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Myristica fragrans is a well-known species for flavoring many food products and for formulation of perfume and medicated balm. It is also used to treat indigestion, stomach ulcers, liver disorders, and, as emmenagogue, diaphoretic, diuretic, nervine, and aphrodisiac. We examined antioxidant properties and bioactive compounds in various solvent extracts from the seeds of M. fragrans. Methanol, ethanol, and acetone extracts exhibited relatively strong antioxidant activities by 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide radical, and hydroxyl radical scavenging tests. Furthermore, methanol extracts also displayed significant anti-α-glucosidase activity. Examined and compared to the various solvent extracts for their chemical compositions using HPLC analysis, we isolated the ten higher content compounds and analyzed antioxidant and anti-α-glucosidase activities. Among the isolates, dehydrodiisoeugenol, malabaricone B and malabaricone C were main antioxidant components in seeds of M. fragrans. Malabaricone C exhibited stronger antioxidant capacities than others based on lower half inhibitory concentration (IC50) values in DPPH and ABTS radical scavenging assays, and it also showed significant inhibition of α-glucosidase. These results shown that methanol was found to be the most efficient solvent for extracting the active components from the seeds of M. fragrans, and this material is a potential good source of natural antioxidant and α-glucosidase inhibitor.

The resinous wood of Aquilaria sinensis, known as agarwood (Chen Xiang in Chinese), is traditionally used for the treatment of abdominal pain, vomiting, circulatory disorders, and dyspnea. Four new 2-(2-phenylethyl)-4H-chromen-4-one derivatives, namely 7-methoxy-2-[2-(4′-hydroxy-phenyl)ethyl]chromone (1), 7-hydroxy-2-[2-(4′-methoxyphenyl)ethyl]chromone (2), 5,6-dihydroxy- 2-[2-(3′-hydroxy-4′-methoxyphenyl)ethyl]chromone (3), and 6-hydroxy-5-methoxy-2-(2-phenyl-ethyl)chromone (4), have been isolated from the resinous wood of A. sinensis, together with nine known compounds. The structures of these compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, neopetasan, 7-methoxy-2-(2-phenylethyl)-chromone, 6,7-dimethoxy-2-(2-phenylethyl)chromone, and 6,7-dimethoxy-2-[2-(4′-methoxy-phenyl)ethyl]chromone inhibited NF-κB activation in LPS-stimulated RAW 264.7 macrophages with relative luciferase activity values of 0.55 ± 0.09, 0.54 ± 0.03, 0.31 ± 0.05, and 0.38 ± 0.14, respectively, versus that of vehicle control (1.03 ± 0.02). In addition, 5,6-dihydroxy-2-[2-(3′-hydroxy-4′-methoxyphenyl)ethyl]chromone, 7-methoxy-2-(2-phenylethyl)chromone, 7-dimethoxy-2-(2-phenylethyl)chromone, and 6,7-dimethoxy-2-[2-(4′-methoxyphenyl)ethyl]chromone could suppress LPS-induced NO production in RAW 264.7 cells and did not induce cytotoxicity against RAW 264.7 cells after 24-h treatment.

Three new and uncommon chromone analogs, epiremisporine F (1), epiremisporine G (2), and epiremisporine H (3), were isolated from marine-origin Penicillium citrinum. Among the isolated compounds, compounds 2–3 remarkably suppressed fMLP-induced superoxide anion generation by human neutrophils, with IC50 values of 31.68 ± 2.53, and 33.52 ± 0.42 μM, respectively. Compound 3 exhibited cytotoxic activities against human colon carcinoma (HT-29) and non-small lung cancer cell (A549) with IC50 values of 21.17 ± 4.89 and 31.43 ± 3.01 μM, respectively, and Western blot assay confirmed that compound 3 obviously induced apoptosis of HT-29 cells, via Bcl-2, Bax, and caspase 3 signaling cascades.

Flavonoids, widely present in medicinal plants and fruits, are known to exhibit multiple pharmacological activities. In this study, we isolated a flavonoid compound, pilloin, from Aquilaria sinensis and investigated its anti-inflammatory activity in bacterial lipopolysaccharide-induced RAW 264.7 macrophages and septic mice. Pilloin inhibited NF-κB activation and reduced the phosphorylation of IκB in LPS-stimulated macrophages. Moreover, pilloin significantly suppressed the production of pro-inflammatory molecules, such as TNF-α, IL-6, COX-2 and iNOS, in LPS-treated RAW 264.7 macrophages. Additionally, pilloin suppressed LPS-induced morphological alterations, phagocytic activity and ROS elevation in RAW 264.7 macrophages. The mitogen-activated protein kinase-mediated signalling pathways (including JNK, ERK, p38) were also inhibited by pilloin. Furthermore, pilloin reduced serum levels of TNF-α (from 123.3 ± 7 to 46.6 ± 5.4 ng/mL) and IL-6 levels (from 1.4 ± 0.1 to 0.7 ± 0.1 ng/mL) in multiple organs of LPS-induced septic mice (liver: from 71.8 ± 3.2 to 36.7 ± 4.3; lung: from 118.6 ± 10.6 to 75.8 ± 11.9; spleen: from 185.9 ± 23.4 to 109.6 ± 18.4; kidney: from 160.3 ± 11.8 to 75 ± 10.8 pg/mL). In summary, our results demonstrate the anti-inflammatory potential of pilloin and reveal its underlying molecular mechanism of action.

Chloranthus oldhamii Solms (CO) is a folk medicine for treating infection and arthritis pain but its pharmacological activity and bioactive compounds remain mostly uncharacterized. In this study, the anti-inflammatory compounds of C. oldhamii were identified using an LPS-stimulated, NF-κB-responsive RAW 264.7 macrophage reporter line. Three diterpenoid compounds, 3α-hydroxy-ent-abieta-8,11,13-triene (CO-9), 3α, 7β-dihydroxy-ent-abieta-8,11,13-triene (CO-10), and decandrin B (CO-15) were found to inhibit NF-κB activity at nontoxic concentrations. Moreover, CO-9 and CO-10 suppressed the expression of IL-6 and TNF-α in LPS-stimulated RAW 264.7 cells. The inhibitory effect of CO-9 on TNF-α and IL-6 expression was further demonstrated using LPS-treated bone marrow-derived macrophages. Furthermore, CO-9, CO-10, and CO-15 suppressed LPS-triggered COX-2 expression and downstream PGE2 production in RAW 264.7 cells. CO-9 and CO-10 also reduced LPS-triggered iNOS expression and nitrogen oxide production in RAW 264.7 cells. The anti-inflammatory mechanism of the most effective compound, CO-9, was further investigated. CO-9 attenuated LPS-induced NF-κB activation by reducing the phosphorylation of IKKα/β (Ser176/180), IκBα (Ser32), and p65 (Ser534). Conversely, CO-9 did not affect the LPS-induced activation of MAPK signaling pathways. In summary, this study revealed new anti-inflammatory diterpenoid compounds from C. oldhamii and demonstrated that the IKK-mediated NK-κB pathway is the major target of these compounds.

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases.

Toll-like receptors (TLRs) play crucial roles in host immune defenses. Recently, TLR-mediated autophagy is reported to promote immune responses via increasing antigen processing and presentation in antigen presenting cells. The present study examined whether the synthetic TLR4 activator (CCL-34) could induce autophagy to promote innate and adaptive immunity. In addition, the potential of CCL-34 as an immune adjuvant in vivo was also investigated. Our data using RAW264.7 cells and bone marrow-derived macrophages showed that CCL-34 induced autophagy through a TLR4-NF-κB pathway. The autophagy-related molecules (Nrf2, p62 and Beclin 1) were activated in RAW264.7 cells and bone marrow-derived macrophages under CCL-34 treatment. CCL-34-stimulated macrophages exhibited significant antigen-processing activity and induced the proliferation of antigen-specific CD4+T cells as well as the production of activated T cell-related cytokines, IL-2 and IFN-γ. Furthermore, CCL-34 immunization in mice induced infiltration of monocytes in the peritoneal cavity and elevation of antigen-specific IgG in the serum. CCL-34 treatment in vivo did not cause toxicity based on serum biochemical profiles. Notably, the antigen-specific responses induced by CCL-34 were attenuated by the autophagy inhibitor, 3-methyladenine. In summary, we demonstrated CCL-34 can induce autophagy to promote antigen-specific immune responses and act as an efficient adjuvant.

COVID-19 is a global epidemic. Developing adjuvant therapies which could prevent the virus from binding to cells may impair viral infection. This study produces a traditional Chinese medicine formula, Jing Guan Fang (JGF), based on ancient medical texts, and examines the efficacy and the mechanism by which JGF prevents viral infections. JGF reduces COVID-19 like symptoms. Functional studies show that JGF inhibits the formation of syncytium and reduces the formation of viral plaque. JGF is not toxic in vitro and in vivo . Mechanistically, JGF induces lysosomal-dependent ACE2 degradation and suppresses mRNA and the protein levels of TMPRSS2 in human lung WI-38 and MRC-5 cells. Mice that inhale JGF exhibit reduced ACE2 and TMPRSS2 protein levels in lung tissues. Together, these findings suggest that JGF may improve the COVID-19 like symptoms and inhibit viral infection. Moreover, JGF may be applicable as an adjuvant preventive strategy against SARS-CoV-2 infection in addition to the use of vaccines.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA binding protein involved in diverse cell processes; it is also a p53 coregulator that initiates apoptosis under DNA damage conditions. However, the upregulation of hnRNPK is correlated with cancer transformation, progression, and migration, whereas the regulatory role of hnRNPK in cancer malignancy remains unclear. We previously showed that arginine methylation of hnRNPK attenuated the apoptosis of U2OS osteosarcoma cells under DNA damage conditions, whereas the replacement of endogenous hnRNPK with a methylation-defective mutant inversely enhanced apoptosis. The present study further revealed that an RNA helicase, DDX3, whose C-terminus preferentially binds to the unmethylated hnRNPK and could promote such apoptotic enhancement. Moreover, C-terminus-truncated DDX3 induced significantly less apoptosis than full-length DDX3. Notably, we also identified a small molecule that docks at the ATP-binding site of DDX3, promotes the DDX3-hnRNPK interaction, and induces further apoptosis. Overall, we have shown that the arginine methylation of hnRNPK suppresses the apoptosis of U2OS cells via interfering with DDX3–hnRNPK interaction. On the other hand, DDX3–hnRNPK interaction with a proapoptotic role may serve as a target for promoting apoptosis in osteosarcoma cells.

Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells. RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2-4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis. Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion. These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK-mediated MMP-2 activity.