Construction and validation of "WCH-nomogram" for predicting the prognosis after resection of colorectal liver metastases.

BACKGROUND: The prognostic predictive tool for patients with colorectal liver metastasis (CRLM) is limited and the criteria for administering preoperative neoadjuvant chemotherapy in CRLM patients remain controversial. METHODS: This study enrolled 532 CRLM patients at West China Hospital (WCH) from January 2009 to December 2019. Prognostic factors were identified from the training cohort to construct a WCH-nomogram and evaluating accuracy in the validation cohort. Receiver operating characteristic (ROC) curve analysis was used to compare the prediction accuracy with other existing prediction tools. RESULTS: From the analysis of the training cohort, four independent prognostic risk factors, namely tumor marker score, KRAS mutation, primary lymph node metastasis, and tumor burden score were identified on which a WCH-nomogram was constructed. The C-index of the two cohorts were 0.674 (95% CI: 0.634-0.713) and 0.655 (95% CI: 0.586-0.723), respectively, which was better than the previously reported predication scores (CRS, m-CS and GAME score). ROC curves showed AUCs for predicting 1-, 3-, and 5-year overall survival (OS) of 0.758, 0.709, and 0.717 in the training cohort, and 0.860, 0.669, and 0.692 in the validation cohort, respectively. A cutoff value of 114.5 points was obtained for the WCH-nomogram total score based on the maximum Youden index of the ROC curve of 5-year OS. Risk stratification showed significantly better prognosis in the low-risk group, however, the high-risk group was more likely to benefit from neoadjuvant chemotherapy. CONCLUSIONS: The WCH-nomogram demonstrates superior prognostic stratification compared to prior scoring systems, effectively identifying CRLM patients who may benefit the most from neoadjuvant chemotherapy.

Experimental Study on the Migration and Distribution of Microplastics in Desert Farmland Soil Under Drip Irrigation.

The microplastics (MPs) formed by broken plastic film may migrate in the soil under drip irrigation. To investigate the migration distribution of MPs in desert farmland soil under drip irrigation conditions, our study was conducted on farmland in Xinjiang (China). A MP drip irrigation penetration migration testing device was set up in combination with Xinjiang farmland irrigation methods to conduct a migration simulation experiment. The results showed that the migration amount of MPs in soil was significantly positively correlated with the amount of drip irrigation, and significantly negatively correlated with the soil depth; in addition, the relationship between the migration amount of MPs in different types of soil was: clay < sandy loam < sandy soil. Under drip irrigation conditions, the migration rates of MPs were 30.51%, 19.41%, and 10.29% in sandy soil, sandy loam soil, and clay, respectively. The migration ability of these three particle sizes of polyethylene MPs in soil was ranked as follows: 25 to 147 µm > 0 to 25 µm > 147 to 250 µm. When the drip irrigation volume was 2.6 to 3.2 L, horizontal migration distances of MPs exceeded 5 cm, and vertical migration distances reached more than 30 cm. Our findings provide reference data for the study of soil MP migration. Environ Toxicol Chem 2024;43:1250-1259. © 2024 SETAC.

Electric field control of perpendicular magnetic tunnel junctions with easy-cone magnetic anisotropic free layers.

Magnetic tunnel junctions (MTJs) are the core element of spintronic devices. Currently, the mainstream writing operation of MTJs is based on electric current with high energy dissipation, and it can be notably reduced if an electric field is used instead. In this regard, it is promising for electric field control of MTJ in the multiferroic heterostructure composed of MTJ and ferroelectrics via strain-mediated magnetoelectric coupling. However, there are only reports on MTJs with in-plane anisotropy so far. Here, we investigate electric field control of the resistance state of MgO-based perpendicular MTJs with easy-cone anisotropic free layers through strain-mediated magnetoelectric coupling in multiferroic heterostructures. A remarkable, nonvolatile, and reversible modulation of resistance at room temperature is demonstrated. Through local reciprocal space mapping under different electric fields for Pb(Mg1/3Nb2/3)0.7Ti0.3O3 beneath the MTJ pillar, the modulation mechanism is deduced. Our work represents a crucial step toward electric field control of spintronic devices with non-in-plane magnetic anisotropy.

Bioinformatics and system biology approaches to determine the connection of SARS-CoV-2 infection and intrahepatic cholangiocarcinoma.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), has infected millions of individuals worldwide, which poses a severe threat to human health. COVID-19 is a systemic ailment affecting various tissues and organs, including the lungs and liver. Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver cancer, and cancer patients are particularly at high risk of SARS-CoV-2 infection. Nonetheless, few studies have investigated the impact of COVID-19 on ICC patients. METHODS: With the methods of systems biology and bioinformatics, this study explored the link between COVID-19 and ICC, and searched for potential therapeutic drugs. RESULTS: This study identified a total of 70 common differentially expressed genes (DEGs) shared by both diseases, shedding light on their shared functionalities. Enrichment analysis pinpointed metabolism and immunity as the primary areas influenced by these common genes. Subsequently, through protein-protein interaction (PPI) network analysis, we identified SCD, ACSL5, ACAT2, HSD17B4, ALDOA, ACSS1, ACADSB, CYP51A1, PSAT1, and HKDC1 as hub genes. Additionally, 44 transcription factors (TFs) and 112 microRNAs (miRNAs) were forecasted to regulate the hub genes. Most importantly, several drug candidates (Periodate-oxidized adenosine, Desipramine, Quercetin, Perfluoroheptanoic acid, Tetrandrine, Pentadecafluorooctanoic acid, Benzo[a]pyrene, SARIN, Dorzolamide, 8-Bromo-cAMP) may prove effective in treating ICC and COVID-19. CONCLUSION: This study is expected to provide valuable references and potential drugs for future research and treatment of COVID-19 and ICC.

Electric-field control of nonvolatile resistance state of perpendicular magnetic tunnel junction via magnetoelectric coupling.

Magnetic tunnel junctions (MTJs) are the core elements of spintronic devices. Now, the mainstream writing operation of MTJs mainly relies on electric current with high energy dissipation, which can be greatly reduced if an electric field is used instead. In this regard, strain-mediated multiferroic heterostructure composed of MTJ and ferroelectrics are promising with the advantages of room temperature and magnetic field-free as already demonstrated by MTJ with in-plane magnetic anisotropy. However, there is no such report on the perpendicular MTJs (p-MTJs), which have been commercialized. Here, we investigate electric-field control of resistance state of MgO-based p-MTJs in multiferroic heterostructures. A remarkable and nonvolatile manipulation of resistance is demonstrated at room temperature without magnetic field assistance. Through various characterizations and micromagnetic simulation, the manipulation mechanism is uncovered. Our work provides an effective avenue for manipulating p-MTJ resistance by electric fields and is notable for high density and ultralow power spintronic devices.

Bioinformatics and system biology approach to identify the influences of SARS-CoV-2 on metabolic unhealthy obese patients.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has posed a significant challenge to individuals' health. Increasing evidence shows that patients with metabolic unhealthy obesity (MUO) and COVID-19 have severer complications and higher mortality rate. However, the molecular mechanisms underlying the association between MUO and COVID-19 are poorly understood. Methods: We sought to reveal the relationship between MUO and COVID-19 using bioinformatics and systems biology analysis approaches. Here, two datasets (GSE196822 and GSE152991) were employed to extract differentially expressed genes (DEGs) to identify common hub genes, shared pathways, transcriptional regulatory networks, gene-disease relationship and candidate drugs. Results: Based on the identified 65 common DEGs, the complement-related pathways and neutrophil degranulation-related functions are found to be mainly affected. The hub genes, which included SPI1, CD163, C1QB, SIGLEC1, C1QA, ITGAM, CD14, FCGR1A, VSIG4 and C1QC, were identified. From the interaction network analysis, 65 transcription factors (TFs) were found to be the regulatory signals. Some infections, inflammation and liver diseases were found to be most coordinated with the hub genes. Importantly, Paricalcitol, 3,3',4,4',5-Pentachlorobiphenyl, PD 98059, Medroxyprogesterone acetate, Dexamethasone and Tretinoin HL60 UP have shown possibility as therapeutic agents against COVID-19 and MUO. Conclusion: This study provides new clues and references to treat both COVID-19 and MUO.

The influence of COVID-19 on colorectal cancer was investigated using bioinformatics and systems biology techniques.

Introduction: Coronavirus disease 2019 (COVID-19) is a global pandemic and highly contagious, posing a serious threat to human health. Colorectal cancer (CRC) is a risk factor for COVID-19 infection. Therefore, it is vital to investigate the intrinsic link between these two diseases. Methods: In this work, bioinformatics and systems biology techniques were used to detect the mutual pathways, molecular biomarkers, and potential drugs between COVID-19 and CRC. Results: A total of 161 common differentially expressed genes (DEGs) were identified based on the RNA sequencing datasets of the two diseases. Functional analysis was performed using ontology keywords, and pathway analysis was also performed. The common DEGs were further utilized to create a protein-protein interaction (PPI) network and to identify hub genes and key modules. The datasets revealed transcription factors-gene interactions, co-regulatory networks with DEGs-miRNAs of common DEGs, and predicted possible drugs as well. The ten predicted drugs include troglitazone, estradiol, progesterone, calcitriol, genistein, dexamethasone, lucanthone, resveratrol, retinoic acid, phorbol 12-myristate 13-acetate, some of which have been investigated as potential CRC and COVID-19 therapies. Discussion: By clarifying the relationship between COVID-19 and CRC, we hope to provide novel clues and promising therapeutic drugs to treat these two illnesses.

Global analysis of the biosynthetic chemical space of marine prokaryotes.

BACKGROUND: Marine prokaryotes are a rich source of novel bioactive secondary metabolites for drug discovery. Recent genome mining studies have revealed their great potential to bio-synthesize novel secondary metabolites. However, the exact biosynthetic chemical space encoded by the marine prokaryotes has yet to be systematically evaluated. RESULTS: We first investigated the secondary metabolic potential of marine prokaryotes by analyzing the diversity and novelty of the biosynthetic gene clusters (BGCs) in 7541 prokaryotic genomes from cultivated and single cells, along with 26,363 newly assembled medium-to-high-quality genomes from marine environmental samples. To quantitatively evaluate the unexplored biosynthetic chemical space of marine prokaryotes, the clustering thresholds for constructing the biosynthetic gene cluster and molecular networks were optimized to reach a similar level of the chemical similarity between the gene cluster family (GCF)-encoded metabolites and molecular family (MF) scaffolds using the MIBiG database. The global genome mining analysis demonstrated that the predicted 70,011 BGCs were organized into 24,536 mostly new (99.5%) GCFs, while the reported marine prokaryotic natural products were only classified into 778 MFs at the optimized clustering thresholds. The number of MF scaffolds is only 3.2% of the number of GCF-encoded scaffolds, suggesting that at least 96.8% of the secondary metabolic potential in marine prokaryotes is untapped. The unexplored biosynthetic chemical space of marine prokaryotes was illustrated by the 88 potential novel antimicrobial peptides encoded by ribosomally synthesized and post-translationally modified peptide BGCs. Furthermore, a sea-water-derived Aquimarina strain was selected to illustrate the diverse biosynthetic chemical space through untargeted metabolomics and genomics approaches, which identified the potential biosynthetic pathways of a group of novel polyketides and two known compounds (didemnilactone B and macrolactin A 15-ketone). CONCLUSIONS: The present bioinformatics and cheminformatics analyses highlight the promising potential to explore the biosynthetic chemical diversity of marine prokaryotes and provide valuable knowledge for the targeted discovery and biosynthesis of novel marine prokaryotic natural products. Video Abstract.

Secondary Metabolic Potential of Kutzneria.

Kutzneria is a rare genus of Actinobacteria that harbors a variety of secondary metabolite gene clusters and produces several interesting types of bioactive secondary metabolites. Recent efforts have partially elucidated the biosynthetic pathways of some of these bioactive natural products, suggesting the diversity and specificity of secondary metabolism within this genus. Here, we summarized the chemical structures, biosynthetic pathways, and key metabolic enzymes of the secondary metabolites isolated from Kutzneria strains. In-depth comparative genomic analysis of all six available high-quality Kutzneria genomes revealed that the majority (77%) of the biosynthetic gene cluster families of Kutzneria were untapped and identified homologues of key metabolic enzymes in the putative gene clusters, including cytochrome P450s, halogenases, and flavin-dependent N-hydroxylases. The present study suggests that Kutzneria exhibits great potential to synthesize novel secondary metabolites, encodes a variety of valuable metabolic enzymes, and also provides valuable information for the targeted discovery and biosynthesis of novel natural products from Kutzneria.

Discovering common pathogenetic processes between COVID-19 and tuberculosis by bioinformatics and system biology approach.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic, stemming from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened the global health system. Meanwhile, tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tuberculosis) still continues to be endemic in various regions of the world. There is a certain degree of similarity between the clinical features of COVID-19 and TB, but the underlying common pathogenetic processes between COVID-19 and TB are not well understood. Methods: To elucidate the common pathogenetic processes between COVID-19 and TB, we implemented bioinformatics and systematic research to obtain shared pathways and molecular biomarkers. Here, the RNA-seq datasets (GSE196822 and GSE126614) are used to extract shared differentially expressed genes (DEGs) of COVID-19 and TB. The common DEGs were used to identify common pathways, hub genes, transcriptional regulatory networks, and potential drugs. Results: A total of 96 common DEGs were selected for subsequent analyses. Functional enrichment analyses showed that viral genome replication and immune-related pathways collectively contributed to the development and progression of TB and COVID-19. Based on the protein-protein interaction (PPI) network analysis, we identified 10 hub genes, including IFI44L, ISG15, MX1, IFI44, OASL, RSAD2, GBP1, OAS1, IFI6, and HERC5. Subsequently, the transcription factor (TF)-gene interaction and microRNA (miRNA)-gene coregulatory network identified 61 TFs and 29 miRNAs. Notably, we identified 10 potential drugs to treat TB and COVID-19, namely suloctidil, prenylamine, acetohexamide, terfenadine, prochlorperazine, 3'-azido-3'-deoxythymidine, chlorophyllin, etoposide, clioquinol, and propofol. Conclusion: This research provides novel strategies and valuable references for the treatment of tuberculosis and COVID-19.

Experimental demonstration of skyrmionic magnetic tunnel junction at room temperature.

Chiral magnetic skyrmions are topological swirling spin textures that hold promise for future information technology. The electrical nucleation and motion of skyrmions have been experimentally demonstrated in the last decade, while electrical detection compatible with semiconductor processes has not been achieved, and this is considered one of the most crucial gaps regarding the use of skyrmions in real applications. Here, we report the direct observation of nanoscale skyrmions in CoFeB/MgO-based magnetic tunnel junction devices at room temperature. High-resolution magnetic force microscopy imaging and tunneling magnetoresistance measurements are used to illustrate the electrical detection of skyrmions, which are stabilized under the cooperation of interfacial Dzyaloshinskii-Moriya interaction, perpendicular magnetic anisotropy, and dipolar stray field. This skyrmionic magnetic tunnel junction shows a stable nonlinear multilevel resistance thanks to its topological nature and tunable density of skyrmions under current pulse excitation. These features provide important perspectives for spintronics to realize high-density memory and neuromorphic computing.

Three-dimensional characterization and calculation of highway space visual perception.

To quantify the impact of three-dimensional highway spatial characteristics on drivers' visual perception, this study analyzes the measurement points of highway spatial visual perception from the perspectives of spatial visual depression and spatial visual continuity based on spatial perception theory. Based on the hemispherical field of view, a spatial enclosure calculation method improved by "Distance/Height value" is proposed. A three-dimensional quantification model of the build-to-line ratio, including the vertical direction, was established using the relative relationship between the maximum section plane and the road area. Finally, a 3D real-scene model of the demonstration highway section was established, the proposed three-dimensional quantization method of visual perception of highway space was applied, and the road area landscape construction and promotion strategy is proposed based on the quantitative calculation results. The results show that: the overall landscape space of the highway section is undulating and that there is a lack of visual continuity. It is advisable to plant an appropriate amount of vegetation on the side of the road at 0 m-250 m and 500 m-700 m of the road section to reduce the fluctuation of its enclosure and enhance its spatial continuity. The improved quantitative results of the spatial enclosure degree and the three-dimensional build-to-line ratio can well characterize the spatial visual depression and the spatial visual continuity and can provide a basis and support for road space reorganization and the improvement of landscape construction.

Non-ribosomal peptide biosynthetic potential of the nematode symbiont Photorhabdus.

Photorhabdus, the symbiotic bacteria of Heterorhabditis nematodes, has been reported to possess many non-ribosomal peptide synthetase (NRPS) biosynthesis gene clusters (BGCs). To provide an in-depth assessment of the non-ribosomal peptide biosynthetic potential of Photorhabdus, we compared the distribution of BGCs in 81 Photorhabdus strains, confirming the predominant presence (44.80%) of NRPS BGCs in Photorhabdus. All 990 NRPS BGCs were clustered into 275 gene cluster families (GCFs) and only 13 GCFs could be annotated with known BGCs, suggesting their great diversity and novelty. These NRPS BGCs encoded 351 novel peptides containing more than four amino acids, and 173 of them showed high sequence similarity to known BGCs encoding bioactive peptides, implying the promising potential of Photorhabdus to produce valuable peptides. Sequence similarity networking of adenylation (A-) domains suggested that the substrate specificity of A-domains was not directly correlated with the sequence similarity. The molecular similarity network of predicted metabolite scaffolds of NRPS BGCs and reported peptides from Photorhabdus and a relevant database demonstrated that the non-ribosomal peptide biosynthetic potential of Photorhabdus was largely untapped and revealed the core peptides deserving intensive studies. Our present study provides valuable information for the targeted discovery of novel non-ribosomal peptides from Photorhabdus.

Integrating network pharmacology and in vivo experimental validation to reveal the alleviation of mailuoning oral liquid on non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) especially the later stage non-alcoholic steatohepatitis (NASH) seriously endangers human's health and has become a global public health issue in recent years. Mailuoning Oral Liquid (MLN) is a modern traditional Chinese medicine prescription composed by Lonicerae japonicae flos, Achyranthis bidentatae radix, Scrophulariae radix and Dendrobium Caulis. MLN is generally used to treat the syndrome of blood stasis in clinical practice. PURPOSE: To observe the alleviation of MLN on NASH in vivo, and explore the possible underlying mechanism. Furthermore, this study also aims to find which Chinese medicinal drug contained in MLN exerts the main pharmacological activity. METHODS: NASH model was induced in mice by feeding with methionine and choline deficient (MCD) diet. The effects of MLN on hepatic lipids accumulation, liver inflammation, hepatic fibrosis, and the expression of some molecules were investigated by histological observation, biochemical index analysis, quantitative real-time PCR and western blot. Network pharmacology was applied to predict those involved molecular targets and potential mechanisms, which was further validated in vivo. BODIPY fluorescence staining assay was used to detect cellular lipids accumulation. RESULTS: MLN (7.8, 23.4 ml/kg) improved NASH in MCD-fed mice. Network pharmacology results demonstrated that peroxisome proliferator-activated receptor α (PPARα) signaling pathway was crucially involved in the MLN-provided alleviation on NASH. Further experimental validation results showed that MLN increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and restored the decreased expression of nuclear PPARα in MCD-fed mice. Further results displayed that Achyranthis bidentatae radix and Lonicerae japonicae flos contributed greatly to the MLN-provided alleviation on NASH in vivo. BODIPY fluorescence staining assay showed that 25R-inokosterone and cynaroside, two compounds from Achyranthis bidentatae radix and Lonicerae japonicae flos, obviously reduced intracellular lipids accumulation in hepatocytes stimulated by non-esterified fatty acid (NEFA). CONCLUSION: MLN improved NASH in MCD-fed mice, and the PGC-1α-PPARα signaling pathway was involved in this process. Moreover, Lonicerae japonicae flos and Achyranthis bidentatae radix contained in MLN contributed greatly to the MLN-provided improvement on NASH.

Sign Change of Spin-Orbit Torque in Pt/NiO/CoFeB Structures.

Antiferromagnetic insulators have recently been proved to support spin current efficiently. Here, we report the dampinglike spin-orbit torque (SOT) in Pt/NiO/CoFeB has a strong temperature dependence and reverses the sign below certain temperatures, which is different from the slight variation with temperature in the Pt/CoFeB bilayer. The negative dampinglike SOT at low temperatures is proposed to be mediated by the magnetic interactions that tie with the "exchange bias" in Pt/NiO/CoFeB, in contrast to the thermal-magnon-mediated scenario at high temperatures. Our results highlight the promise to control the SOT through tuning the magnetic structure in multilayers.

Saccharina japonica fucan suppresses high fat diet-induced obesity and enriches fucoidan-degrading gut bacteria.

Low molecular weight seaweed polysaccharides exhibit promising potential as novel therapeutics for the prevention of obesity and gut microbiota dysbiosis. The interplay between polysaccharides and gut microbiota may play crucial roles in their anti-obesity effects, but is largely unknown, including the impact of polysaccharides on the composition of the gut microbiota with polysaccharide-degrading capacity. The primary structure of a 5.1 kDa fucan (J2H) from Saccharina japonica was characterized and oral administration of J2H effectively suppressed high-fat diet-induced obesity, blood glucose metabolic dysfunction, dyslipidemia, and gut microbiota dysbiosis. Furthermore, the Jensen-Shannon divergence analysis demonstrated that J2H enriched at least four gut bacterial species with fucoidan-degrading potential, including Bacteroides sartorii and Bacteroides acidifaciens. Our findings suggest that the low molecular weight S. japonica fucan, J2H, is a promising potential agent for obesity prevention and its enrichment of gut bacteria with fucoidan-degrading potential may play a vital role in the anti-obesity effects.

Chlorogenic acid improves diabetic retinopathy by alleviating blood-retinal-barrier dysfunction via inducing Nrf2 activation.

As one of the major diabetic microvascular complications, diabetic retinopathy (DR) is mainly initiated by the blood-retinal barrier (BRB) dysfunction. Chlorogenic acid (CGA) is a natural polyphenolic compound in Lonicerae Japonicae Flos, which traditionally has the beneficial function for eyes and is commonly included in many anti-diabetic formulas. In this study, the potential protective mechanism of CGA against DR was investigated. Streptozotocin (STZ) was used to induce diabetes in mice. CGA attenuated BRB dysfunction and reversed endothelial-mesenchymal transition (EndoMT) and epithelial-mesenchymal transition (EMT) in retinas in vivo. CGA inhibited microglia activation and reduced tumor necrosis factor (TNF)α release both in vivo and in vitro. CGA promoted nuclear factor erythroid 2-related factor 2 (Nrf2) activation and prevented EndoMT/EMT in TNFα-treated human retinal endothelial cells (HRECs) or retinal pigment epithelial APRE19 cells. CGA alleviated endothelial/epithelial barrier oxidative injury in HRECs or APRE19 cells stimulated with TNFα, but this effect was disappeared in cells co-incubated with Nrf2 inhibitor. Additionally, the CGA-supplied alleviation on BRB damage and EndoMT/EMT was markedly weakened in retinas from STZ-treated Nrf2 knock-out mice. All results suggest that CGA improves DR through attenuating BRB injury by reducing microglia-initiated inflammation and preventing TNFα-induced EndoMT/EMT and oxidative injury via inducing Nrf2 activation.

Si-Miao-Yong-An Decoction for Diabetic Retinopathy: A Combined Network Pharmacological and In Vivo Approach.

Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese medicine formula, is mainly used to clear away heat and detoxify and to promote blood circulation and relieve pain. Diabetic retinopathy (DR) is the most common type of microvascular complication caused by diabetes. This study is designed to examine the protective effect of SMYAD against DR and further to reveal the engaged mechanism via integrating network pharmacology and in vivo experimental evidence. Streptozotocin (STZ) was intraperitoneally injected into mice to induce diabetes. The dysfunction of the blood retina barrier (BRB) was observed by conducting Evan's blue leakage assay, detecting tight junction (TJ) protein expression and counting the number of acellular capillaries in retinas. Our results showed that SMYAD alleviated BRB breakdown in vivo. Network pharmacology results demonstrated that regulating inflammation, immune responses, and angiogenesis might be associated with the efficacy of SMYAD in alleviating DR, in which the tumor necrosis factor (TNF) and hypoxia inducible factor 1 (HIF1) signal pathways were involved. Next, immunofluorescence staining results showed that SMYAD decreased microglia activation in retinas and reduced the enhanced adhesion of leukocytes into retinal vessels. SMYAD reduced the elevated serum TNFα content and retinal TNFα expression. SMYAD abrogated the activation of nuclear factor κB (NFκB) and HIF1α and consequently decreased the enhanced expression of some pro-inflammatory molecules and vascular endothelial growth factor (VEGF) in retinas. These results indicate that SMYAD attenuated DR development through suppressing retinal inflammation and angiogenesis via abrogating NFκB-TNFα and HIF1α-VEGF signal pathways.

An atlas of bacterial secondary metabolite biosynthesis gene clusters.

Bacterial secondary metabolites are rich sources of novel drug leads. The diversity of secondary metabolite biosynthetic gene clusters (BGCs) in genome-sequenced bacteria, which will provide crucial information for the efficient discovery of novel natural products, has not been systematically investigated. Here, the distribution and genetic diversity of BGCs in 10 121 prokaryotic genomes (across 68 phyla) were obtained from their PRISM4 outputs using a custom python script. A total of 18 043 BGCs are detected from 5743 genomes with non-ribosomal peptide synthetases (25.4%) and polyketides (15.9%) as the dominant classes of BGCs. Bacterial strains harbouring the largest number of BGCs are revealed and BGC count in strains of some genera vary greatly, suggesting the necessity of individually evaluating the secondary metabolism potential. Additional analysis against 102 strains of discovered bacterial genera with abundant amounts of BGCs confirms that Kutzneria, Kibdelosporangium, Moorea, Saccharothrix, Cystobacter, Archangium, Actinosynnema, Kitasatospora, and Nocardia, may also be important sources of natural products and worthy of priority investigation. Comparative analysis of BGCs within these genera indicates the great diversity and novelty of the BGCs. This study presents an atlas of bacterial secondary metabolite BGCs that provides a lot of key information for the targeted discovery of novel natural products.

Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli ß-glucuronidase inhibitors.

Gut microbial ß-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli ß-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 µM to 2.13 µM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 µM) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.