The mitochondrial pathway and reactive oxygen species are critical contributors to interferon-α/ß-mediated apoptosis in Ubp43-deficient hematopoietic cells.

UBP43 (also known as USP18) plays a role in the negative regulation of interferon-α/ß signaling, and bone marrow cells in Ubp43-deficient mice exhibited hypersensitivity to interferon-α/ß-mediated apoptosis. Here, we show that the mitochondrial apoptotic pathway and reactive oxygen species are major contributors to the elevated interferon-α/ß-mediated apoptosis in Ubp43-deficient mouse bone marrow cells and in UBP43-knockdown THP-1 cells. Furthermore, TRAIL and FASL, which were proposed as apoptosis inducers upon interferon-α/ß treatment in UBP43-knockdown adherent cancer cells, did not cause apoptosis in these hematopoietic cells. Therefore, although UBP43 depletion can cause hypersensitivity to interferon-α/ß-mediated apoptosis in a broad range of cell types, the downstream pathway may vary depending on the cell type.

Dietary antigens suppress the proliferation of type 2 innate lymphoid cells by restraining homeostatic IL-25 production.

Dietary antigens affect the adaptive immunity of the host by inducing regulatory T cells and IgE-producing B cells. However, their roles in innate immune compartments such as innate lymphoid cells (ILCs) and intestinal epithelial cells (IECs) are unclear. Here, using antigen-free (AF) mice, which are germ-free (GF) mice fed with amino-acid-based diet, we found dietary proteins suppress the development of GATA-3-expressing ILC2s independent of the adaptive immune cells. These cells produce more type 2 cytokines and upregulated proliferation and activation markers such as Ki-67, CD69, and CD25. With this, AF mice had increased expressions of tuft cell-specific transcripts such as Il25, Il33, Dclk1, Trpm5, and Pou2f3 in IECs. Accordingly, expanded ILC2s upregulated IL-17RB, a receptor of IL-25, and their proliferation was blocked by IL-25 neutralizing or IL-17RB blocking antibodies. These results suggest a new dialogue between dietary antigens, IECs, and ILCs in which dietary antigens suppress ILC2 activation and proliferation by restraining homeostatic IL-25 production, potentially limiting type 2 immunity by food antigens.

Homeostatic serum IgE is secreted by plasma cells in the thymus and enhances mast cell survival.

Increased serum levels of immunoglobulin E (IgE) is a risk factor for various diseases, including allergy and anaphylaxis. However, the source and ontogeny of B cells producing IgE under steady state conditions are not well defined. Here, we show plasma cells that develop in the thymus and potently secrete IgE and other immunoglobulins, including IgM, IgA, and IgG. The development of these IgE-secreting plasma cells are induced by IL-4 produced by invariant Natural Killer T cells, independent of CD1d-mediated interaction. Single-cell transcriptomics suggest the developmental landscape of thymic B cells, and the thymus supports development of transitional, mature, and memory B cells in addition to plasma cells. Furthermore, thymic plasma cells produce polyclonal antibodies without somatic hypermutation, indicating they develop via the extra-follicular pathway. Physiologically, thymic-derived IgEs increase the number of mast cells in the gut and skin, which correlates with the severity of anaphylaxis. Collectively, we define the ontogeny of thymic plasma cells and show that steady state thymus-derived IgEs regulate mast cell homeostasis, opening up new avenues for studying the genetic causes of allergic disorders.

Styrylpyrones from the medicinal fungus Phellinus baumii and their antioxidant properties.

During the search for natural antioxidants from basidiomycetes, a new styrylpyrone, baumin (1), was isolated from the cultivated medicinal fungus Phellinus baumii, together with known compounds, davallialactone (2), hispidin (3), hypholomine B (4), interfungin A (5), inoscavin A (6), and phelligridin D (7), which were previously isolated from the medicinal fungi Phellinusignarius, Phellinuslinteus, and Inonotus xeranticus. Their structures were elucidated by extensive spectroscopic methods. These compounds exhibited antioxidant activity through Fenton reaction inhibition via iron chelation and free radical scavenging.

Von Hippel-Lindau regulates interleukin-32ß stability in ovarian cancer cells.

Hypoxia-induced interleukin-32ß (IL-32ß) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32ß stability is regulated was investigated in ovarian cancer cells. IL-32ß expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32ß was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32ß was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex. Oxygen deficiency or reactive oxygen species (ROS) disrupted the interaction between IL-32ß and VHL, leading to the accumulation of the cytokine. The fact that IL-32ß is regulated by the energy-consuming ubiquitination system implies that it plays an important role in oxidative stress. We found that IL-32ß reduced protein kinase Cδ (PKCδ)-induced apoptosis under oxidative stress. This implies that the hypoxia- and ROS-stabilized IL-32ß contributes to sustain survival against PKCδ-induced apoptosis.

Differential Modulation of Lipopolysaccharide-Induced Inflammatory Cytokine Production by and Antioxidant Activity of Fomentariol in RAW264.7 Cells.

Medicinal mushrooms have been used worldwide to treat cancer and modulate the immune system. Over the last several years, there has been increasing interest in isolating bioactive compounds from medicinal mushrooms and evaluating their health beneficial effects. Fomes fomentarius is used in traditional oriental medicine and is known to possess antioxidant, anti-inflammatory, antidiabetic, and antitumor effects. In the present study, we isolated fomentariol from Fomes fomentarius and investigated its anti-inflammatory effect in murine macrophages (RAW264.7 cells) stimulated with lipopolysaccharides. Fomentariol inhibited the production of nitric oxide and intracellular reactive oxygen species triggered by lipopolysaccharides. Interestingly, fomentariol differentially regulated cytokine production triggered by lipopolysaccharides. Fomentariol effectively suppressed the production of interleukin-1ß and interleukin-6 but not tumor necrosis factor-α. The inhibitory effect of fomentariol against nitric oxide, interleukin-1ß, and interleukin-6 production was possibly mediated by downregulation of the extracellular signal-regulated kinase signaling pathway. Taken together, our results suggest that fomentariol differentially modulated inflammatory responses triggered by lipopolysaccharides in macrophages and is one of the bioactive compounds that mediate the physiological effects of Fomes fomentarius.

Chemical Constituents of the Culture Broth of Phellinus linteus and Their Antioxidant Activity.

The medicinal fungus Phellinus linteus, in the family Hymenochaetaceae, has been used as a traditional medicine for the treatment of various diseases. In this study, the chemical constituents of the culture broth of P. linteus were investigated. P. linteus was cultured in potato dextrose broth medium, and the culture broth was extracted with ethyl acetate. The ethyl acetate-soluble portion was concentrated and subjected to ODS column chromatography, followed by Sephadex LH-20 column chromatography. Six compounds (1~6) were purified by preparative reversed-phase high-performance liquid chromatography. Spectroscopic methods identified their structures as caffeic acid (1), inotilone (2), 4-(3,4-dihydroxyphenyl)-3-buten-2-one (3), phellilane H (4), (2E,4E)-(+)-4'-hydroxy-γ-ionylideneacetic acid (5), and (2E,4E)-γ-ionylideneacetic acid (6). Compounds 1, 2, and 3 exhibited potent dose-dependent antioxidant activity.

Methyl 9-Oxo-(10E,12E)-octadecadienoate Isolated from Fomes fomentarius Attenuates Lipopolysaccharide-Induced Inflammatory Response by Blocking Phosphorylation of STAT3 in Murine Macrophages.

Fomes fomentarius is a fungus of the Polyporaceae family and is used in traditional oriental therapies. Although the anti-inflammatory activities of this species have been previously reported, the identity of the bioactive compounds responsible for this activity remains unknown. Here, we investigated whether methyl 9-oxo-(10E,12E)-octadecadienoate (FF-8) purified from F. fomentarius exerts anti-inflammatory activity in murine macrophages stimulated with lipopolysaccharide (LPS). FF-8 suppressed secretion of nitric oxide (NO) and prostaglandin E2 through downregulation of inducible NO synthase and cyclooxygenase-2 expression induced by LPS. In addition, pretreatment of cells with FF-8 led to a reduction in levels of secreted inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in macrophages stimulated with LPS. Conversely, FF-8 did not affect nuclear factor κB, p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase pathways. Instead, FF-8 specifically interfered with signal transducer and activator of transcription 3 (STAT3) phosphorylation induced by LPS. Collectively, this study demonstrated that FF-8 purified from F. fomentarius suppresses inflammatory responses in macrophages stimulated with LPS by inhibiting STAT3 activation. Further studies will be required to elucidate the anti-inflammatory effect of FF-8 in vivo.

Neuraminidase Inhibitors from the Fermentation Broth of Phellinus linteus.

During a search for neuraminidase inhibitors derived from medicinal fungi, we found that the fermentation broth of Phellinus linteus exhibited potent neuraminidase inhibitory activity. Through bioassay-guided fractionation, two active compounds were purified from the ethyl acetate-soluble portion of the fermentation broth of P. linteus. These structures were identified as inotilone (1) and 4-(3,4-dihydroxyphenyl)-3-buten-2-one (2) by spectroscopic methods. Compounds 1 and 2 inhibited H1N1 neuraminidase activity with IC50 values of 29.1 and 125.6 µM, respectively, in a dose-dependent manner. They also exhibited an antiviral effect in a viral cytopathic effect reduction assay using MDCK cells. These results suggest that compounds 1 and 2 from the culture broth of P. linteus would be good candidates for the prevention and therapeutic strategies towards viral infections.

p-Terphenyls from fungus Paxillus curtisii chelate irons: a proposed role of p-terphenyls in fungus.

Diverse p-terphenyl compounds, named curtisians, have been isolated from the fungus Paxillus curtisii, and degradation of wood by this fungus is thought to be progressed by iron chelation of p-terphenyl curtisians. In this study, the iron chelation ability of p-terphenyls has been proved by chrome azurol S (CAS) assay, reducing power, and UV-visible spectroscopic analyses. The catechol moiety of p-terphenyl is an essential factor for the potent iron chelation ability, and thus deacylated curtisian with a tetrahydroxyl moiety in the central ring of p-terphenyl is more effective than acylated curtisians.

Neuraminidase Inhibitors from the Culture Broth of Phellinus linteus.

During the search for neuraminidase inhibitors from medicinal fungi, we found that the culture broth of Phellinus linteus exhibited potent inhibitory activity. Solvent partition, Sephadex LH-20 column chromatography, and high-performance liquid chromatography (HPLC) were performed for purification of two active substances from the culture broth. According to (1)H NMR measurements and comparison of HPLC retention times with those of authentic compounds, their chemical structures were identified as hispidin and hypholomine B. Compounds (hispidin) 1 and 2 (hypholomine B) inhibited neuraminidase, with IC(50) values of 13.1 and 0.03 µM, respectively.

Fomitoside K, a New Lanostane Triterpene Glycoside from the Fruiting Body of Fomitopsis nigra.

In an effort to identify the chemical constituents of fruiting bodies of Fomitopsis pinicola, a new lanostane triterpene glycoside, designated as fomitoside K, has been isolated from its methanolic extract. Its chemical structure was assigned on the basis of various spectroscopic studies.

Mushrooms collected from deogyu mountain, muju, Korea and their antioxidant activity.

Mushrooms collected from Deogyu mountain, Korea, in 2011, were identified as four classes, four orders, 13 families, 22 genera, and 33 species. In particular, agaricales was most abundant and comprised more than 70%. Their antioxidant activities were estimated using three different bioassay methods, the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and reducing power assay. As a result, the methanol extracts of Stereum ostrea, Laetiporus sulphureus var. miniatus, and Tyromyces sambuceus exhibited potent antioxidant activity in all bioassays tested.