shown to exert anti-inflammatory effects in allergic asthma. Mouse model of airway inflammation was used to examine the suppressive activity of luteolin-induced CD4 + CD25 + regulatory T cells (Tregs) in vivo. In this study, BALB/c mice were sensitized with ovalbumin antigen (OVA) by aerosol challenge. Then, various biological processes were examined, including airway eosinophilia; mucus hypersecretion; elevation of OVA-specific IgE, expression of Th2 cytokines and chemokine levels; expression of eotaxin 2 and CCR3; and airway hyper responsiveness (AHR). Luteolin significantly inhibited OVA-induced increase in immune cell and eosinophil counts as well as IL-4, IL-5, IL-13, and eotaxin levels in bronchoalveolar lavage fluid (BAL Fluid). Luteolin and cyclosporine A (CsA) which was a positive control also substantially reduced OVA-specific IgE levels, eotaxin 2 levels, and CCR3 expression in BAL Fluid. In contrast, luteolin significantly increased IL-10 and IFN-γ protein levels, as well as IL-10 and TGF-β1 mRNA expression in the lung. In vitro studies showed that the number of luteolin-induced CD4 + CD25 + Treg (iTreg) cells was higher, with elevated levels of TGF-β1 and foxp3 mRNA expression in lungs tissue. Transfer of iTreg cells into OVA-sensitized mice reduced AHR, eosinophil recruitment, eotaxin, IgE, and Th2 cytokine expressions, and increased IFN-γ production in BAL Fluid after allergen challenge. Furthermore, adoptive transfer of iTreg cells prevented disease in a CD25-depleted mouse asthma model. Luteolin via induction of foxp3 and CD4 + CD25 + Treg cells may represent a new strategy in the development of therapies for managing asthma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Effective transmission of sound from water to air is crucial for the enhancement of the detection sensitivity of underwater sound. However, only 0.1% of the acoustic energy is naturally transmitted at such a boundary. At audio frequencies, quarter-wave plates or multilayered antireflection coatings are too bulky for practical use for such enhancement. Here we present an acoustic metasurface of a thickness of only ∼λ/100, where λ is the wavelength in air, consisting of an array of meta-atoms that each contain a set of membranes and an air-filled cavity. We experimentally demonstrate that such a meta-atom increases the transmission of sound at ∼700  Hz by 2 orders of magnitude, allowing about 30% of the incident acoustic power from water to be transmitted into air. Applications include underwater sonic sensing and communication.

Background: Red ginseng oil (RGO) is produced by supercritical CO 2 extraction of secondary products derived from Korean Red Ginseng extract. As the use of RGO has increased, product safety concerns have become more important., Methods: In the present study, the subacute oral toxicity and bacterial reverse mutagenicity of RGO were evaluated. Sprague-Dawley rats were orally administered with RGO for 28 d by gavage. Daily RGO dose concentrations were 0 mg/kg body weight (bw), 500 mg/kg bw, 1,000 mg/kg bw, or 2,000 mg/kg bw per day. Bacterial reverse mutation tests included five bacterial strains ( Escherichia coli WP2 and Salmonella typhimurium TA98, TA100, TA1535, and TA1537), which were used in the presence or absence of metabolic activation. The plated incorporation method for mutation test was used with RGO concentrations ranging from 312.5 μg to 5,000 μg per plate., Results: The subacute oral toxicity test results did not reveal any marked changes in clinical characteristics. There were no toxicological changes related to RGO administration in hematological and serum biochemical characteristics in either control or treatment animals. Furthermore, no gross or histopathological changes related to RGO treatment were observed. The bacterial reverse mutation test results did not reveal, at any RGO concentration level and in all bacterial strains, any increase in the number of revertant colonies in the RGO treatment group compared to that in the negative control group., Conclusion: The no-observed-adverse-effect level of RGO is greater than 2,000 mg/kg bw and RGO did not induce genotoxicity related to bacterial reverse mutations.

Background: The chemical constituents of Panax ginseng are changed by processing methods such as steaming or sun drying. In the present study, the chemical change of Panax ginseng induced by steaming was monitored in situ ., Methods: Samples were separated from the same ginseng root by incision during the steaming process, for in situ monitoring. Sampling was sequentially performed in three stages; FG (fresh ginseng) → SG (steamed ginseng) → RG (red ginseng) and 60 samples were prepared and freeze dried. The samples were then analyzed to determine 43 constituents among three stages of P. ginseng ., Results: The results showed that six malonyl-ginsenoside (Rg1, Rb1, Rb3, Rc, Rd, Rb2) and 15 amino acids were decreased in concentration during the steaming process. In contrast, ginsenoside-Rh1, 20( S )-Rg2, 20( S, R )-Rg3 and Maillard reaction product such as AF (arginine-fructose), AFG (arginine-fructose-glucose), and maltol were newly generated or their concentrations were increased., Conclusion: This study elucidates the dynamic changes in the chemical components of P. ginseng when the steaming process was induced. These results are thought to be helpful for quality control and standardization of herbal drugs using P. ginseng and they also provide a scientific basis for pharmacological research of processed ginseng (Red ginseng).

Severe and potentially fatal hypotension and cardiac contractile dysfunction are common symptoms in patients with sepsis. LPS was previously found to dramatically upregulate expression of fibrosis-related factors FGF-2, uPA, MMP-2, and MMP-9 in primary cardiac fibroblasts. MMPs are capable of denaturing and degrading fibrillar collagens and other components of the extracellular matrix (ECM). Studies have shown that dysregulation of expression of MMPs is associated with development of myocardial extracellular matrix remodeling and cardiac fibrosis, which contribute to progression of heart failure. In this study, H9c2 cells and cardiac fibroblasts were divided into five treatment groups: control, LPS (1 μg/mL) and three concentrations of FC EtOH (Carthami Flos ethanolic extract) (31.25, 62.5, and 125 μg/mL). Phosphorylation of ERK-1/2 was observed to be rapidly induced upon treatment with LPS. In contrast, it was significantly suppressed by the administration of FC EtOH (125 μg/mL). Effects of FC EtOH on LPS-induced MMP-2 and MMP-9 expression in H9c2 cells occurred directly through ERK1/2 were determined. H9c2 cells were therefore pretreated with EGF-R to activate ERK pathway. Both protein levels of MMP-2 and MMP-9 and immunefluorescent signals of MMP-9 were significantly enhanced by EGFR. In contrast, MMP-2 and MMP-9 were significantly reduced after FC EtOH administration. Based on these findings, the authors concluded that FC EtOH elicits a protective effect against LPS-induced cardio-fibrosis through the ERK1/2 pathway. Carthamus tinctorius L may potentially serve as a cardio-protective agent against LPS- induced cardiac fibrosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 754-763, 2017., (© 2016 Wiley Periodicals, Inc.)

Exercise training can reduce hepatic fat accumulation and cardiovascular risk among patients with non-alcoholic fatty liver disease (NAFLD), but how long these benefits extend beyond the period of active intervention is unclear. Intrahepatic triglyceride (IHTG) content, measured by proton magnetic resonance spectroscopy, and metabolic risk factors among 220 obese people with NAFLD, who were randomly assigned to vigorous/moderate exercise, moderate exercise or no exercise (control), were assessed at 1 year after the 12-month exercise intervention. IHTG content was significantly reduced in the 2 exercise groups compared with the control group over the 12-month active intervention. It was significantly lower (by -2.39%) in the vigorous/moderate exercise group compared with the control group at the 1-year follow-up (95% confidence interval -4.72 to -0.05%; P = .045). Waist circumference and blood pressure remained significantly lower in the vigorous/moderate exercise group and the moderate exercise group compared with the control group at the 1-year follow-up. Visceral adipose fat remained significantly reduced, but with no differences among 3 groups. These findings suggest 12-month exercise intervention induced reductions in hepatic fat accumulation, abdominal obesity and blood pressure for up to 1 year after the active intervention, with some attenuation of the benefits., (© 2016 John Wiley & Sons Ltd.)

The therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

Panax ginseng C.A. MEYER is one of the most popular medicinal herbs in Asia and the chemical constituents are changed by processing methods such as steaming or sun drying. Metabolomic analysis was performed to distinguish age discrimination of four- and six-year-old red ginseng using ultra-performance liquid chromatography quadruple time of flight mass spectrometry (UPLC-QToF-MS) with multivariate statistical analysis. Principal component analysis (PCA) showed clear discrimination between extracts of red ginseng of different ages and suggest totally six discrimination markers (two for four-year-old and four for six-year-old red ginseng). Among these, one marker was isolated and the structure determined by NMR spectroscopic analysis was 13-cis-docosenamide (marker 6-1) from six-year-old red ginseng. This is the first report of a metabolomic study regarding the age differentiation of red ginseng using UPLC-QToF-MS and determination of the structure of the marker. These results will contribute to the quality control and standardization as well as provide a scientific basis for pharmacological research on red ginseng.

Importance: Nonalcoholic fatty liver disease (NAFLD) is a prevalent risk factor for chronic liver disease and cardiovascular disease., Objective: To compare the effects of moderate and vigorous exercise on intrahepatic triglyceride content and metabolic risk factors among patients with NAFLD., Design, Setting, and Participants: In this randomized clinical trial, participants with central obesity and NAFLD were recruited from community-based screening in Xiamen, China, from December 1, 2011, through December 25, 2013. Data analysis was performed from August 28, 2015, through December 15, 2015., Interventions: Participants were randomly assigned to vigorous-moderate exercise (jogging 150 minutes per week at 65%-80% of maximum heart rate for 6 months and brisk walking 150 minutes per week at 45%-55% of maximum heart rate for another 6 months), moderate exercise (brisk walking 150 minutes per week for 12 months), or no exercise., Main Outcomes and Measures: Primary outcome, change in intrahepatic triglyceride content measured by proton magnetic resonance spectroscopy at 6 and 12 months; secondary outcomes, changes in body weight, waist circumference, body fat, and metabolic risk factors., Results: A total of 220 individuals (mean [SD] age, 53.9 [7.1] years; 149 woman [67.7%]) were randomly assigned to control (n = 74), moderate exercise (n = 73), and vigorous-moderate exercise (n = 73) groups. Of them, 211 (95.9%) completed the 6-month follow-up visit; 208 (94.5%) completed the 12-month follow-up visit. Intrahepatic triglyceride content was reduced by 5.0% (95% CI, -7.2% to 2.8%; P < .001) in the vigorous-moderate exercise group and 4.2% (95% CI, -6.3% to -2.0%; P < .001) in the moderate exercise group compared with the control group at the 6-month assessment. It was reduced by 3.9% (95% CI, -6.0% to -1.7%; P < .001) in the vigorous-moderate exercise group and 3.5% (95% CI, -5.6% to -1.3%; P = .002) in the moderate exercise group compared with the control group at the 12-month assessment. Changes in intrahepatic triglyceride content were not significantly different between vigorous-moderate and moderate exercise at the 6- or 12-month assessment. Body weight, waist circumference, and blood pressure were significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 6-month assessment and in the vigorous-moderate and moderate exercise groups compared with the control group at the 12-month assessment. In addition, body fat was significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 12-month assessment. After adjusting for weight loss, the net changes in intrahepatic triglyceride content were diminished and became nonsignificant between the exercise and control groups (except for the moderate exercise group at the 6-month assessment)., Conclusions and Relevance: Vigorous and moderate exercise were equally effective in reducing intrahepatic triglyceride content; the effect appeared to be largely mediated by weight loss., Trial Registration: clinicaltrials.gov Identifier: NCT01418027.

Children comprise the largest proportion of the population in sub-Saharan Africa. Of these, millions are orphaned. Orphanhood increases the likelihood of growing up in poverty, dropping out of school, and becoming infected with HIV. Therefore, programs aimed at securing a healthy developmental trajectory for these orphaned children are desperately needed. We conducted a two-arm cluster-randomized controlled trial to evaluate the effectiveness of a family-level economic strengthening intervention with regard to school attendance, school grades, and self-esteem in AIDS-orphaned adolescents aged 12-16 years from 10 public rural primary schools in southern Uganda. Children were randomly assigned to receive usual care (counseling, school uniforms, school lunch, notebooks, and textbooks), "bolstered" with mentorship from a near-peer (control condition, n = 167), or to receive bolstered usual care plus a family-level economic strengthening intervention in the form of a matched Child Savings Account (Suubi-Maka treatment arm, n = 179). The two groups did not differ at baseline, but 24 months later, children in the Suubi-Maka treatment arm reported significantly better educational outcomes, lower levels of hopelessness, and higher levels of self-concept compared to participants in the control condition. Our study contributes to the ongoing debate on how to address the developmental impacts of the increasing numbers of orphaned and vulnerable children and adolescents in sub-Saharan Africa, especially those affected by HIV/AIDS. Our findings indicate that innovative family-level economic strengthening programs, over and above bolstered usual care that includes psychosocial interventions for young people, may have positive developmental impacts related to education, health, and psychosocial functioning.

Exposure to tobacco smoke has epidemiologically been linked to the occurrence of cardiovascular disease among nonsmokers but the associated molecular events are not well elucidated yet. When Sprague Dawley rats were exposed to second-hand tobacco cigarette smoke twice a day for a 30 days period at an exposure rate of 10 cigarettes/30 min, they showed adverse effects including reduced left ventricle weight, increased cardiac damages, deteriorated cardiac features, and cardiac fibrosis. Exposure to second-hand smoking (SHS) increased the molecular markers of cardiac fibrosis such as urokinase plasminogen activator and matrix metallopeptidases. The modulations in the protein levels were led by the activation of extracellular signal-regulated kinases (ERK1/2), the transcription factor-specificity protein 1 (SP1), and the fibrogenic master switch-connective for epithelial-mesenchymal transition tissue growth factor there by indicating their effective role in SHS-induced myocardial infraction. Dilong, an edible earthworm extract used in Chinese medicine and its bioactive fibrinolytic enzyme product-lumbrokinase, when administered in rats, restricted the SHS exposure induced cardiac fibrosis and provided cardio-protection. The results show that lumbrokinase and dilong administration can efficiently prevent epidemiological incidence of cardiac disease among SHS-exposed nonsmokers., (© 2014 Wiley Periodicals, Inc.)