Identification of Potential Anti-Neuroinflammatory Inhibitors from Antarctic Fungal Strain Aspergillus sp. SF-7402 via Regulating the NF-κB Signaling Pathway in Microglia

Microglia play a significant role in immune defense and tissue repair in the central nervous system (CNS). Microglial activation and the resulting neuroinflammation play a key role in the pathogenesis of neurodegenerative disorders. Recently, inflammation reduction strategies in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the anti-neuroinflammatory potential of compounds from the Antarctic fungi strain Aspergillus sp. SF-7402 in lipopolysaccharide (LPS)-stimulated BV2 cells. Four metabolites were isolated from the fungi through chemical investigations, namely, 5-methoxysterigmatocystin (1), sterigmatocystin (2), aversin (3), and 6,8-O-dimethylversicolorin A (4). Their chemical structures were elucidated by extensive spectroscopic analysis and HR-ESI-MS, as well as by comparison with those reported in literature. Anti-neuroinflammatory effects of the isolated metabolites were evaluated by measuring the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in LPS-activated microglia at non-cytotoxic concentrations. Sterigmatocystins (1 and 2) displayed significant effects on NO production and mild effects on TNF-α and IL-6 expression inhibition. The molecular mechanisms underlying this activity were investigated using Western blot analysis. Sterigmatocystin treatment inhibited NO production via downregulation of inducible nitric oxide synthase (iNOS) expression in LPS-stimulated BV2 cells. Additionally, sterigmatocystins reduced nuclear translocation of NF-κB. These results suggest that sterigmatocystins present in the fungal strain Aspergillus sp. are promising candidates for the treatment of neuroinflammatory diseases.     

New alkaloids and isocoumarins from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501

Abstract

Two new β-carboline alkaloids, aspergillspins A-B (1–2), three new quinolone alkaloids, aspergillspins C-E (3–5), and two new isocoumarins, aspergillspins F-G (6–7), together with four known alkaloids were isolated from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. Their structures were identified by spectroscopic analysis, and the absolute configurations of several chiral carbons in 2 and 3 were further established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Their cytotoxic and antibacterial activities were also evaluated.     

Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases

Non-canonical nuclear factor kappa B (NF-κB) signaling pathway regulates many physiological and pathological processes, including liver homeostasis and diseases. Recent studies demonstrate that non-canonical NF-κB signaling pathway plays an essential role in hyperglycemia, non-alcoholic fatty liver disease, alcoholic liver disease, liver regeneration, liver injury, autoimmune liver disease, viral hepatitis, and hepatocellular carcinoma. Small-molecule inhibitors targeting to non-canonical NF-κB signaling pathway have been developed and shown promising results in the treatment of liver injuries. Here, the recent advances and future prospects in understanding the roles of the non-canonical NF-κB signaling pathways in the regulation of liver diseases are discussed.     

Diversified Chaetoglobosins from the Marine-Derived Fungus Emericellopsis sp. SCSIO41202

Two undescribed cytochalasins, emeriglobosins A (1) and B (2), together with nine previously reported analogues (3–11) and two known tetramic acid derivatives (12, 13) were isolated from the solid culture of Emericellopsis sp. SCSIO41202. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis and the calculated ECD. Some of the isolated compounds were evaluated for their cytotoxicity and enzyme inhibitory activity against acetylcholinesterase (AChE) in vitro. Among them, 8 showed potent AChE inhibitory activity, with an IC₅₀ value of 1.31 μM, and 5 showed significant cytotoxicity against PC-3 cells, with an IC₅₀ value of 2.32 μM.     

Antiviral peptides from marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501

A new cyclic pentapeptide and three new linear peptides, namely, aspergillipeptides D–G (1–4), were isolated from a culture broth of marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. Their structures were elucidated by spectroscopic analysis, and their absolute configurations were confirmed by Marfey’s method. Compounds 1 and 2 showed evident antiviral activity against herpes simplex virus type 1 (HSV-1) with IC₅₀ values of 9.5 and 19.8 µM under their non-cytotoxic concentrations against a Vero cell line, respectively, and 1 also had antiviral activity against acyclovir-resistant clinical isolates of HSV-1.     

Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids

Unsaturated nitro fatty acids (NO₂-FAs) constitute a category of molecules that may be formed endogenously by the reaction of unsaturated fatty acids (UFAs) with secondary species of nitrogen monoxide and nitrite anions. The warhead of NO₂-FAs is a nitroalkene moiety, which is a potent Michael acceptor and can undergo nucleophilic attack from thiol groups of biologically relevant proteins, showcasing the value of these molecules regarding their therapeutic potential against many diseases. In general, NO₂-FAs inhibit nuclear factorκ-B (NF-κB), and simultaneously they activate nuclear factor (erythroid derived)-like 2 (Nrf2), which activates an antioxidant signaling pathway. NO₂-FAs can be synthesized not only endogenously in the organism, but in a synthetic laboratory as well, either by a step-by-step synthesis or by a direct nitration of UFAs. The step-by-step synthesis requires specific precursor compounds and is in position to afford the desired NO₂-FAs with a certain position of the nitro group. On the contrary, the direct nitration of UFAs is not a selective methodology; thus, it affords a mixture of all possible nitro isomers.     

Furanone Derivatives from Aspergillus sp. XW‐12, an Endophytic Fungus in Huperzia serrata

Two new 5‐methoxyfuran‐3(2H)‐one derivatives, huaspenone A ( 1 ) and B ( 2 ), together with four known ones, i.e., aspertetronin A ( 3 ), aspertetronin B ( 4 ), gregatin E ( 5 ), and penicilliol A ( 6 ), were isolated from the cultures of an endophytic fungus Aspergillus sp. XW‐12, derived from the stems of Huperzia serrata. The structures of the new isolates were established by detailed interpretation of the 1D‐ and 2D‐NMR and HR‐ESI‐MS data.     

Two New Meroterpenes from the Mangrove Endophytic Fungus Aspergillus sp. 085241B

Two new meroterpenes, ‘acetoxydehydroaustin B’ ( 1 ) and ‘1,2‐dihydro‐acetoxydehydroaustin B’ ( 2 ) were isolated in the form of a mixed crystal from the mangrove endophytic fungus Aspergillus sp. 085241B. Their structures and absolute configurations were determined by extensive analysis of their spectra and X‐ray diffraction data. In a preliminary bioassay, the mixed crystal did not exhibit activities against cancer cell lines of MDA‐MB‐435, SKBR3, HepG2, HEP3B, PC‐3, and A549, as well as against α‐glucosidase and tyrosinase.     

Diterpenoid Compounds Isolated from Chloranthus oldhamii Solms Exert Anti-Inflammatory Effects by Inhibiting the IKK/NF-κB Pathway

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.     

Anti-Cancer Potential of Synthetic Oleanolic Acid Derivatives and Their Conjugates with NSAIDs

Naturally occurring pentacyclic triterpenoid oleanolic acid (OA) serves as a good scaffold for additional modifications to achieve synthetic derivatives. Therefore, a large number of triterpenoids have been synthetically modified in order to increase their bioactivity and their protective or therapeutic effects. Moreover, attempts were performed to conjugate synthetic triterpenoids with non-steroidal anti-inflammatory drugs (NSAIDs) or other functional groups. Among hundreds of synthesized triterpenoids, still the most promising is 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which reached clinical trials level of investigations. The new group of synthetic triterpenoids are OA oximes. The most active among them is 3-hydroxyiminoolean-12-en-28-oic acid morpholide, which additionally improves the anti-cancer activity of standard NSAIDs. While targeting the Nrf2 and NF-κB signaling pathways is the main mechanism of synthetic OA derivatives′ anti-inflammatory and anti-cancer activity, most of these compounds exhibit multifunctional activity, and affect cross-talk within the cellular signaling network. This short review updates the earlier data and describes the new OA derivatives and their conjugates in the context of modification of signaling pathways involved in inflammation and cell survival and subsequently in cancer development.     

Ochraceopyronide,a Rare α-Pyrone-C-lyxofuranoside from a Soil-Derived Fungus Aspergillus ochraceopetaliformis

The fungal strain was isolated from a soil sample collected in Giza province, Egypt, and was identified as Aspergillus ochraceopetaliformis based on phenotypic and genotypic data. The ethyl acetate extract of the fungal strain exhibited promising activity levels against several pathogenic test organisms and through a series of ¹H NMR guided chromatographic separations, a new α-pyrone-C-lyxofuranoside (1) along with four known compounds (2–5) were isolated. The planar structure of the new metabolite was elucidated by detailed analysis of its 1D/2D NMR and HRMS/IR/UV spectroscopic data, while the relative configuration of the sugar moiety was determined by a combined study of NOESY and coupling constants data, with the aid of theoretical calculations. The structures of the known compounds—isolated for the first time from A. ochraceopetaliformis—were established by comparison of their spectroscopic data with those in the literature. All isolated fungal metabolites were evaluated for their antibacterial and antifungal activities against six Gram-positive and Gram-negative bacteria as well as against three human pathogenic fungi.     

Diketopiperazine Alkaloids Produced by the Endophytic Fungus Aspergillus fumigatus from the Stem of Erythrophloeum fordii Oliv.

Four new diketopiperazine alkaloids, rel‐(8R)‐9‐hydroxy‐8‐methoxy‐18‐epi‐fumitremorgin C ( 1 ), rel‐(8S)‐19,20‐dihydro‐9,20‐dihydroxy‐8‐methoxy‐9,18‐di‐epi‐fumitremorgin C ( 2 ), rel‐(8S,19S)‐19,20‐dihydro‐9,19,20‐trihydroxy‐8‐methoxy‐9‐epi‐fumitremorgin C ( 3 ), and (3S,8S,9S,18S)‐8,9‐dihydroxyspirotryprostatin A ( 4 ), together with the eight known compounds 5 – 12 , were isolated from the endophytic fungus Aspergillus fumigatus. The structures of the new compounds were determined by extensive spectroscopic methods including HR‐ESI‐MS, NMR, and CD experiments. Compound 12 showed weak inhibitory activity in vitro against the release of β‐glucuronidase in rat polymorphonuclear leukocytes induced by the platelet‐activating factor. None of the twelve compounds exhibited detectable cytotoxic activities toward five human tumor cell lines (HCT‐8, Bel‐7402, BGC‐823, A549, and A2780) in the MTT assay.     

Stevioside Activates AMPK to Suppress Inflammation in Macrophages and Protects Mice from LPS-Induced Lethal Shock

Stevioside, a diterpenoid glycoside, is widely used as a natural sweetener; meanwhile, it has been proven to possess various pharmacological properties as well. However, until now there were no comprehensive evaluations focused on the anti-inflammatory activity of stevioside. Thus, the anti-inflammatory activities of stevioside, both in macrophages (RAW 264.7 cells, THP-1 cells, and mouse peritoneal macrophages) and in mice, were extensively investigated for the potential application of stevioside as a novel anti-inflammatory agent. The results showed that stevioside was capable of down-regulating lipopolysaccharide (LPS)-induced expression and production of pro-inflammatory cytokines and mediators in macrophages from different sources, such as IL-6, TNF-α, IL-1β, iNOS/NO, COX2, and HMGB1, whereas it up-regulated the anti-inflammatory cytokines IL-10 and TGF-β1. Further investigation showed that stevioside could activate the AMPK -mediated inhibition of IRF5 and NF-κB pathways. Similarly, in mice with LPS-induced lethal shock, stevioside inhibited release of pro-inflammatory factors, enhanced production of IL-10, and increased the survival rate of mice. More importantly, stevioside was also shown to activate AMPK in the periphery blood mononuclear cells of mice. Together, these results indicated that stevioside could significantly attenuate LPS-induced inflammatory responses both in vitro and in vivo through regulating several signaling pathways. These findings further strengthened the evidence that stevioside may be developed into a therapeutic agent against inflammatory diseases.     

Acetylharpagide Protects Mice from Staphylococcus Aureus-Induced Acute Lung Injury by Inhibiting NF-κB Signaling Pathway

Staphylococcus aureus (S. aureus)-induced acute lung injury (ALI) is a serious disease that has a high risk of death among infants and teenagers. Acetylharpagide, a natural compound of Ajuga decumbens Thunb. (family Labiatae), has been found to have anti-tumor, anti-inflammatory and anti-viral effects. This study investigates the therapeutic effects of acetylharpagide on S. aureus-induced ALI in mice. Here, we found that acetylharpagide alleviated S. aureus-induced lung pathological morphology damage, protected the pulmonary blood-gas barrier and improved the survival of S. aureus-infected mice. Furthermore, S. aureus-induced myeloperoxidase (MPO) activity of lung homogenate and pro-inflammatory factors in bronchoalveolar lavage (BAL) fluid were suppressed by acetylharpagide. Mechanically, acetylharpagide inhibited the interaction between polyubiquitinated receptor interacting protein 1 (RIP1) and NF-κB essential modulator (NEMO), thereby suppressing NF-κB activity. In summary, these results show that acetylharpagide protects mice from S. aureus-induced ALI by suppressing the NF-κB signaling pathway. Acetylharpagide is expected to become a potential treatment for S. aureus-induced ALI.     

Sophorolipid Suppresses LPS-Induced Inflammation in RAW264.7 Cells through the NF-κB Signaling Pathway

Objectives: Biosurfactants with anti-inflammatory activity may alleviate skin irritation caused by synthetic surfactants in cleaning products. Sophorolipid (SL) is a promising alternative to synthetic surfactants. However, there are few reports on the anti-inflammatory activity of SL and the underlying mechanism. The purpose of this work is to verify that lipopolysaccharide (LPS)-induced inflammation could be inhibited through targeting the pathway of nuclear factor-κB (NF-κB) in RAW264.7 cells. Methods: The influence of SL on cytokine release was investigated by LPS-induced RAW264.7 cells using ELISA. The quantification of the protein expression of corresponding molecular markers was realized by Western blot analysis. Flow cytometry was employed to determine the levels of Ca²⁺ and reactive oxygen species (ROS). The relative expression of inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX-2) was determined by RT-PCR. An immunofluorescence assay and confocal microscope were used to observe the NF-κB/p65 translocation from the cytoplasm into the nucleus. The likely targets of SL were predicted by molecular docking analysis. Results: SL showed anti-inflammatory activity and reduced the release of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO). The experimental results show that SL suppressed the Ca²⁺ and ROS levels influx in the LPS-induced RAW264.7 cells and alleviated the LPS-induced expression of iNOS and COX-2, the LPS-induced translocation of NF-κB (p65) from the cytoplasm into the nucleus, and the expression of phosphorylated proteins such as p65 and IκBα. Furthermore, molecular docking analysis showed that SL may inhibit inflammatory signaling by competing with LPS to bind TLR4/MD-2 through hydrophobic interactions and by inhibiting IKKβ activation through the hydrogen bonding and hydrophobic interactions. Conclusion: This study demonstrated that SL exerted anti-inflammatory activity via the pathway of NF-κB in RAW264.7 cells.     

Meroterpenoids and Steroids from the Marine-Derived Fungus Trametes sp. ZYX-Z-16

Marine fungi can metabolize structurally diverse active components, and have become an important source of drug lead molecules. In the present study, the chemical investigation on the EtOAc extract of the fermentation broth of the marine-derived fungus Trametes sp. ZYX-Z-16 led to the isolation of eight meroterpenoids (1–8), including two undescribed ones, together with ten ergostane steroid analogues (9–18). The structures of two new spiromeroterpenoids, asnovolin H (1) and asnovolin I (2), were determined based on 1D, 2D NMR, and HRESIMS spectroscopic data along with ECD spectra calculations. All compounds were tested for antibacterial and α-glucosidase inhibitory activity. Among them, compound 12 showed definite antibacterial activities against Staphylococcus aureus ATCC 6538 (MIC 32 μg/mL) and Bacillus subtilis ATCC 6633 (MIC 16 μg/mL). In addition, compounds 9 and 10 showed superior inhibitory activity, with IC₅₀ values of 104.1 and 111.3 μM, respectively, to the positive control acarbose (304.6 μM).     

Myrothecoside,a Novel Glycosylated Polyketide from the Terrestrial Fungus Myrothecium sp. GS‐17

Based on the chemical analysis and targeted bioactivity screening, a new polyketide glycoside, myrothecoside, was isolated from a terrestrial halotolerant fungus, Myrothecium sp. GS‐17. The structure of myrothecoside was elucidated on the basis of extensive spectroscopic analysis including 1D‐ and 2D‐NMR (¹H,¹H‐COSY, HSQC, HMBC, and NOESY) experiments, combined with mass spectroscopic data and physicochemical properties. This compound exhibited weak cytotoxicity against human leukemia (HL‐60) cancer cell with an IG₅₀ value of 63.61 μm , and also antifungal activities against plant pathogenic fungi Rhizoctonia solani and Fusarium oxysporum using standard agar diffusion tests at 20 μg/disk.