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Seven rare C3-C6 reduced 3-acyl tetramic acid derivatives, lecanicilliumins A–G (1–7), along with the known analogue cladosporiumin D (8), were obtained from the extract of the deep-sea-derived fungus Lecanicillium fusisporum GXIMD00542 within the family Clavipitacae. Their structures were elucidated by extensive spectroscopic data analysis, quantum chemistry calculations and chemical reaction. Compounds 1, 2, 5–7 exhibited moderate anti-inflammatory activity against NF-κB production using lipopolysaccharide (LPS) induced RAW264.7 cells with EC50 values range of 18.49–30.19 μM.

The development of ruthenium-based complexes or antimicrobial peptides are identified as a promising strategy for combating drug-resistant bacteria. In this work, four biphenyl-based antibacterial ruthenium complexes by targeting membrane integrity, which act as antimicrobial peptides mimics, were designed and synthesized. In vitro antimicrobial screening demonstrated that four complexes could absolutely inhibit the growth of Staphylococcus aureus (S. aureus) with MIC values ranging from 15.6 to 100 μg/mL. The most active complex Ru(Ⅱ)-1 (MIC = 15.6 μg/mL) could kill S. aureus through targeting the membrane integrity without detectably resistance frequencies. Further investigation including bacteria biofilm formation, hemolysin activity and checkerboard assay were performed as well. The results revealed that Ru(Ⅱ)-1 could inhibit the biofilm formation and α-hemolysis secretion in S. aureus at subinhibitory concentration. More interestingly, the combination use of Ru(Ⅱ)-1 and five traditional antibiotics showing synergistic effect. Finally, based on the mouse model of S. aureus skin infection, Ru(Ⅱ)-1 showed important antibacterial efficacy against S. aureus in vivo, and almost non-toxic against mouse tissue. Our study indicates that introducing membrane targeting ligands onto ruthenium complexes may be an underappreciated strategy for developing antibacterial agents.

Marine sponge-derived fungi have been proven to be a prolific source of bioactive natural products. Two new alkaloids, polonimides E (1) and D (2), and a new butenolide derivative, eutypoid F (11), were isolated from the Beibu Gulf sponge-derived fungus, Penicillium sp. SCSIO 41413, together with thirteen known compounds (3–10, 12–16). Their structures were determined by detailed NMR, MS spectroscopic analyses, and electronic circular dichroism (ECD) analyses. Butenolide derivatives 11 and 12 exhibited inhibitory effect against the enzyme PI3K with IC50 values of 1.7 μM and 9.8 μM, respectively. The molecular docking was also performed to understand the inhibitory activity, while 11 and 12 showed obvious protein/ligand-binding effects to the PI3K protein. Moreover, 4 and 15 displayed obvious inhibitory activity against LPS-induced NF-κB activation in RAW264.7 cells at 10 µM.

Background Osteolytic diseases share symptoms such as bone loss, fracture and pain, which are caused by over-activated osteoclasts. Targeting osteoclast differentiation has emerged as a therapeutic strategy clinically. Dendrobine is an alkaloid isolated from Chinese herb Dendrobium nobile, with knowing effects of analgesia and anti-inflammation. The roles of dendrobine on osteoclasts and osteolysis remain unclear. Purpose Herein, the possible roles of dendrobine in osteoclastogenesis, inflammatory osteolysis and the underlying mechanism were explored. Methods Bone marrow-derived macrophages (BMMs) and RAW264.7 cells were employed to evaluate the roles of dendrobine on osteoclastogenesis, bone absorption and the underlying mechanism in vitro. LPS injection was used to cause inflammatory osteolysis in vivo. Results Dendrobine repressed osteoclastogenesis, bone resorption induced by receptor activator of nuclear factor kappa B ligand (RANKL) in vitro. Mechanistically, dendrobine inhibited RANKL-upregulated intracellular (ROS), p-p38, c-Fos expression and nuclear factor of activated T cells (NFATc1) nuclear translocation. Osteoclastic genes were reduced, and among them matrix metalloproteinase 9 (MMP9) mRNA was dramatically blocked by dendrobine. Moreover, it substantially suppressed MMP9 protein expression during osteoclastogenesis in vitro. Accordingly, oral 20 mg/kg/day dendrobine was capable of preventing LPS-induced osteolysis with decreased osteoclasts in vivo. Conclusion Taken together, dendrobine suppresses osteoclastogenesis through restraining ROS, p38-c-Fos and NFATc1-MMP9 in vitro, thus attenuates inflammatory osteolysis in vivo. This finding supports the discover of dendrobine as a novel osteoclast inhibitor for impeding bone erosion in the future.

Three new chlorinated orsellinic aldehyde derivatives, orsaldechlorins A - C (1-3) and a naturally new brominated orsellinic acid (7), along with ten known biosynthetically related phenolic (4-6, 8-13) and cyclohexanone (14) derivatives, were identified from the Beibu Gulf coral-derived fungus Acremonium sclerotigenum GXIMD 02501. Their structures were determined by spectroscopic data interpretation and comparison with those reported in the literature. Several of them showed inhibition of lipopolysaccharide (LPS)-induced NF-κB activation in RAW 264.7 macrophages at 20 μM. Moreover, the two new potent inhibitors (1 and 2) suppressed RANKL-induced osteoclast differentiation without cytotoxicity in bone marrow macrophages cells (BMMs). Our findings reveal that the phenolic compounds could be potential candidates for the prevention and treatment of osteolytic bone diseases.

One new depsidone derivative, aspergillusidone H (3), along with seven known biosynthetically related chlorinated polyketides, were obtained from the Beibu Gulf coral-derived fungus Aspergillus unguis GXIMD 02505. Their structures were determined by comprehensive physicochemical and spectroscopic data interpretation. Notably, the X-ray crystal structure of 2 and the previously unknown absolute configuration of 8, assigned by ECD calculations, are described here for the first time. Compounds 1–5, 7 and 8 exhibited inhibition of lipopolysaccharide (LPS)-induced NF-κB in RAW 264.7 macrophages at 20 μM. In addition, the two potent inhibitors (2 and 7) dose-dependently suppressed RANKL-induced osteoclast differentiation without any evidence of cytotoxicity in bone marrow macrophages cells (BMMs). This is the first report of osteoclastogenesis inhibitory activity for the metabolites of these kinds. Besides, compounds 1, 2, 4, and 6–8 showed inhibitory activity against marine biofilm-forming bacteria, methicillin-resistant Staphylococcus aureus, Microbulbifer variabilis, Marinobacterium jannaschii, and Vibrio pelagius, with their MIC values ranging from 2 to 64 μg/mL. These findings provide a basis for further development of chlorinated polyketides as potential inhibitors of osteoclast differentiation and/or for use as anti-fouling agents.

A sensitive and ratiometric electrochemical biosensor was developed for the determination of dimethoate via alkaline phosphatase (ALP) mediated dissolution of nano-MnO2 and [Ru(NH3)6]3+(Ru(III)) redox recycling. The electroactive probe Ru(III) was adsorbed on the nano-MnO2 with the high specific surface area through electrostatic interaction to form the MnO2-Ru(III) nanocomposite, which was then fixed on the surface of the glassy carbon electrode. When the dimethoate inhibited the catalytic activity of ALP in a homogeneous system, the hydrolysate L -ascorbic acid (AA) produced by ALP hydrolysis of L -ascorbic acid-trisodium 2-phosphate (AAP) decreased. The solution was then incubated with a glassy carbon electrode modified by MnO2-Ru(III). At this time, only a small amount of MnO2-Ru(III) was decomposed and Ru(III) was rapidly electroreduced to Ru(II) on the surface of the electrode. The in-situ produced Ru(II) was chemically oxidized back to Ru(III) by Fe(III). The redox recycling of Ru(III) was completed and the Ru(III) reduction current signal was amplified. The process consumed part of Fe(III) to reduce the reduction current signal of Fe(III), and the ratio of the two reduction currents (IRu(III)/IFe(III)) increased significantly. The IRu(III)/IFe(III) value increased with the increase of dimethoate concentration in the linear range of 0.01–300 ng mL−1, and the detection limit was 6.3 pg mL−1. It has been successfully applied to the determination of dimethoate in oilseed rape and lettuce with a satisfactory result.

Background Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear. Purpose We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo. Methods The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model. Results We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2–10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression. Conclusions Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis.

Nitrobenzoyl sesquiterpenoids are rare from natural sources. Two new nitrobenzoyl sesquiterpenoids, insulicolide B (1) and insulicolide C (3), and the new natural product 14-O-acetylinsulicolide A (2) were isolated from culture extracts of the marine-derived fungus Aspergillus ochraceus Jcma1F17, together with three known nitrobenzoyl sesquiterpenoids (4-6) and a derivative sesquiterpenoid (7). The structures of the new compounds, including their absolute configurations, were determined by NMR and MS spectroscopic data analyses and comparison between the calculated and experimental ECD spectra. The nitrobenzoyl sesquiterpenoids (1-6) were evaluated for their cytotoxicities against three renal carcinoma cell lines, ACHN, OS-RC-2, and 786-O cells, and compounds 2, 4, and 5 displayed activities with IC50 values of 0.89 to 8.2 μM. Further studies indicated that 2 arrested the cell cycle at the G0/G1 phase at a concentration of 1 μM and induced late apoptosis at a concentration of 2 μM after a 72 h treatment of 786-O cells.