Castanea crenata honey reduces influenza infection by activating the innate immune response.

Influenza is an acute respiratory disorder caused by the influenza virus and is associated with prolonged hospitalization and high mortality rates in older individuals and chronically ill patients. Vaccination is the most effective preventive strategy for ameliorating seasonal influenza. However, the vaccine is not fully effective in cases of antigenic mismatch with the viral strains circulating in the community. The emergence of resistance to antiviral drugs aggravates the situation. Therefore, developing new vaccines and antiviral drugs is essential. Castanea crenata honey (CH) is an extensively cultivated food worldwide and has been used as a nutritional supplement or herbal medicine. However, the potential anti-influenza properties of CH remain unexplored. In this study, the in vitro and in vivo antiviral effects of CH were assessed. CH significantly prevented influenza virus infection in mouse Raw264.7 macrophages. CH pretreatment inhibited the expression of the viral proteins M2, PA, and PB1 and enhanced the secretion of proinflammatory cytokines and type-I interferon (IFN)-related proteins in vitro. CH increased the expression of RIG-1, mitochondrial antiviral signaling (MAVS) protein, and IFN-inducible transmembrane protein, which interferes with virus replication. CH reduced body weight loss by 20.9%, increased survival by 60%, and decreased viral replication and inflammatory response in the lungs of influenza A virus-infected mice. Therefore, CH stimulates an antiviral response in murine macrophages and mice by preventing viral infection through the RIG-1-mediated MAVS pathway. Further investigation is warranted to understand the molecular mechanisms involved in the protective effects of CH on influenza virus infection.

Garcinia mangostana Suppresses Triacylglycerol Synthesis in Hepatocytes and Enterocytes.

Regulation of diacylglycerol acyltransferase (DGAT) and pancreatic lipase (PL) activities is important in the treatment of triacylglycerol (TG)-related metabolic diseases. Garcinia mangostana, also known as mangosteen, is a traditional medicine ingredient used in the treatment of inflammation in Southeast Asia. In this study, The ethanolic extract of G. mangostana peel inhibited human recombinant DGAT1 and DGAT2, and PL enzyme activities in vitro. The inhibitory activity of DGAT1 and DGAT2 enzymes of four representative bioactive substances in mangosteen was confirmed. In addition, G. mangostana was confirmed to suppress the serum TG levels in C57 mice by inhibiting the absorption and synthesis of TG in the gastrointestinal tract. Through this study, it was revealed that G. mangostana extract could be useful for the prevention and amelioration of TG-related metabolic diseases such as obesity and fatty liver.

Antiviral activity of soybean GL 2626/96 (Glycine max) ethanolic extract against influenza A virus in vitro and in vivo.

Influenza viruses cause respiratory infections in humans with high morbidity and mortality rates. Neuraminidase inhibitors such as oseltamivir and peramivir are the most commonly used drugs for influenza virus infections. However, the emergence of resistant viruses necessitates the urgent need to develop next-generation anti-influenza drugs. Soybean (Glycine max L. Merr.) is widely cultivated and used as food worldwide. In addition, soybean has long been used as a nutritional supplement and herbal medicine. However, the potential anti-influenza properties of the soybean cultivar "GL 2626/96″ (SG2626) are yet to be investigated. Herein, we determined whether the ethanolic extract of SG2626 (SG2626E) has anti-viral activity through performing SG2626E pre-, co-, and post-treatment assays, using the influenza green fluorescent protein (GFP)-tagged influenza A/PR/8/34 (A/PR/8/34-GFP) virus. SG2626E showed anti-influenza virus activity in pre- and co-treated cells in a dose-dependent manner, but not in post-treated cells. SG2626E imparted a considerable inhibitory effect on influenza A virus (IAV) infection through blocking viral attachment. SG2626E inhibited the activity of viral hemagglutinin, but not viral neuraminidase of the IAV. SG2626E inhibited IAV infection by reducing intracellular calcium levels in infected human lung epithelial A549 cells. Additionally, SG2626E reduced body weight loss, decreased mortality, and increased the survival rate through reducing viral replication in the lungs of IAV-infected mice. Overall, these results suggest that SG2626E inhibits IAV infection and is a potential novel anti-influenza agent.

Mulberrofuran G, a Mulberry Component, Prevents SARS-CoV-2 Infection by Blocking the Interaction between SARS-CoV-2 Spike Protein S1 Receptor-Binding Domain and Human Angiotensin-Converting Enzyme 2 Receptor.

Despite the recent development of RNA replication-targeted COVID-19 drugs by global pharmaceutical companies, their prescription in clinical practice is limited by certain factors, including drug interaction, reproductive toxicity, and drug resistance. COVID-19 drugs with multiple targets for the SARS-CoV-2 life cycle may lead to a successful reduction in drug resistance as well as enhanced therapeutic efficacy, and natural products are a potential source of molecules with therapeutic effects against COVID-19. In this study, we investigated the inhibitory efficacy of mulberrofuran G (MG), a component of Morus alba L., also known as mulberry, which has been used as food and traditional medicine, on the binding of the spike S1 receptor-binding domain (RBD) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is the initial stage of the SARS-CoV-2 infection. In competitive enzyme-linked immunosorbent assays, MG effectively blocked the spike S1 RBD: ACE2 receptor molecular binding, and investigations using the BLItz system and in silico modeling revealed that MG has high affinity for both proteins. Finally, we confirmed that MG inhibits the entry of SARS-CoV-2 spike pseudotyped virus and a clinical isolate of SARS-CoV-2 into cells, suggesting that MG might be a promising therapeutic candidate for preventing SARS-CoV-2 binding to the cell surface during early infection.

A Herbal Mixture Formula of OCD20015-V009 Prophylactic Administration to Enhance Interferon-Mediated Antiviral Activity Against Influenza A Virus.

OCD20015-V009 is an herbal mix of water-extracted Ginseng Radix, Poria (Hoelen), Rehmanniae Radix, Adenophorae Radix, Platycodi Radix, Crataegii Fructus, and Astragali Radix. In this study, its in vitro and in vivo antiviral activity and mechanisms against the influenza A virus were evaluated using a GFP-tagged influenza A virus (A/PR/8/34-GFP) to infect murine macrophages. We found that OCD20015-V009 pre-treatment substantially reduced A/PR/8/34-GFP replication. Also, OCD20015-V009 pre-treatment increased the phosphorylation of type-I IFN-related proteins TBK-1 and STAT1 and the secretion of pro-inflammatory cytokines TNF-α and IL-6 by murine macrophages. Moreover, OCD20015-V009 prophylactic administration increased IFN-stimulated genes-related 15, 20, and 56 and IFN-ß mRNA in vitro. Thus, OCD20015-V009 likely modulates murine innate immune response via macrophages. This finding is potentially useful for developing prophylactics or therapeutics against the influenza A virus. Furthermore, pre-treatment with OCD20015-V009 decreased the mortality of the mice exposed to A/PR/8/34-GFP by 20% compared to that in the untreated animals. Thus, OCD20015-V009 stimulates the antiviral response in murine macrophages and mice to viral infections. Additionally, we identified chlorogenic acid and ginsenoside Rd as the antiviral components in OCD20015-V009. Further investigations are needed to elucidate the protective effects of active components of OCD20015-V009 against influenza A viruses.

Mori ramulus and its Major Component Morusin Inhibit Herpes Simplex Virus Type 1 Replication and the Virus-Induced Reactive Oxygen Species.

Herpes simplex virus type 1 (HSV-1) is ubiquitous in many populations despite the use of acyclovir or related nucleoside analogs for treating infection. Drug resistance impairs the treatment of HSV-infected individuals who have immune deficits, underscoring the need for new safe and effective antiviral agents. Mori ramulus (the young twig of Morus alba L.) has long been used to treat diseases in Korea, Japan, and China. Recent studies have reported multiple pharmacological activities of Mori ramulus and its constituent morusin, but their effects on HSV-1 remain unknown. Here, we found that treatment with Mori ramulus ethanol extract (MRE) significantly reduced the replication of fluorescently labeled HSV-1 in Vero cells and inhibited the expression of HSV-1 envelope glycoprotein D (gD) and tegument protein VP16. MRE, furthermore, blocked HSV-1-induced production of reactive oxygen species (ROS), and this mediated the inhibition of viral replication. We identified morusin as the active antiviral component of MRE and found that morusin post-treatment was sufficient to inhibit viral gD and VP16 in addition to HSV-1-induced ROS production. Therefore, the inhibition of HSV-1-induced ROS may explain the antiviral activity of MRE against HSV-1. MRE or its component morusin may be potentially developed for anti-HSV-1 agents.

Acacetin enhances glucose uptake through insulin-independent GLUT4 translocation in L6 myotubes.

BACKGROUND: Lowering blood glucose levels by increasing glucose uptake in insulin target tissues, such as skeletal muscle and adipose tissue, is one strategy to discover and develop antidiabetic drugs from natural products used as traditional medicines. PURPOSE: Our goal was to reveal the mechanism and activity of acacetin (5,7-dihydroxy-4'-methoxyflavone), one of the major compounds in Agastache rugose, in stimulating glucose uptake in muscle cells. METHODS: To determine whether acacetin promotes GLUT4-dependent glucose uptake in cultured L6 skeletal muscle cells, we performed a [14C] 2-deoxy-D-glucose (2-DG) uptake assay after treating differentiated L6-GLUT4myc cells with acacetin. RESULTS: Acacetin dose-dependently increased 2-DG uptake by enhancing GLUT4 translocation to the plasma membrane. Our results revealed that acacetin activated the CaMKII-AMPK pathway by increasing intracellular calcium concentrations. We also found that aPKCλ/ζ phosphorylation and intracellular reactive oxygen species (ROS) production were involved in acacetin-induced GLUT4 translocation. Moreover, acacetin-activated AMPK inhibited intracellular lipid accumulation and increased 2-DG uptake in HepG2 cells. CONCLUSION: Taken together, these results suggest that acacetin might be useful as an antidiabetic functional ingredient. Subsequent experiments using disease model animals are needed to verify our results.

Xanthones from the stems of Cudrania tricuspidata and their inhibitory effects on pancreatic lipase and fat accumulation.

Nine new xanthones, cudracuspixanthones I - Q (12-14, 25, 32-36), and 30 known xanthones (1-11, 15-24, 26-31, 37-39) were isolated from the stems of Cudrania tricuspidata (Moraceae). The structures of isolated compounds were established by using 1D and 2D NMR in combination with HR-TOF-MS. Xanthones from the stems of C. tricuspidata exerted pancreatic lipase inhibitory activity. In addition, cudracuspixanthone P (35), a new xanthone, reduced the fat accumulation in liver cells stimulated with fatty acids. Therefore, these compounds might be beneficial in the treatment of metabolic diseases.

Corrigendum to "Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells".

[This corrects the article DOI: 10.1155/2018/3140267.].

Derrone induces autophagic cell death through induction of ROS and ERK in A549 cells.

We studied the effect of derrone (DR), one of the major compounds of unripe fruits of Cudrania tricuspidata, on cancer cell death. DR inhibited cell growth of various cancer cells, and that was partially associated with apoptosis in A549 cells. DR showed the autophagic features, such as the conversion of LC3-I to LC3-II, the formation of autophagosome and the downregulation of SQSTM1/p62 (p62). The treatment of autophagy inhibitor reversed DR-mediated cell death, suggesting that DR induces autophagic cell death. The increase of cytoplasmic Ca2+ and ROS by DR treatment significantly influences the formation of autophagosomes; however, only ROS scavengers significantly rescued the reduced cell viability. Additional results revealed that treatment of DR induces sustained phosphorylation of ERK and the inhibition of ERK phosphorylation using U0126 (ERK inhibitor) markedly attenuated DR-induced cell death. Overall, these results suggest that DR induces autophagic cell death through intracellular ROS and sustained ERK phosphorylation in A549 cells.

Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells.

Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF-α, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells.

Tripterygium regelii decreases the biosynthesis of triacylglycerol and cholesterol in HepG2 cells.

In the course of screening to find a plant material decreasing the activity of triacylglycerol and cholesterol, we identified Tripterygium regelii (TR). The methanol extract of TR leaves (TR-LM) was shown to reduce the intracellular lipid contents consisting of triacylglycerol (TG) and cholesterol in HepG2 cells. TR-LM also downregulated the mRNA and protein expression of the lipogenic genes such as SREBP-1 and its target enzymes. Consequently, TR-LM reduced the TG biosynthesis in HepG2 cells. In addition, TR-LM decreased SREBP2 and its target enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. In this study, we evaluated that TR-LM attenuated cellular lipid contents through the suppression of de novo TG and cholesterol biosynthesis in HepG2 cells. All these taken together, TR-LM could be beneficial in regulating lipid metabolism and useful preventing the hyperlipidemia and its complications, in that liver is a crucial tissue for the secretion of serum lipids.

Oleanane-type triterpenoids of Aceriphyllum rossii and their diacylglycerol acyltransferase-inhibitory activity.

Six known triterpenoid compounds, 3-oxoolean-12-en-27-oic acid (1), gypsogenic acid (2), 3α-hydroxyolean-12-en-27-oic acid (3), 3ß-hydroxyolean-12-en-27-oic acid (4), aceriphyllic acid A (5), and oleanolic acid (6), were isolated from the roots of Aceriphyllum rossii. Their chemical structures were determined by comparison with available (1)H-NMR and (13)C-NMR data on known compounds. All the isolated compounds were evaluated for inhibitory activity against human diacylglycerol acyltransferases 1 and 2. Most of the isolates exhibited a better inhibitory activity against diacylglycerol acyltransferase 2 (IC50: 11.6-44.2 µM) than against diacylglycerol acyltransferase 1 (IC50: 22.7-119.5 µM). In particular, compounds 1 and 5 showed strong inhibition efficacy towards diacylglycerol acyltransferases 1 and 2, and appeared to act competitively against oleoyl-CoA in vitro. The results also indicated that both compounds reduced newly synthesized triacylglycerol in HuTu80 and HepG2 cells. Oral administration of compound 1 significantly reduced postprandial triacylglycerol in mice following an oral lipid challenge. In conclusion, the current study indicates that compound 1 suppresses both de novo triacylglycerol biosynthesis and resynthesis through the inhibition of diacylglycerol acyltransferase activity, and therefore may be a useful agent for treating diseases associated with a high triacylglycerol level.