Yu Mu

Bafilomycins and Odoriferous Sesquiterpenoids from Streptomyces albolongus Isolated from Elephas maximus Feces

From a fermentation broth of Streptomyces albolongus obtained from Elephas maximus feces, nine bafilomycins (1-9) and seven odoriferous sesquiterpenoids (10-16) were isolated. The structures of the new compounds, including three bafilomycins, 19-methoxybafilomycin C1 amide (1), 21-deoxybafilomycin A1 (2), and 21-deoxybafilomycin A2 (3), and two sesquiterpenoid degradation products, (1β,4β,4aβ,8aα)-4,8a-dimethyloctahydronaphthalene-1,4a(2H)-diol (10) and (1β,4β,4aβ,7α,8aα)-4,8a-dimethyloctahydronaphthalene-1,4a,7(2H)-triol (11), were elucidated by comprehensive spectroscopic data analysis. The cytotoxicity activity against four human cancer cell lines and antimicrobial activities against a panel of bacteria and fungi of all compounds isolated were evaluated. Compounds 1, 7, and 8 were cytotoxic, with IC50 values ranging from 0.54 to 5.02 μM. Compounds 2, 7, 8, and 10 showed strong antifungal activity against Candida parapsilosis, with MIC values of 3.13, 1.56, 1.56, and 3.13 μg/mL respectively.

Phloroglucinol Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activities from Eugenia jambolana Seeds

Fifteen new phloroglucinol derivatives, jamunones A-O (1-8 and 10-16, respectively), along with one known analogue spiralisone C (9), were isolated from Eugenia jambolana seeds. Their structures were elucidated by detailed nuclear magnetic resonance and mass spectrometry spectroscopic data interpretation. Compounds 1-9, 11, 12, and 14-16 inhibited protein tyrosine phosphatase 1B activity with IC50 values ranging from 0.42 to 3.2 μM.

Design, Synthesis and Evaluation of Novel Tacrine-Ferulic Acid Hybrids as Multifunctional Drug Candidates against Alzheimer's Disease.

Five novel tacrine-ferulic acid hybrid compounds (8a–e) were synthesized and their structures were identified on the basis of a detailed spectroscopic analysis. The activities of inhibiting acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE), reducing self-induced β-amyloid (Aβ) aggregation and chelating Cu2+ were evaluated in vitro. Among them, 8c and 8d displayed the higher selectivity in inhibiting AChE over BuChE. Moreover, 8d also showed dramatic inhibition of self-Aβ aggregation, activity of chelating Cu2+ and activity against Aβ-induced neurotoxicity in Neuro-2A cells.

Urolithins Attenuate LPS-Induced Neuroinflammation in BV2Microglia via MAPK, Akt, and NF-κB Signaling Pathways

Emerging data suggest that urolithins, gut microbiota metabolites of ellagitannins, contribute toward multiple health benefits attributed to ellagitannin-rich foods, including walnuts, red raspberry, strawberry, and pomegranate. However, there is limited data on whether the potential neuroprotective effects of these ellagitannin-rich foods are mediated by urolithins. Herein, we evaluated the potential mechanisms of antineuroinflammatory effects of urolithins (urolithins A, B, and C; 8-methyl-O-urolithin A; and 8,9-dimethyl-O-urolithin C) in BV2 murine microglia in vitro. Nitrite analysis and qRT-PCR suggested that urolithins A and B reduced NO levels and suppressed mRNA levels of pro-inflammatory genes of TNF-α, IL-6, IL-1β, iNOS, and COX-2 in LPS-treated microglia. Western blot revealed that urolithins A and B decreased phosphorylation levels of Erk1/2, p38 MAPK, and Akt, prevented IκB-α phosphorylation and degradation, and inhibited NF-κB p65 subunit phosphorylation and nuclear translocation in LPS-stimulated microglia. Our results indicated that urolithins A and B attenuated LPS-induced inflammation in BV2 microglia, which may be mediated by inhibiting NF-κB, MAPKs (p38 and Erk1/2), and Akt signaling pathway activation. The antineuroinflammatory activities of urolithins support their role in the potential neuroprotective effects reported for ellagitannin-rich foods warranting further in vivo studies on these ellagitannin gut microbial derived metabolites.

Effect of borrelidin on hepatocellular carcinoma cells in vitro and in vivo

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high prevalence and mortality. Borrelidin, produced by several actinomycete bacteria of Streptomycin sp. exhibited diversiform activities including anti-bacterial, anti-viral, anti-angiogenic, and anti-tumor. However, the effect of borrelidin on HCC cells has not been characterized. The present study demonstrated borrelidin exhibited great potential to inhibit the growth of HCC cells, HepG2 and SMMC7721 in vitro. Western blot and real-time qPCR analysis revealed that borrelidin decreased the expressions of cyclin D1, cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and increased the expression of p21, thereby inducing G0/G1 cell cycle arrest. Moreover, borrelidin down-regulated expression of Bcl-2, up-regulated expression of Bax and increased cleavages of caspase-9 and caspase-3 to activate caspase-dependent apoptosis in HCC cells. Borrelidin inhibited migration and invasion through suppressing the expression of MMP-2 and MMP-9 in HCC cells. Further investigation indicated that the anti-tumor effect of borrelidin was mediated by MAPKs signaling pathway. In addition, an in vivo experiment revealed that borrelidin suppressed tumor growth in SMMC7721 xenograft model mice with few side effects. Cell cycle arrest and induced apoptosis were also observed in tumor tissues of model mice treated with borrelidin.

Anti-Inflammatory Activities and Liver Protection of Alisol F and 25-Anhydroalisol F through the Inhibition of MAPK, STAT3, and NF-κB Activation In Vitro and In Vivo

Alisol F and 25-anhydroalisol F isolated from Alisma orientale, were proved to exhibit anti-inflammatory potential in our previous work. In the current study, the anti-inflammatory effects and action mechanisms of alisol F and 25-anhydroalisol F were investigated in vitro. Moreover, the pharmacological effects of alisol F in lipopolysaccharide (LPS)/d-galactosamine (d-gal)-induced acute liver-injured mice were evaluated. The results demonstrated that alisol F and 25-anhydroalisol F could suppress LPS-induced production of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), as well as inhibit the mRNA and protein levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2). In addition, we investigated the role of alisol F and 25-anhydroalisol F in mediating mitogen-activated protein kinases (MAPKs), signal transducers, and activators of transcription 3 (STAT3) and nuclear factor κB (NF-κB) pathways involved in the inflammation process of LPS-stimulated RAW 264.7 cells. The phosphorylation of ERK, JNK, p38, and STAT3, and the NF-κB signaling pathway, were obviously suppressed in alisol F and 25-anhydroalisol F treated cells. Results obtained from in vitro experiments suggested alisol F obviously improved liver pathological injury by inhibiting the production of TNF-α, IL-1β, and IL-6, and significantly decreasing the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in LPS/d-gal-induced mice. Furthermore, the reduction of phosphorylation of ERK and JNK, as well as suppression of the NF-κB signaling pathway, were also observed in liver tissues of the alisol F-treated mice model. Alisol F and 25-anhydroalisol F may serve as potential leads for development of anti-inflammatory agents for acute liver failure treatment.

New Sesquiterpenoids from Eugenia jambolana Seeds and Their Anti-microbial Activities

Twenty four sesquiterpenoids, 1-24, including 11 new sesquiterpenoids, jambolanins A-K, and two new norsesquiterpenoids, jambolanes A and B, along with six known triterpenoids, were isolated from the seeds of Eugenia jambolana fruit. Their structures were elucidated on the basis of NMR and MS spectrometry data analysis. Among the isolates, compound 13 possessed a rare 6,7-seco-guaiene skeleton, and compounds 14 and 15 were norsesquiterpenoids containing a spiro[4.4]nonane skeleton. Antimicrobial assay evaluation revealed that sesquiterpenoids, 4, 5/6, 17, 19, 21, 23, and 24 inhibited the growth of the Gram-positive bacterium, Staphylococcus aureus. The current study advances scientific knowledge of E. jambolana phytochemicals and suggests that its sesquiterpenoids may contribute, in part, to the anti-infective effects attributed to the edible fruit of this plant.

A unique macrolactam derivative via a [4+6]-cycloaddition from Streptomyces niveus

One new macrolactam derivative, nivelactam (1) and one new polyenoic acid derivative, niveamide (2), along with two other known 20-atom macrolactams (3 and 4) were isolated from the fermentation broth of Streptomyces niveus, which obtained from the forest soil in northeastern China. The structures of 1 and 2 were elucidated on the basis of HRESIMS, IR, and NMR spectroscopic data analyses. Compound 1 was proposed as an intramolecular [4+6]-cycloaddition product of 3 by S. niveus, and displayed moderate cytotoxic activity against a panel of human tumor cell lines in vitro, with IC50 values ranging from 3.76 ± 0.58 to 15.02 ± 2.81 μM.

Anti-Inflammatory Effects, SAR, and Action Mechanism of Monoterpenoids from Radix Paeoniae Alba on LPS-Stimulated RAW 264.7 Cells

Nine monoterpenoids from Radix Paeoniae Alba, including paeoniflorin derivatives, paeoniflorin (PF), 4-O-methylpaeoniflorin (MPF), 4-O-methylbenzoylpaeoniflorin (MBPF); paeonidanin derivatives, paeonidanin (PD), paeonidanin A (PDA), albiflorin derivatives, albiflorin (AF), benzoylalbiflorin (BAF), galloylalbiflorin (GAF), and debenzoylalbiflorin (DAF), were obtained in our previous phytochemistry investigations. Their anti-inflammatory effects were determined in the present study. The expression and production of pro-inflammatory cytokines in lipopolysaccharides (LPS)-stimulated RAW 264.7 cells were measured using an Elisa assay and nitric oxide (NO) release was determined using the Griess method. The results demonstrated that the most of the monoterpenoids suppressed the LPS-induced production of NO, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The anti-inflammatory activities of these monoterpenoids were closely related to their structural characteristics. Paeoniflorins and paeonidanins presented stronger anti-inflammatory activities than those of albiflorin derivatives. Furthermore, the action mechanisms of MBPF, having a strong anti-inflammatory effect, were investigated using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods. The results indicated that MBPF could down-regulate the mRNA and protein expression level of inducible nitric oxide synthase (iNOS) in LPS-stimulated RAW 264.7 cells. The mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT and nuclear factor κB (NF-κB) signaling pathways are involved in mediating the role of MBPF in suppressing the expression and production of pro-inflammatory cytokines in RAW 264.7 cells.

Structure determination of two new sesquiterpenoids from Streptomyces sanglieri.

Sesquiterpenoids are a group of abundant and structurally diverse secondary metabolites mainly derived from plant and fungi. By contrast, they are rarely isolated from bacteria, and the terpene synthase genes had been considered to be silent in prokaryotes. Recently, more and more terpenes were identified from bacteria, and the biosynthesis of some terpenes has been discussed in heterologous bacteria. Actually, it demonstrated that the terpene synthases are widely distributed in bacteria, including streptomycete, and some new sesquiterpenoids and diterpenoids had been obtained through heterologous expression of terpene synthase genes derived from Streptomyces microorganism. In our ongoing investigation of new bioactive natural products from streptomycete, two new sesquiterpenes, 15-hydroxy-(+)-epicubenol (1) and 7β-hydroxy-7-epi-α-eudesmol (2), were identified from a fermentation broth of Streptomyces sanglieri (YIM 121209-2), which was isolated from the forest soil sample collected from Wuyi Mountain, Fujian Province, China. The structures of compounds 1 and 2 (Fig. 1) were elucidated based on detailed spectroscopic data analyses, including 1D and 2D NMR techniques. The cytotoxicity against two human cancer cell lines and antimicrobial activity against a panel of bacteria and fungi of 1 and 2 were evaluated. None of them showed cytotoxic or antimicrobial activities at 100μg/ml.