7-MEGA™ inhibits adipogenesis in 3T3-L1 adipocytes and suppresses obesity in high-fat-diet-induced obese C57BL/6 mice.

BACKGROUND: Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community. METHOD: This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes. RESULTS: 7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate. CONCLUSION: In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.

Interferon-ß alleviates sepsis by SIRT1-mediated blockage of endothelial glycocalyx shedding.

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-ß (IFN-ß) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-ß effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-ß, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-ß plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-ß upregulated SIRT1 protein expression in endothelial cells in a protein synthesisindependent manner. IFN-ß plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-ß plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-ß plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway. [BMB Reports 2023; 56(5): 314-319].

Regulatory Effects of Lycium barbarum Extract and Isolated Scopoletin on Atopic Dermatitis-Like Skin Inflammation.

Lycium barbarum and scopoletin are widely used in oriental Eastern medicine and are often consumed as teas. In this study, proinflammatory cytokines expressed in human keratinocytes (HaCaT) were induced by skin diseases caused by 2,4-dinitrochlorobenzene (DNCB) and tumor necrosis factor alpha (TNF-α)/interferon gamma (IFN-γ). The inhibitory activity of L. barbarum EtOH extract (LBE) and scopoletin on proinflammatory cytokines and chemokines was investigated. In the DNCB-induced animal model, oral administration of LBE inhibited skin lesions and proinflammatory cytokines and chemokines and showed inhibitory effects in vitro. Additionally, as a result of examining the efficacy of scopoletin isolated from L. barbarum, scopoletin in HaCaT cells showed inhibitory effects on proinflammatory cytokines and chemokines. It shows promise in the treatment of chronic skin diseases.

Changes in the phosphorylation of nucleotide metabolism­associated proteins by leukemia inhibitory factor in mouse embryonic stem cells.

Leukemia inhibitory factor (LIF) is a stem cell growth factor that maintains self­renewal of mouse embryonic stem cells (mESCs). LIF is a cytokine in the interleukin­6 family and signals via the common receptor subunit gp130 and ligand­specific LIF receptor. LIF causes heterodimerization of the LIF receptor and gp130, activating the Janus kinase/STAT and MAPK pathways, resulting in changes in protein phosphorylation. The present study profiled LIF­mediated protein phosphorylation changes in mESCs via proteomic analysis. mESCs treated in the presence or absence of LIF were analyzed via two­dimensional differential in­gel electrophoresis and protein and phosphoprotein staining. Protein identification was performed by matrix­assisted laser desorption/ionization­time of flight mass spectrophotometry. Increased phosphorylation of 16 proteins and decreased phosphorylation of 34 proteins in response to LIF treatment was detected. Gene Ontology terms enriched in these proteins included 'organonitrogen compound metabolic process', 'regulation of mRNA splicing via spliceosome' and 'nucleotide metabolic process'. The present results revealed that LIF modulated phosphorylation levels of nucleotide metabolism­associated proteins, thus providing insight into the mechanism underlying LIF action in mESCs.

Eudebeiolide B Inhibits Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss by Regulating RANKL-Induced NF-κB, c-Fos and Calcium Signaling.

Eudebeiolide B is a eudesmane-type sesquiterpenoid compound isolated from Salvia plebeia R. Br., and little is known about its biological activity. In this study, we investigated the effects of eudebeiolide B on osteoblast differentiation, receptor activator nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. Eudebeiolide B induced the expression of alkaline phosphatase (ALP) and calcium accumulation during MC3T3-E1 osteoblast differentiation. In mouse bone marrow macrophages (BMMs), eudebeiolide B suppressed RANKL-induced osteoclast differentiation of BMMs and bone resorption. Eudebeiolide B downregulated the expression of nuclear factor of activated T-cells 1 (NFATc1) and c-fos, transcription factors induced by RANKL. Moreover, eudebeiolide B attenuated the RANKL-induced expression of osteoclastogenesis-related genes, including cathepsin K (Ctsk), matrix metalloproteinase 9 (MMP9) and dendrocyte expressed seven transmembrane protein (DC-STAMP). Regarding the molecular mechanism, eudebeiolide B inhibited the phosphorylation of Akt and NF-κB p65. In addition, it downregulated the expression of cAMP response element-binding protein (CREB), Bruton's tyrosine kinase (Btk) and phospholipase Cγ2 (PLCγ2) in RANKL-induced calcium signaling. In an ovariectomized (OVX) mouse model, intragastric injection of eudebeiolide B prevented OVX-induced bone loss, as shown by bone mineral density and contents, microarchitecture parameters and serum levels of bone turnover markers. Eudebeiolide B not only promoted osteoblast differentiation but inhibited RANKL-induced osteoclastogenesis through calcium signaling and prevented OVX-induced bone loss. Therefore, eudebeiolide B may be a new therapeutic agent for osteoclast-related diseases, including osteoporosis, rheumatoid arthritis and periodontitis.

Oleanolic Acid Acetate Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis in Mice by Regulating Toll-Like Receptor 2 Signaling.

Toll-like receptor 2 (TLR2) is expressed by several immune cells in the central nervous system and plays an important role in neuroinflammation. TLR2 upregulation has been reported in multiple sclerosis patients and in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Therefore, modulating TLR2 signaling can be an effective treatment strategy against MS. Oleanolic acid acetate (OAA) has antiinflammatory and immunomodulatory effects. Hence, this study aimed to examine the effects of OAA on TLR2 signaling and neuroinflammation in EAE. EAE was induced in C57/BL6 mice using synthesized myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, and OAA was administered daily. Hind limb paralysis and inflammatory cell infiltration were observed in the spinal cords of EAE mice. Moreover, T-cell proliferation was significantly stimulated in splenic cells from EAE mice. The expression of proinflammatory cytokines in the spinal cord was upregulated, and their serum protein levels were increased in EAE mice. Furthermore, upregulation of TLR2 and downstream signaling molecules was observed in the spinal cord. These pathological changes were reversed by OAA treatment. Our results suggest that OAA might have promising therapeutic properties and that the TLR signaling pathway is an effective therapeutic target against multiple sclerosis.

STAT3-inhibitory activity of sesquiterpenoids and diterpenoids from Curcuma phaeocaulis.

Three new sesquiterpenoids (compounds 4, 5, and 26), along with 23 known sesquiterpenoids (compounds 1-3 and 6-25) and two diterpenoids (compounds 27 and 28), were obtained from Curcuma phaeocaulis, and their chemical structures were determined through nuclear magnetic resonance (NMR), circular dichroism (CD), and high-resolution electrospray ionization (HRESIMS) spectroscopic data, which were compared to the data from previous studies. All isolates were tested for inhibitory activity against interleukin (IL)-6-stimulated STAT3 expression using a luciferase reporter assay, and curzerenone (21) and 8-epi-galanolactone (28) displayed promising signal transducer and activator of transcription (STAT3)-inhibitory activities with IC50 values of 4.8 and 4.1 µM, respectively. In addition, these candidates significantly suppressed the mRNA expression levels of the proinflammatory genes IL-1ß and C-reactive protein (CRP) via blockade of the IL-6-activated Janus kinase 2 (JAK2)/STAT3 and ERK-MAPK signaling pathways. These results suggest that curzerenone (21) and 8-epi-galanolactone (28) may be potential candidates for ameliorating severe inflammatory diseases.

Adaptive Ground Control System of Multiple-UAV Operators in a Simulated Environment.

INTRODUCTION: In the present study, an Adaptive Ground Control System for Multiple-UAV Operator Workload Decrement (AGCS) has been developed and the effectiveness of the system has been analyzed using eye-tracking and task performance data. The AGCS contained four more functions than the conventional GCS (CGCS) functions. The functions were based on real-time operator gaze information, multiple UAV operational state, and mission state information to help safe and efficient multiple UAV operation.METHODS: A total of 30 volunteers participated in the human-in-the-loop experiment to compare the performances of the newly developed AGCS and CGCS while executing reconnaissance and strike missions by operating multiple UAVs.RESULTS: According to the results, the AGCS demonstrates a statistically significant increase in mission performance, such as the mission completion rate (M = 97.3 vs. M = 95.4; SD = 3.1 vs. SD = 4.9) and mission success rate (M = 90.4 vs. M = 88.4; SD = 5.7 vs. SD = 5.6). In addition, the subjects' pupil diameter and gaze indicator show significant differences in the direction of workload reduction (α = 0.05). The subjects expressed positive opinions about using the AGCS.DISCUSSION: The originally developed AGCS showed a promising future extension based on the experimental data. After completion of the experiment, domain experts were interviewed and the next version will reflect their opinion.Lim H-J, Choi S-H, Oh J, Kim BS, Kim S, Yang JH. Adaptive ground control system of muliple-UAV operators in a simulated environment. Aerosp Med Hum Perform. 2019; 90(10):841-850.

Diarylheptanoids from Curcuma phaeocaulis Suppress IL-6-Induced STAT3 Activation.

Three undescribed diarylheptanoids (3: -5: ) and six known curcuminoids (1, 2: , and 6: -9: ) were obtained from the ethyl acetate-soluble fraction of an ethanolic extract of Curcuma phaeocaulis. Their chemical structures and absolute configurations were elucidated by high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, circular dichroism spectroscopy, and the modified Mosher's method. Previous studies constructed Hep3B cells stably transfected with pSTAT3-Luc plasmid containing STAT3 binding site to discover STAT3 inhibitors from natural products. The STAT3 inhibitory activities of all isolates were measured in transfected Hep3B cells after treatment with IL-6. Compound 5: ((5R)-1,7-Bis(3,4-dimethoxyphenyl)-3-methoxy-1-hepten-5-ol), demethoxycurcumin (7: ), and curcumin (8: ) exhibited significant inhibitory activity (IC50 values: 11.1, 1.9, and 1.6 µM, respectively). Furthermore, IL-6-induced phosphorylation of STAT3, and the mRNA expression levels of inflammation-related genes such as CRP, IL-1ß, ICAM-1, and SOCS3 were significantly reduced by exposure to compound 5: . These data suggested that the inhibitory activity of 5: is associated with the suppression of STAT3 phosphorylation. Thus, compound 5: may be a promising candidate for the treatment of cancer or inflammatory diseases related to the IL-6/STAT3 signaling pathway.

Inhibitory Effects of Compounds and Extracts from Ampelopsis brevipedunculata on IL-6-Induced STAT3 Activation.

Ampelopsis brevipedunculata (Maxim.) Trautv. (AB), a traditional East Asian medicine, exhibits protective effects against several inflammatory diseases. Our search for an inhibitor of IL-6-induced JAK2/STAT3 activation revealed that AB ethanolic extract (ABE) had a significant inhibitory effect on IL-6-induced STAT3 expression in Hep3B cells. The isolation and purification of an EtOAc-soluble fraction of ABE (ABEA) using reversed-phase high-performance liquid chromatography (RP-HPLC) afforded 17 compounds. The structures of these compounds (1-17) were elucidated based on 1H and 13C nuclear magnetic resonance (NMR) spectroscopy as well as electrospray-ionization mass spectrometry (ESI-MS) data. ABE and ABEA were screened by a luciferase assay using Hep3B cells transfected with the STAT3 reporter gene. ABEA exhibited potent inhibitory effects on IL-6-induced STAT3 expression; moreover, these effects arose from the inhibition of the phosphorylation of the STAT3, JAK2, and ERK proteins in U266 cells. In addition, the compounds isolated from ABEA were measured for their inhibitory effects on IL-6-stimulated STAT3 expression. Of the compounds isolated, betulin showed the greatest inhibitory effects on IL-6-induced STAT3 activation in the luciferase assay (IC50 value: 3.12 µM). Because of its potential for inhibiting STAT3 activation, A. brevipedunculata could be considered a source of compounds of pharmaceutical interest.

Anti-inflammatory Activity of Eudesmane-Type Sesquiterpenoids from Salvia plebeia.

Nine new sesquiterpenoid lactones and 11 known analogues were isolated from the aerial parts of Salvia plebeia R.Br. Their structures were elucidated via HRESIMS and NMR data, and their absolute configurations were defined via electronic circular dichroism data, X-ray crystallographic analysis, and the modified Mosher's ester method. Compounds 1-20 were investigated for their ability to inhibit LPS-stimulated nitric oxide production in murine macrophage cells. Of the isolates, epi-eudebeiolide C (20) showed the highest inhibitory effect (IC50 of 17.9 µM). mRNA and protein expression of inducible nitric oxide synthase (iNOS), but not that of cyclooxygenase-2 (COX-2), was dose-dependently decreased by 20 in LPS-activated RAW 264.7 cells. Based on a mechanistic study involving the nuclear factor-κB (NF-κB) signaling pathway, the anti-inflammatory effect of 20 was attributed to NF-κB activation blockade via inhibition of NF-κB (IκB) phosphorylation. Therefore, 20 might be a potential candidate for relieving inflammatory diseases.