Expression of SARS-CoV-2 receptor angiotensin-converting enzyme 2 by activating protein-1 in human mast cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates mast cells and induces a cytokine storm, leading to severe Coronavirus disease in 2019 (COVID-19). SARS-CoV-2 employs angiotensin-converting enzyme 2 (ACE2) for cell entry. In the present study, the expression of ACE2 and its mechanism in activated mast cells were studied utilizing the human mast cell line, HMC-1 cells and it was elucidated whether dexamethasone used as a treatment for COVID-19 could regulate ACE2 expression. Here we documented for the first time that levels of ACE2 were increased by stimulation of phorbol 12-myristate 13-acetate and A23187 (PMACI) in HMC-1 cells. Increased levels of ACE2 were significantly diminished by treatment with Wortmannin, SP600125, SB203580, PD98059, or SR11302. The expression of ACE2 was most significantly reduced by the activating protein (AP)-1 inhibitor SR11302. PMACI stimulation enhanced the expression of the transcription factor AP-1 for ACE2. In addition, levels of transmembrane protease/serine subfamily member 2 (TMPRSS2) and tryptase were increased in PMACI-stimulated HMC-1 cells. However, dexamethasone significantly lowered levels of ACE2, TMPRSS2, and tryptase generated by PMACI. Treatment with dexamethasone also reduced activation of signaling molecules linked to ACE2 expression. According to these findings, levels of ACE2 were up-regulated through activation of AP-1 in mast cells, suggesting that suppressing ACE2 levels in mast cells would be a therapeutic approach to lessen the harm caused by COVID-19.

Euscaphic acid relieves fatigue by enhancing anti-oxidative and anti-inflammatory effects.

BACKGROUND: Oxidative stress and inflammation are involved in chronic fatigue. Euscaphic acid (EA) is an active compound of Eriobotrya japonica (Loquat) and has anti-oxidative effect. METHODS: The goal of present study is to prove whether EA could relieve fatigue through enhancing anti-oxidant and anti-inflammatory effects in in vitro/in vivo models. RESULTS: EA notably improved activity of superoxide dismutase (SOD) and catalase (CAT), while EA reduced levels of malondiadehyde (MDA) and inflammatory cytokines without cytotoxicity in H2O2-stimulated in myoblast cell line, C2C12 cells. EA significantly reduced levels of fatigue-causing factors such as lactate dehydrogenase (LDH) and creatin kinase (CK), while EA significantly incresed levels of anti-fatigue-related factor, glycogen compared to the H2O2-stimulated C2C12 cells. In treadmill stress test (TST), EA significantly enhanced activities of SOD and CAT as well as exhaustive time and decreased levels of MDA and inflammatory cytokines. After TST, levels of free fatty acid, citrate synthase, and muscle glycogen were notably enhanced by oral administration of EA, but EA decreased levels of lactate, LDH, cortisol, aspartate aminotransferase, alanine transaminase, CK, glucose, and blood urea nitrogen compared to the control group. Furthermore, in forced swimming test, EA significantly increased levels of anti-fatigue-related factors and decreased excessive accumulations of fatigue-causing factors. CONCLUSIONS: Therefore, the results indicate that potent anti-fatigue effect of EA can be achieved via the improvement of anti-oxidative and anti-inflammatory properties, and this study will provide scientific data for EA to be developed as a novel and efficient component in anti-fatigue health functional food.

RANKL down-regulates the mast cell proliferation through inducing senescence.

An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated ß-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.

Exposure of ovalbumin during pregnancy prevents the development of allergic rhinitis in offspring through the induction of mast cell autophagy.

Most allergic disease studies have focused on postnatal chemical or microbial exposure. Recent studies have indicated that allergic diseases are associated with the immunological interaction between the mother and her offspring, but the relevant mechanisms are unclear. The aim of this study was to assess whether maternal exposure to allergens during pregnancy could affect allergic rhinitis (AR) in the offspring. Compared with offspring of naïve mothers, offspring of ovalbumin (OVA)-exposed mothers exhibited a significant reduction in AR clinical symptoms and levels of histamine, IgE, T helper type-2(Th2) cytokines, thymic stromal lymphopoietin, cyclooxygenase-2, chemokines, infiltration of inflammatory cell, and activity of caspase-1. Interestingly, we observed that offspring of OVA-exposed mothers regulated OVA-induced Th2 responses by inducing autophagy in mast cells. Our data demonstrated that maternal exposure to OVA during pregnancy decreased allergic sensitivity in offspring, suggesting that the vertical transmission of maternal immune responses may be involved. These findings have important implications in the regulation of AR. Furthermore, we propose that the autophagy of mast cells may be a potential target for AR prevention or treatment.

A calcium channel blocker, manoalide exerts an anti-allergic inflammatory effect through attenuating NF-κB activity.

BACKGROUND: Many people are troubled by allergic inflammation including ocular allergic diseases, anaphylaxis, allergic rhinitis, atopic dermatitis, and eczema. Consequently, finding medications for use in allergic inflammation therapy is crucial in human health. Manoalide, a marine natural product isolated as an anti-bacterial metabolite from Luffariella variabilis, is a calcium channel blocker. However, its latent ability as an anti-allergic inflammatory agent has not yet been reported. Our research aimed to elucidate whether manoalide exerts an anti-allergic inflammatory effect in the human mast cell line, HMC-1. METHODS: Herein, we investigated the immunoregulatory effects and molecular mechanisms of manoalide in HMC-1 cells. RESULTS: Manoalide significantly alleviated secretion of the inflammatory cytokines interleukin (IL)-1ß, thymic stromal lymphopoietin, tumor necrosis factor-α, IL-6, and IL-8 via blockage of caspase-1 without cytotoxicity in activated HMC-1 cells. Activation of nuclear factor-κB increased by mast cell stimulation was attenuated by treatment with manoalide. In addition, we demonstrated that manoalide treatment remarkably attenuated the activation of mitogen-activated protein kinases in activated-HMC-1 cells. CONCLUSIONS: Taken together, our findings indicate manoalide has an anti-allergic inflammatory role, and we propose that manoalide might have potential as a novel anti-allergic inflammatory agent.

The ameliorative effect of AST2017-01 in an ovalbumin-induced allergic rhinitis animal model.

OBJECTIVE: AST2017-01 is developed to be used for treatment and prevention of allergic diseases and composed of processed-Cordyceps militaris and processed-Rumex crispus. But, effect of AST2017-01 remains unclear in an allergic rhinitis (AR). So, this study aimed to explore the effects of AST2017-01 in ovalbumin (OVA)-induced AR animal model. METHODS: OVA-induced AR animals were orally administered AST2017-01 and chrysophanol, an active component of AST2017-01 for 10 days. RESULTS: In mice with AR, AST2017-01 and chrysophanol markedly decreased number of rubs, IgE, histamine, thymic stromal lymphopoietin, tumor necrosis factor-α, interleukin (IL)-1ß, IL-4, IL-5, and IL-13 in serum or nasal mucosa tissues. Moreover, activities and protein levels of caspase-1 were markedly diminished by oral administration of AST2017-01 and chrysophanol. Declines of macrophage inflammatory protein-2, intercellular adhesion molecules-1, eosinophil, and mast cells were also noted in nasal mucosa tissues of AST2017-01 and chrysophanol groups. CONCLUSIONS: Taken together, these findings indicate that AST2017-01 has an anti-allergic effect as a therapeutic agent or functional food for treating and preventing AR.

Chrysophanol, an anthraquinone from AST2017-01, possesses the anti-proliferative effect through increasing p53 protein levels in human mast cells.

OBJECTIVE: Natural products are well known as the source of drugs in the treatment of allergic inflammation. Chrysophanol, an anthraquinone from the AST2017-01 extract, showed a beneficial anti-inflammatory effect on activated human mast cells in our previous study. However, a regulatory effect of AST2017-01 and chrysophanol on mast cell proliferation induced by thymic stromal lymphopoietin (TSLP) remains unclear. The present study determined the anti-proliferative effect and the fundamental mechanism of AST2017-01 and chrysophanol in mast cells. METHODS: We evaluated an anti-proliferative effect of AST2017-01 and chrysophanol in TSLP-stimulated human mast cell line, HMC-1. RESULTS: Without cytotoxicity, AST2017-01 and chrysophanol decreased mast cells growth and Ki67 mRNA expression increased by TSLP. AST2017-01 and chrysophanol enhanced expressions of p53 and Bax, whereas inhibited expression of Bcl-2. AST2017-01 and chrysophanol restored caspase-3 activity which was decreased by TSLP. AST2017-01 and chrysophanol suppressed expressions of murine double minute-2 protein and phosphorylated-signal transducer and activator of transcription six which are associated with the regulation of p53 protein. AST2017-01 and chrysophanol decreased levels of interleukin (IL)-13, IL-6, and tumor necrosis factor-α. Moreover, AST2017-01 and chrysophanol reduced mRNA expressions of TSLP receptor and IL-7 receptor α. CONCLUSIONS: Therefore, this study proposes that AST2017-01 and chrysophanol may be promising candidates for the development of potent anti-inflammatory or health functional foods.

Functions of the Signal Transducer and Activator of Transcription 6 in a Behavioral Animal Model of Depression.

AIMS: Depression is one of the most common inflammatory and mental disorders. Signal transducer and activator of transcription 6 (STAT6) plays a crucial role in the pathology of mental disorders as well as inflammatory diseases. METHODS: Here we determined the role of STAT6 in the pathogenesis of depression using STAT6-deficient mice in a forced swimming test. RESULTS: The immobility time was significantly decreased in STAT6-deficient mice compared to wild-type mice without alteration of locomotor activity. STAT6-deficient mice exhibited a significantly enhancing dopamine and 5-hydroxytryptamine (5-HT, serotonin) in brain. In addition, the expression of serotonin transporter in the hippocampus was markedly downregulated in STAT6-deficient mice. These results provide the first evidence that STAT6 affects depressive-like behavior through downregulating monoamines, including dopamine and 5-HT in the hippocampus of brain. CONCLUSIONS: In conclusion, identification of STAT6 signaling pathways on depression might open new perspectives for antidepressant therapies.

2-(4-{2-[(phenylthio)acetyl]carbonohydrazonoyl}phenoxy)acetamide as a new lead compound for management of allergic rhinitis.

OBJECTIVE: We selected a hit compound, 2-(4-{2-[(phenylthio)acetyl]-carbonohydrazonoyl}-phenoxy)acetamide (PA), by a molecular docking simulation between 636,565 compounds and caspase-1 protein. We examined the effect of PA on allergic rhinitis (AR) animal model. METHODS: We assessed the therapeutic effects and the regulatory mechanisms of ovalbumin (OVA)-sensitized mouse model of AR. RESULTS: A molecular docking simulation and a kinetic assay indicated that PA regulates the caspase-1 activation through the interaction with the caspase-1 active site. In the AR animal model, PA significantly reduced the rub scoring increased by OVA. The up-regulated IgE, histamine, interleukin (IL)-1ß, and thymic stromal lymphopoietin (TSLP) levels in the serum of OVA-sensitized mice were significantly decreased by the treatment with PA. Protein levels of IL-1ß, IL-5, IL-6, IL-13, tumor necrosis factor-α, TSLP, cyclooxygenase-2, macrophage inflammatory protein-2, and intercellular adhesion molecule-1 were also significantly inhibited by the treatment with PA in the nasal mucosa tissues of the OVA-sensitized mice. In the PA-treated mice, the number of eosinophils and mast cells infiltrated by OVA-sensitization were also reduced. In addition, PA reduced the mast cell-derived caspase-1 activity and expression in the nasal mucosa tissues of the OVA-sensitized mice. CONCLUSIONS: PA showed the possibility to regulate AR in OVA-induced AR models, suggesting that it has therapeutic potential for the management of AR as a lead compound.

Cucurbita moschata Duch. and its active component, ß-carotene effectively promote the immune responses through the activation of splenocytes and macrophages.

Cucurbita moschata Duch. has long been used for traditional health food in many countries. However, to enhance the immune system of Cucurbita moschata Duch. and its major component, ß-carotene is not clear. Here, we determined the immune enhancement effect of Cucurbita moschata Duch. and ß-carotene in mouse splenocytes and RAW 264.7 macrophage cell line. We prepared baked Cucurbita moschata Duch. (Sweetme Sweet Pumpkin(TM), SSP) and steamed Cucurbita moschata Duch. (SC). Splenocytes isolated from the spleen of BALB/c mice were treated with SSP, SC, and ß-carotene for 24 h. RAW 264.7 cells were stimulated with recombinant interferon-γ (rIFN-γ) for 6 h before treatment with SSP, SC, or ß-carotene. SSP, SC and ß-carotene significantly up-regulated the proliferation of splenocyte and mRNA expression of KI-67. The levels of interleukin-2 and IFN-γ were up-regulated by SSP, SC, or ß-carotene in the splenocytes. SC and ß-carotene also increased the levels of tumor necrosis factor-α (TNF-α) in the splenocytes. In addition, SSP, SC, or ß-carotene significantly increased the levels of TNF-α through the nuclear translocation of the nuclear factor-κB and phosphorylation of IκBα in the rIFN-γ-primed RAW 264.7 cells. These data indicate that Cucurbita moschata Duch. and ß-carotene may have an immune-enhancing effect through the production of Th1 cytokines by activation of splenocytes and macrophages.

Protective effect of porcine placenta in a menopausal ovariectomized mouse.

Menopause is a significant physiological phase that occurs as women's ovaries stop producing ovum and the production of estrogen declines. Human placenta and some amino acids are known to improve menopausal symptoms. In this study, we investigated that porcine placenta extract (PPE) and arginine (Arg), a main amino acid of PPE, would have estrogenic activities in ovariectomized (OVX) mice as a menopause mouse model, human breast cancer cell line (MCF-7) cells, and human osteoblast cell line (MG-63) cells. PPE or Arg significantly inhibited the body weight and increased the vagina weight compared to the OVX mice. PPE or Arg ameliorated the vaginal atrophy in the OVX mice. The levels of 17ß-estradiol and the activities of alkaline phosphatase (ALP) were significantly increased by PPE or Arg in the serum of OVX mice. Trabecular bone parameters such as bone mineral density and porosity were also improved by PPE or Arg in the OVX mice. In the MCF-7 and MG-63 cells, PPE or Arg significantly increased the cell proliferation, estrogen receptor ß mRNA expression, and estrogen-response elements luciferase activity. Finally, PPE or Arg increased the activations of ALP and extracellular signal-regulated kinase 1/2 in the MG-63 cells. These results indicate that PPE or Arg would have estrogenic and osteoblastic activity. Therefore, PPE or Arg may be useful as new pharmacological tools for treating menopausal symptoms including osteoporosis. Free Korean abstract: A Korean translation of this abstract is freely available at http://www.reproduction-online.org/content/150/3/173/suppl/DC1.

The Sound of a Buk (Korean Traditional Drum) Attenuates Anaphylactic Reactions by the Activation of Estrogen Receptor-ß.

BACKGROUND: Anaphylaxis is associated with systemic vasodilation that causes low blood pressure and induces hypoxic brain damage. The sound of a Buk (Korean traditional drum) is similar to the human heart beat and affects blood pressure, heart rate, and the nervous system by increasing physiological excitation and sympathetic nervous system activity. So, this study focused on the effect of Buk music as a means of treating anaphylaxis. METHODS: Mice were given an intraperitoneal injection of compound 48/80 (6.5 mg/kg, a mast cell degranulator). After compound 48/80 injection, mice were exposed to Buk music and white noise for 5 min in a sound isolation booth. The mortality rate was checked over the next 40 min. Levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in the serum and brain tissues were analyzed by Western blotting, quantitative real-time PCR, and ELISA methods. RESULTS: Exposure to Buk music significantly reduced compound 48/80-induced mortality and histamine release, as well as HIF-1α and VEGF levels compared with the compound 48/80 group or compound 48/80 and white noise group. Buk music also reduced levels of tumor necrosis factor-α, and significantly increased estrogen receptor-ß mRNA levels. CONCLUSION: These results indicate that Buk music has potential for the treatment of anaphylaxis.

Anti-inflammatory effects of isoacteoside from Abeliophyllum distichum.

Isoacteoside, a dihydroxypheynylethyl glycoside, is a major bioactive component of Abeliophyllum distichum (White Forsythia) which is a deciduous shrub native to the south and central areas of Korea. The present study is designed to evaluate the anti-inflammatory activities and underlying mechanisms of isoacteoside in human mast cell line, HMC-1 cells. We isolated isoacteoside from A. distichum. The anti-inflammatory effect of isoacteoside was investigated in HMC-1 cells by studying the following markers: phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-induced interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) secretion and mRNA expression by ELISA and RT-PCR, respectively. In addition, mechanism related to anti-inflammatory was investigated by Western blotting. Isoacteoside significantly suppressed the production and mRNA expression of proinflammatory cytokines including IL-1ß, IL-6, IL-8 and TNF-α in PMACI-stimulated HMC-1 cells without cytotoxicity. It was found that anti-inflammatory effects of isoacteoside are mediated by action on caspase-1, mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, extracellular signal-regulated protein kinase) and nuclear factor-kappa B pathways. Taken together, the present findings provide new insights that isoacteoside may be a promising anti-inflammatory agent for inflammatory disorders.

Sambou Bamboo salt™ down-regulates the expression levels of angiotensin-converting enzyme 2 in activated human mast cells.

Mast cells have a detrimental impact on coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Sambou Bamboo salt™ (BS) suppresses mast cell-mediated inflammatory response and enhances immunity. In this study, we investigated the regulatory effects of BS on expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) in human mast cell line (HMC)-1 cells. BS resulted in significant reductions in expression levels of ACE2 and TMPRSS2 in activated HMC-1 cells. Levels of tryptase were reduced by BS. In addition, BS blocked activation of activator protein 1 (AP-1), c-Jun NH2-terminal kinases (JNK), p38, and phosphatidylinositide-3-kinase (PI3K) in activated HMC-1 cells. Therefore, these results show that BS reduces levels of ACE2, TMPRSS2, and tryptase by inhibiting AP-1/JNK/p38/PI3K signaling pathways in mast cells. These findings can serve as valuable foundational data for the development of therapeutic agents aimed at preventing SARS-CoV-2 infection.

Modulating effect of Eunkyo-san on expression of inflammatory cytokines and angiotensin-converting enzyme 2 in human mast cells.

Eunkyo-san is widely used in the treatment of severe respiratory infections. Mast cells not only serve as host cells for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also they also exacerbate Coronavirus disease in 2019 (COVID-19) by causing a cytokine storm. Here we investigated whether Eunkyo-san and its active compound naringenin regulate the expression of inflammatory cytokines and factors connected to viral infection in activated human mast cell line, HMC-1 cells. Eunkyo-san and naringenin significantly reduced levels of inflammatory cytokines including interleukin (IL)-1ß, IL-6, IL-8, thymic stromal lymphopoietin, and tumor necrosis factor-α without impacting cytotoxicity. Eunkyo-san and naringenin reduced levels of factors connected to SARS-CoV-2 infection such as angiotensin-converting enzyme 2 (ACE2, SARS-CoV-2 receptor), transmembrane protease/serine subfamily member 2, and tryptase in activated HMC-1 cells. Treatment with Eunkyo-san and naringenin considerably reduced expression levels of ACE2 transcription factor, AP-1 (C-JUN and C-FOS) by blocking phosphatidylinositide-3-kinase and c-Jun NH2-terminal kinases signaling pathways. In addition, Eunkyo-san and naringenin effectively suppressed activation of signal transducer and activator of transcription 3, nuclear translocation of nuclear factor-κB, and activation of caspase-1 in activated HMC-1 cells. Furthermore, Eunkyo-san and naringenin reduced expression of ACE2 mRNA in two activated mast cell lines, RBL-2H3 and IC-2 cells. The overall study findings showed that Eunkyo-san diminished the expression levels of inflammatory cytokines and ACE2, and these findings imply that Eunkyo-san is able to effectively mitigating the cytokine storm brought on by SARS-CoV-2 infection.

Anti-tumor activity of trimethoprim-sulfamethoxazole against melanoma skin cancer through triggering allergic reaction and promoting immunity.

The anti-cancer impact of an allergic reaction is strongly linked to immunity enhancement. Trimethoprim-sulfamethoxazole (TMP-SMX), an antibiotic, has potential immunomodulatory effects, but has side effects such as allergies. Thus far, the effects and underlying mechanisms of TMP-SMX in melanoma have not been clarified. This study examined the potential roles of TMP-SMX in melanoma skin cancer using an immunodeficient mouse model. TMP-SMX significantly improved the survival rate and reduced the tumor weight and growth and vascular endothelial growth factor levels in melanoma skin cancer of immunodeficient mice. In the forced swimming test, TMP-SMX significantly reduced immobility time compared to the melanoma skin cancer of immunodeficient mice, indicating improved immunity. TMP-SMX significantly increased infiltration of mast cells and release of allergy-related mediators (IgE, histamine, interleukin (IL)-4, IL-5, IL-13, and IL-33) and immune-enhancing mediators (tumor necrosis factor-α, IL-2, IL-6, and IL-12). In addition, the administration of TMP-SMX significantly increased the caspase-3, 8, and 9 activities. Furthermore, mice given TMP-SMX showed no adverse reactions according to the blood biochemical parameters. TMP-SMX significantly inhibits the growth of melanoma skin cancer by triggering an allergic reaction and promotingimmunity. Hence, we propose that TMP-SMX may be used as an immune booster in cancer chemotherapy.

Caudatin attenuates inflammatory reaction by suppressing JNK/AP-1/NF-κB/caspase-1 pathways in activated HMC-1 cells.

One of the interfering factors in Coronavirus disease 2019 (COVID-19) is the cytokine storm, which contributes to hyperinflammation. Mast cells cause COVID-19 hyperinflammation by increasing inflammatory cytokine levels. We investigated whether caudatin, an active compound of Cynanchum auriculatum, could suppress inflammatory response signaling in human mast cell line, HMC-1 cells. Caudatin suppressed activation of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) in HMC-1 cells. Caudatin suppressed nuclear translocation of catalytic subunit (p65) of nuclear factor (NF)-κB by blocking IκBα phosphorylation and degradation. Caudatin also reduced levels of activated-caspase-1 protein and activation of caspase-1. Non-toxic caudatin doses inhibited the mRNA expression and protein synthesis of pro-inflammatory cytokines. A significant finding was that caudatin inhibited JNK/AP-1/NF-κB/caspase-1 signaling molecules, reducing the secretion of inflammatory cytokines. Consequently, we propose that caudatin might be used as a material in health functional foods to alleviate mast cell-mediated inflammatory conditions like COVID-19.

Anti-fatigue effect of tormentic acid through alleviating oxidative stress and energy metabolism-modulating property in C2C12 cells and animal models.

BACKGROUND/OBJECTIVES: Oxidative stress is caused by reactive oxygen species and free radicals that accelerate inflammatory responses and exacerbate fatigue. Tormentic acid (TA) has antioxidant and anti-inflammatory properties. Thus, the aim of present study is to determine the fatigue-regulatory effects of TA in H2O2-stimulated myoblast cell line, C2C12 cells and treadmill stress test (TST) and forced swimming test (FST) animal models. MATERIALS/METHODS: In the in vitro study, C2C12 cells were pretreated with TA before stimulation with H2O2. Then, malondialdehyde (MDA), lactate dehydrogenase (LDH), creatine kinase (CK) activity, tumor necrosis factor (TNF)-α, interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glycogen, and cell viability were analyzed. In the in vivo study, the ICR male mice were administered TA or distilled water orally daily for 28 days. FST and TST were then performed on the last day. In addition, biochemical analysis of the serum, muscle, and liver was performed. RESULTS: TA dose-dependently alleviated the levels of MDA, LDH, CK activity, TNF-α, and IL-6 in H2O2-stimulated C2C12 cells without affecting the cytotoxicity. TA increased the SOD and CAT activities and the glycogen levels in H2O2-stimulated C2C12 cells. In TST and FST animal models, TA decreased the FST immobility time significantly while increasing the TST exhaustion time without weight fluctuations. The in vivo studies showed that the levels of SOD, CAT, citrate synthase, glycogen, and free fatty acid were increased by TA administration, whereas TA significantly reduced the levels of glucose, MDA, LDH, lactate, CK, inflammatory cytokines, alanine transaminase, aspartate transaminase, blood urea nitrogen, and cortisol compared to the control group. CONCLUSIONS: TA improves fatigue by modulating oxidative stress and energy metabolism in C2C12 cells and animal models. Therefore, we suggest that TA can be a powerful substance in healthy functional foods and therapeutics to improve fatigue.

Compound of Cynanchum wilfordii and Humulus lupulus L. Ameliorates Menopausal Symptoms in Ovariectomized Mice.

Cynanchum wilfordii and Humulus lupulus L. have been used for their various pharmacological properties in South Korea as a traditional medicine or health functional food, respectively, and their intake may relieve menopausal symptoms. The purpose of current study was to determine the effect of compound of Cynanchum wilfordii and Humulus lupulus L. (CWHL) in menopausal symptoms of ovariectomized (OVX) mice. OVX mice received CWHL or caudatin (an active ingredient of CWHL) once daily for 7 weeks. Values for hypothalamic serotonin (5-HT), dopamine, norepinephrine, estrogen receptor (ER)-ß, 5-HT1A, and 5-HT2A were significantly enhanced, while value for hypothalamic monoamine oxidase A was reduced in CWHL and caudatin groups compared with the OVX group. CWHL and caudatin significantly reduced tail skin temperature and rectal temperature of OVX mice through partial recovering of the levels of serum estrogen, nitric oxide, follicle-stimulating hormone, luteinizing hormone, and receptor-activator of the NF-κB ligand (RANKL). Moreover, CWHL and caudatin improved bone mineral density via decreasing levels of serum RANKL, tartrate-resistant acid phosphatase, and collagen type 1 cross-linked N-telopeptide and improving levels of serum alkaline phosphatase, osteoprotegerin, and osteocalcin compared with the OVX group without adverse effects such as dyslipidemia. CWHL increased uterine ER-ß levels but did not change uterus and vaginal weights. Taken together, the results indicate that CWHL may relieve menopausal symptoms by controlling depression-, hot flashes-, and osteoporosis-associated biomarkers. Therefore, we propose that CWHL might be a safe and potential candidate for management of menopause as a health functional food.

High performance of InGaN light-emitting diodes by air-gap/GaN distributed Bragg reflectors.

The effect of air-gap/GaN DBR structure, fabricated by selective lateral wet-etching, on InGaN light-emitting diodes (LEDs) is investigated. The air-gap/GaN DBR structures in LED acts as a light reflector, and thereby improve the light output power due to the redirection of light into escape cones on both front and back sides of the LED. At an injection current of 20 mA, the enhancement in the radiometric power as high as 1.91 times as compared to a conventional LED having no DBR structure and a far-field angle as low as 128.2° are realized with air-gap/GaN DBR structures.