A microbial knowledge graph-based deep learning model for predicting candidate microbes for target hosts.

Predicting interactions between microbes and hosts plays critical roles in microbiome population genetics and microbial ecology and evolution. How to systematically characterize the sophisticated mechanisms and signal interplay between microbes and hosts is a significant challenge for global health risks. Identifying microbe-host interactions (MHIs) can not only provide helpful insights into their fundamental regulatory mechanisms, but also facilitate the development of targeted therapies for microbial infections. In recent years, computational methods have become an appealing alternative due to the high risk and cost of wet-lab experiments. Therefore, in this study, we utilized rich microbial metagenomic information to construct a novel heterogeneous microbial network (HMN)-based model named KGVHI to predict candidate microbes for target hosts. Specifically, KGVHI first built a HMN by integrating human proteins, viruses and pathogenic bacteria with their biological attributes. Then KGVHI adopted a knowledge graph embedding strategy to capture the global topological structure information of the whole network. A natural language processing algorithm is used to extract the local biological attribute information from the nodes in HMN. Finally, we combined the local and global information and fed it into a blended deep neural network (DNN) for training and prediction. Compared to state-of-the-art methods, the comprehensive experimental results show that our model can obtain excellent results on the corresponding three MHI datasets. Furthermore, we also conducted two pathogenic bacteria case studies to further indicate that KGVHI has excellent predictive capabilities for potential MHI pairs.

PTBGRP: predicting phage-bacteria interactions with graph representation learning on microbial heterogeneous information network.

Identifying the potential bacteriophages (phage) candidate to treat bacterial infections plays an essential role in the research of human pathogens. Computational approaches are recognized as a valid way to predict bacteria and target phages. However, most of the current methods only utilize lower-order biological information without considering the higher-order connectivity patterns, which helps to improve the predictive accuracy. Therefore, we developed a novel microbial heterogeneous interaction network (MHIN)-based model called PTBGRP to predict new phages for bacterial hosts. Specifically, PTBGRP first constructs an MHIN by integrating phage-bacteria interaction (PBI) and six bacteria-bacteria interaction networks with their biological attributes. Then, different representation learning methods are deployed to extract higher-level biological features and lower-level topological features from MHIN. Finally, PTBGRP employs a deep neural network as the classifier to predict unknown PBI pairs based on the fused biological information. Experiment results demonstrated that PTBGRP achieves the best performance on the corresponding ESKAPE pathogens and PBI dataset when compared with state-of-art methods. In addition, case studies of Klebsiella pneumoniae and Staphylococcus aureus further indicate that the consideration of rich heterogeneous information enables PTBGRP to accurately predict PBI from a more comprehensive perspective. The webserver of the PTBGRP predictor is freely available at http://120.77.11.78/PTBGRP/.

Pathogenic fungi synergistically cooperate with Serratia marcescens to increase cockroach mortality.

The abuse of chemical insecticides has led to strong resistance in cockroaches, and biopesticides with active ingredients based on insect pathogens have good development prospects; however, their slow effect has limited their practical application, and improving their effectiveness has become an urgent problem. In this study, the interaction between Serratia marcescens and Metarhizium anisopliae enhanced their virulence against Blattella germanica and exhibited a synergistic effect. The combination of S. marcescens and M. anisopliae caused more severe tissue damage and accelerated the proliferation of the insect pathogen. The results of high-throughput sequencing demonstrated that the gut microbiota was dysbiotic, the abundance of the opportunistic pathogen Weissella cibaria increased, and entry into the hemocoel accelerated the death of the German cockroaches. In addition, the combination of these two agents strongly downregulated the expression of Imd and Akirin in the IMD pathway and ultimately inhibited the expression of antimicrobial peptides (AMPs). S. marcescens released prodigiosin to disrupted the gut homeostasis and structure, M. anisopliae released destruxin to damaged crucial organs, opportunistic pathogen Weissella cibaria overproliferated, broke the gut epithelium and entered the hemocoel, leading to the death of pests. These findings will allow us to optimize the use of insect pathogens for the management of pests and produce more effective biopesticides.

Lidocaine hampers colorectal cancer process via circITFG2/miR-1204/SOCS2 axis.

Colorectal cancer (CRC) is a deadly disease with a poor prognosis. Lidocaine is preferred by surgical procedures due to the excellent anesthesia. Circular RNA integrin alpha FG-GAP repeat containing 2 (circITFG2) has been recognized as a momentous participator in CRC progression. The specific role of circITFG2 was further studied in this research. Quantitative real-time PCR (qRT-PCR) was devoted to examining the expression of circITFG2, microRNA-1204 (miR-1204) and SOCS2 mRNA in CRC cells. Western blot was used to determine SOCS2 protein expression in CRC cells. Cell viability, colony formation and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay respectively. Cell migration and invasion were tested by wound healing assay and transwell assay. Dual-luciferase reporter system, RNA pull down and RNA-binding protein immunoprecipitation (RIP) assays were applied to verify the combination between miR-1204 and circITFG2 or SOCS2. CircITFG2 was strikingly downregulated; however, lidocaine treatment induced a significant increase in the expression of circITFG2 and SOCS2 and a decrease in miR-1204 expression in CRC cells. Meanwhile, SOCS2 protein expression was upregulated by lidocaine treatment or miR-1204 silence in CRC cells and downregulated by circITFG2 knockdown or miR-1204 overexpression in lidocaine-treated CRC cells. CircITFG2 knockdown or miR-1204 overexpression abolished lidocaine-induced inhibition in proliferation, metastasis and promotion in apoptosis in CRC cells. CircITFG2 overexpression, SOCS3 overexpression or lidocaine treatment suppressed proliferation, metastasis and facilitated apoptosis in CRC cells. CircITFG2 sponged miR-1204 to regulate SOCS3 expression in lidocaine-treated CRC cells. Lidocaine hindered CRC progression by circITFG2/miR-1204/SOCS2 axis. This finding might beat a path in improving CRC therapy.

Structural Evolution of Cellulose from Bamboo Fibers and Parenchyma Cells during Ionic Liquid Pretreatment for Enhanced Hydrolysis.

Bamboo fibers and parenchyma cells, the two dominant types of cells in bamboo, exhibit some interesting differences in cellulose crystalline structures. In the present investigation, we further demonstrated that these structural differences affect their response during ionic liquid (IL) pretreatment and the sugar conversion yield, by tracking their changes in morphology, chemical, and crystalline structures. All of the results pointed to the fact that the cellulose from bamboo fibers exhibited higher recalcitrance to IL pretreatment, with a significantly lower change in crystallinity index, d spacings from the (110) and (11̅0) planes, crystallite sizes, and easier transformation from cellulose I to cellulose II after pretreatment, as compared to that from parenchyma cells. Furthermore, the crystalline parameters of (110) and (11̅0) lattice planes exhibited more changes compared to the (200) direction. This investigation highlights the significance of parenchyma cell wastes from bamboo processing plants as a competitive candidate for the biorefinery industry.

Why Do Bamboo Parenchyma Cells Show Higher Nanofibrillation Efficiency than Fibers: An Investigation on Their Hierarchical Cell Wall Structure.

The cell walls of parenchyma cells and fibers in bamboo are both highly lignified with secondary thickening. However, the former were found to have much higher nanofibrillation efficiency than fibers via both protocols of ultrasonication and high pressure homogenization. To elucidate the inherent mechanism, detailed comparisons of chemical composition, cell morphology, cell wall density, pore structures, and structural organization of cell wall polymers were performed on native and pretreated cell walls of both parenchyma cells and fibers. Chemical compositional analysis showed that fibers have much higher cellulose (49.8% to 35.5%) but lower xylan content (21.1% to 36.2%) than parenchyma, while their lignin contents were similar (24.9% vs 22.9%). Polarized FTIR further revealed clear differences in the structural organization of polymers between the two types of cells, with all the polymers of fibers being more orderly assembled than those of parenchyma cells. The compact arrangement of polymers in the fibers was also supported by the much higher cell wall density (1.52 vs 1.28 g/cm3) and lower porosity (0.007 vs 0.013 cc/g after chemical pretreatments), as compared to the parenchyma cells. The study provides evidence that the anatomical characteristics of huge cavity-wall ratio, higher cell wall porosity, and less ordered arrangement of cell wall matrix polymers (mainly lignin) in parenchyma cells contribute to their higher nanofibrillation efficiency compared to fibers.

Immunosuppressive Cytochalasins from the Mangrove Endophytic Fungus Phomopsis asparagi DHS-48.

Three new cytochalasins, phomoparagins A-C (1-3), along with five known analogs (4-8), were isolated from Phomopsis asparagi DHS-48, a mangrove-derived endophytic fungus. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD techniques. Notably, 1 possessed an unprecedented 5/6/5/8/5-fused pentacyclic skeleton. These compounds were tested for their inhibitory activity against concanavalin A (ConA)/lipopolysaccharide (LPS)-induced spleen lymphocyte proliferation and calcineurin (CN) enzyme. Several metabolites (2 and 4-6) exhibited fascinating inhibitory activities with a relatively low toxicity. Furthermore, 2 was demonstrated to inhibit ConA-stimulated activation of NFAT1 dephosphorylation and block NFAT1 translocation in vitro, subsequently inhibiting the transcription of interleukin-2 (IL-2). Our results provide evidence that 2 may, at least partially, suppress the activation of spleen lymphocytes via the CN/NFAT signaling pathway, highlighting that it could serve as an effective immunosuppressant that is noncytotoxic and natural.

Isoquinoline Alkaloids as Protein Tyrosine Phosphatase Inhibitors from a Deep-Sea-Derived Fungus Aspergillus puniceus.

Puniceusines A-N (1-14), 14 new isoquinoline alkaloids, were isolated from the extracts of a deep-sea-derived fungus, Aspergillus puniceus SCSIO z021. Their structures were elucidated by spectroscopic analyses. The absolute configuration of 9 was determined by ECD calculations, and the structures of 6 and 12 were further confirmed by a single-crystal X-ray diffraction analysis. Compounds 3-5 and 8-13 unprecedentedly contained an isoquinolinyl, a polysubstituted benzyl or a pyronyl at position C-7 of isoquinoline nucleus. Compounds 3 and 4 showed selective inhibitory activity against protein tyrosine phosphatase CD45 with IC50 values of 8.4 and 5.6 µM, respectively, 4 also had a moderate cytotoxicity towards human lung adenocarcinoma cell line H1975 with an IC50 value of 11.0 µM, and 14, which contained an active center, -C=N+, exhibited antibacterial activity. An analysis of the relationship between the structures, enzyme inhibitory activity and cytotoxicity of 1-14 revealed that the substituents at C-7 of the isoquinoline nucleus could greatly affect their bioactivity.

Comparative genomics and transcriptomics analyses provide insights into the high yield and regulatory mechanism of Norvancomycin biosynthesis in Amycolatopsis orientalis NCPC 2-48.

BACKGROUND: Norvancomycin has been widely used in clinic to treat against MRSA (Methicillin-resistant Staphylococcus aureus) and MRSE (Methicillin-resistant Staphylococcus epidermidis) infections in China. Amycolatopsis orientalis NCPC 2-48, a high yield strain derived from A. orientalis CPCC 200066, has been applied in industrial large-scale production of norvancomycin by North China Pharmaceutical Group. However, the potential high-yield and regulatory mechanism involved in norvancomycin biosynthetic pathway has not yet been addressed. RESULTS: Here we sequenced and compared the genomes and transcriptomes of A. orientalis CPCC 200066 and NCPC 2-48. These two genomes are extremely similar with an identity of more than 99.9%, and no duplication and structural variation was found in the norvancomycin biosynthetic gene cluster. Comparative transcriptomic analysis indicated that biosynthetic genes of norvancomycin, as well as some primary metabolite pathways for the biosynthetic precursors of norvancomycin were generally upregulated. AoStrR1 and AoLuxR1, two cluster-situated regulatory genes in norvancomycin cluster, were 23.3-fold and 5.8-fold upregulated in the high yield strain at 48 h, respectively. Over-expression of AoStrR1 and AoLuxR1 in CPCC 200066 resulted in an increase of norvancomycin production, indicating their positive roles in norvancomycin biosynthesis. Furthermore, AoStrR1 can regulate the production of norvancomycin by directly interacting with at least 8 promoters of norvancomycin biosynthetic genes or operons. CONCLUSION: Our results suggested that the high yield of NCPC 2-48 can be ascribed to increased expression level of norvancomycin biosynthetic genes in its cluster as well as the genes responsible for the supply of its precursors. The norvancomycin biosynthetic genes are presumably regulated by AoStrR1 and AoLuxR1, of them AoStrR1 is possibly the ultimate pathway-specific regulator for the norvancomycin production. These results are helpful for further clarification of the holistic and pathway-specific regulatory mechanism of norvancomycin biosynthesis in the industrial production strain.

Talaromyoxaones A and B: Unusual Oxaphenalenone Spirolactones as Phosphatase Inhibitors from the Marine-Derived Fungus Talaromyces purpureogenus SCSIO 41517.

(+)- and (-)-talaromyoxaones A and B (1 and 2, respectively), two new oxaphenalenone derivatives with a hemiacetal frame and an unprecedented spirolactone frame of a 2'H,3H,4'H-spiro[isobenzofuran-1,3'-pyran]-3-one unit that show biosynthetic enantiodivergence, and two new oxaphenalenone analogues (±)-11-apopyrenulin (3) and (+)- or (-)-abeopyrenulin (4) were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. Compounds 1 and 2 showed selective inhibitory activity against phosphatases SHP1, SHP2, and MEG2 with IC50 values of 1.3-3.4 µM, and the potential modes of action for 1 were investigated by a preliminary molecular docking study.

Vomifoliol isolated from mangrove plant Ceriops tagal inhibits the NFAT signaling pathway with CN as the target enzyme in vitro.

Vomifoliol, a natural sesquiterpene compound, is a secondary metabolite isolated from the mangrove plant Ceriops tagal. The present study aimed to determine the immunosuppressive effects and underlying mechanisms of vomifoliol on Jurkat cells in vitro. The results show that vomifoliol significantly inhibited calcineurin (CN) at concentrations resulting in relatively low cytotoxicity. Moreover, vomifoliol was found to exert an inhibitory effect on phorbol 12-myristate 13-acetate (PMA)/ ionomycin (Io) -induced Jurkat cells and the dephosphorylation of NFAT1. In addition, it reduced the expression of IL-2. Based on these results, we concluded that vomifoliol may inhibit the immune response of Jurkat cells, and vomifoliol may use CN as the target enzyme to inhibit NFAT signaling pathway. Therefore, vomifoliol may be promising as a low-toxic natural immunosuppressant.

Efophylins A and B, Two C2-Asymmetric Macrodiolide Immunosuppressants from Streptomyces malaysiensis.

Genomics-inspired isolation led to the identification of two new natural congeneric C2-asymmetric macrodiolide immunosuppressants, named efophylins A (1) and B (2), from Streptomyces malaysiensis DSM 4137. Their structures were elucidated by spectroscopic and computational methods and were in agreement with biosynthetic predictions from the efophylin gene cluster. Compound 2 exhibited potent immunosuppressive activity and demonstrated to inhibit the activation of the NFAT and block NFAT dephosphorylation in vitro. The immunosuppressive activity of compound 2 is possibly at least in part via the CaN/NFAT signaling pathway.

Mycotoxins as inhibitors of protein tyrosine phosphatases from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC50 = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed.

Four New Chromones from the Endophytic Fungus Phomopsis asparagi DHS-48 Isolated from the Chinese Mangrove Plant Rhizophora mangle.

Four new chromones, phomochromenones D-G (1-4), along with four known analogues, diaporchromone A (5), diaporchromanone C (6), diaporchromanone D (7), and phomochromenone C (8), were isolated from the culture of Phomopsis asparagi DHS-48 from Chinese mangrove Rhizophora mangle. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. The absolute configurations of 1 and 4 were assigned on the basis of experimental and calculated electronic circular dichroism (ECD) data, and those of enantiomers 2 and 3 were determined by a modified Mosher's method and basic hydrolysis. To the best of our knowledge, phomochromenones D-F (1-4) possessing a 3-substituted-chroman-4-one skeleton are rarely found in natural sources. Diaporchromone A (5) showed moderate to weak immunosuppressive activity against T and/or B lymphocyte cells with IC50 of 34 µM and 117 µM.

[Effect of Nrf2/HO-1 signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis in mice].

The present study aimed to explore the effect of nuclear factor erythroid 2 related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis(UC). After the UC model was induced by 3% dextran sodium sulfate(DSS), experimental animals were randomly divided into control group, model group, salazosulfapyridine(SASP) group, and low-and high-dose Sishen Pills groups. Drug intervention(ig) was performed for seven consecutive days during modeling. On the 7 th day, the mice were euthanized. The body weight and colon length were recorded, and the histopathological changes of the colon were observed by HE staining. Serum interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and reactive oxygen species(ROS) were detected by ELISA. The protein and mRNA expression of Nrf2, HO-1, and NADPH quinine oxidoreductase-1(NQO-1) was determined by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Compared with the normal group, the model group exhibited reduced body weight, colon length, and T-AOC, increased IL-6, TNF-α, MDA, and ROS, and diminished protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. Compared with the model group, the SASP group and high-dose Sishen Pills group showed elevated body weight, colon length, and T-AOC, lowered IL-6, TNF-α, MDA, and ROS levels, and increased protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. As assessed by HE staining, Sishen Pills could improve the pathological changes of the colon. The findings suggested that Sishen Pills could protect the colon against UC induced by 3% DSS. The specific mechanism of action may be related to the anti-inflammatory and anti-oxidative stress effects by the activation of the Nrf2/HO-1 signaling pathway.

Landscape genetics reveals that adaptive genetic divergence in Pinus bungeana (Pinaceae) is driven by environmental variables relating to ecological habitats.

BACKGROUND: Understanding the genetic basis of local adaptation has long been the concern of biologists. Identifying these adaptive genetic variabilities is crucial not only to improve our knowledge of the genetic mechanism of local adaptation but also to explore the adaptation potential of species. RESULTS: Using 10 natural populations and 12 start codon targeted (SCoT) markers, a total of 430 unambiguous loci were yielded. The Bayesian analysis of population structure clearly demonstrated that the 10 populations of P. bungeana could be subdivided into three groups. Redundancy analysis showed that this genetic divergence was caused by divergence selection from environmental variables related to the ecological habitats of "avoidance of flooding" and "avoidance of high temperature and humidity." LFMM results indicated that Bio1, Bio5, Bio8, Bio12, Bio14, and Bio16, which are related to the ecological habitat of P. bungeana, were correlated with the highest numbers of environment-associated loci (EAL). CONCLUSIONS: The results of EAL characterization in P. bungeana clearly supported the hypothesis that environmental variations related to the ecological habitat of species are the key drivers of species adaptive divergence. Moreover, a method to calculate the species landscape adaptation index and quantify the adaptation potential of species was proposed and verified using ecological niche modeling. This model could estimate climatically suitable areas of species spatial distribution. Taking the results together, this study improves the current understanding on the genetic basis of local adaptation.

Long non-coding RNA UCA1 promotes breast cancer by upregulating PTP1B expression via inhibiting miR-206.

BACKGROUND: The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) is involved in various cancers and often functions through microRNAs. The pro-survival protein PTP1B is known to play important roles in cancer development. However, the connection between UCA1 and PTP1B in breast cancer is not well studied. METHODS: In this study, we first evaluated the correlation between UCA1 level and PTP1B expression in breast tissues, which showed the expression of PTP1B were much higher in the breast tumor tissues than in the peritumor normal tissues. The UCA1 level was positively associated with PTP1B expression in breast tumor tissues. RESULTS: We observed that UCA1 could up-regulate PTP1B expression in breast cancer cells. We also found that miR-206 could inhibit the expression of PTP1B by directly binding to the 3'-UTR of its mRNA. Interestingly, UCA1 could increase the expression of PTP1B through sequestering miR-206 at post-transcriptional level. The results also suggested that UCA1-induced PTP1B expression facilitated the proliferation of breast cancer cells. CONCLUSIONS: We conclude that UCA1 can up-regulates PTP1B to enhance cell proliferation through sequestering miR-206 in breast cancer. Our finding provides new insights into the mechanism of breast cancer regulation by UCA1, which could be a potential target for breast cancer treatment.Trial registration 2012N5hSYSU48573. Registered at Oct 12, 2012.

Discovery of naphthacemycins as a novel class of PARP1 inhibitors.

Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein that plays important roles in a variety of nuclear processes, and it has been proved a prominent target in oncology for its key function in DNA damage repair. In this study, we discovered a series of naphthacemycins as a new class of PARP1 inhibitors from a microbial metabolites library via high-throughput screening. Compound I, one of this series of compounds, could reduce cellular poly (ADP-ribose) level, trap PARP1 on the damaged DNA and elevate the level of γ-H2AX, and showed the selective cytotoxicity against BRCA1-deficient cell line. Our study provided a potential scaffold for the development of new PARP1 inhibitors in cancer therapy.

Adaptive genetic differentiation in Pterocarya stenoptera (Juglandaceae) driven by multiple environmental variables were revealed by landscape genomics.

BACKGROUND: The investigation of the genetic basis of local adaptation in non-model species is an interesting focus of evolutionary biologists and molecular ecologists. Identifying these adaptive genetic variabilities on the genome responsible can provide insight into the genetic mechanism of local adaptation. RESULTS: We investigated the spatial distribution of genetic variation in 22 natural populations of Pterocarya stenoptera across its distribution area in China to provide insights into the complex interplay between multiple environmental variables and adaptive genetic differentiation. The Bayesian analysis of population structure showed that the 22 populations of P. stenoptera were subdivided into two groups. Redundancy analysis demonstrated that this genetic differentiation was caused by the divergent selection of environmental difference. A total of 44 outlier loci were mutually identified by Arlequin and BayeScan, 43 of which were environment-associated loci (EAL). The results of latent factor mixed model analysis showed that solar radiation in June (Sr6), minimum temperature of the coldest month (Bio6), temperature seasonality (Bio4), and water vapor pressure in January (Wvp1) were associated with the highest numbers of EAL. Sr6 was associated with the ecological habitat of "prefered light", and Bio6 and Wvp1 were associated with the ecological habitat of "warm and humid environment". CONCLUSIONS: Our results provided empirical evidence that environmental variables related to the ecological habitats of species play key roles in driving adaptive differentiation of species genome.

Altenusin, a Nonsteroidal Microbial Metabolite, Attenuates Nonalcoholic Fatty Liver Disease by Activating the Farnesoid X Receptor.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose, and lipids. FXR agonists have shown promise for the treatment of NAFLD. In this study, we report altenusin (2076A), a natural nonsteroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3.2 ± 0.2 µM. Administration of 2076A protected mice from high-fat diet (HFD)-induced obesity by reducing the body weight and fat mass by 22.9% and 50.0%, respectively. Administration of 2076A also decreased the blood glucose level from 178.3 ± 12.4 mg/dl to 116.2 ± 4.1 mg/dl and the serum insulin level from 1.4 ± 0.6 ng/dl to 0.4 ± 0.1 ng/dl. Moreover, 2076A treatment nearly reversed HFD-induced hepatic lipid droplet accumulation and macrovesicular steatosis. These metabolic effects were abolished in FXR knockout mice. Mechanistically, the metabolic benefits of 2076A might have been accounted for by the increased insulin sensitivity and suppression of genes that are involved in hepatic gluconeogenesis and lipogenesis. In summary, we have uncovered a new class of nonsteroidal FXR agonist that shows promise in treating NAFLD and the associated metabolic syndrome.