Epidemiological and Genomic analysis of Vibrio parahaemolyticus isolated from imported travelers at the port of Shanghai, China (2017-2019).

BACKGROUND: Vibrio parahaemolyticus is the predominant etiological agent of seafood-associated foodborne illnesses on a global scale. It is essential to elucidate the mechanisms by which this pathogen disseminates. Given the existing research predominantly concentrates on localized outbreaks, there is a pressing necessity for a comprehensive investigation to capture strains of V. parahaemolyticus cross borders. RESULTS: This study examined the frequency and genetic attributes of imported V. parahaemolyticus strains among travelers entering Shanghai Port, China, between 2017 and 2019.Through the collection of 21 strains from diverse countries and regions, Southeast Asia was pinpointed as a significant source for the emergence of V. parahaemolyticus. Phylogenetic analysis revealed clear delineation between strains originating from human and environmental sources, emphasizing that underlying genome data of foodborne pathogens is essential for environmental monitoring, food safety and early diagnosis of diseases. Furthermore, our study identified the presence of virulence genes (tdh and tlh) and approximately 120 antibiotic resistance-related genes in the majority of isolates, highlighting their crucial involvement in the pathogenesis of V. parahaemolyticus. CONCLUSIONS: This research enhanced our comprehension of the worldwide transmission of V. parahaemolyticus and its antimicrobial resistance patterns. The findings have important implications for public health interventions and antimicrobial stewardship strategies, underscoring the necessity for epidemiological surveillance of pathogen at international travel hubs.

Liquidambaric acid inhibits the proliferation of hepatocellular carcinoma cells by targeting PPARα-RXRα to down-regulate fatty acid metabolism.

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. As the global obesity rate rises, non-alcoholic fatty liver disease (NAFLD) has emerged as the most rapidly increasing cause of HCC. Consequently, the regulation of lipid metabolism has become a crucial target for the prevention and treatment of HCC. Liquidambaric acid (LDA), a pentacyclic triterpenoid compound derived from various plants, exhibits diverse biological activities. We found that LDA could inhibit HCC cell proliferation by arresting cell cycle and prompting apoptosis. Additionally, LDA can augment the therapeutic efficacy of Regorafenib in HCC in vitro and vivo. Our study utilized transcriptome analysis, luciferase reporter assays, and co-immunocoprecipitation experiments to elucidate the anti-HCC mechanism of LDA. We discovered that LDA disrupts the formation of the PPARα-RXRα heterodimer, leading to the down-regulation of the ACSL4 gene and subsequently impacting the fatty acid metabolism of HCC cells, ultimately inhibiting HCC proliferation. Our research contributes to the identification of novel therapeutic agents and targets for the treatment of HCC.

A novel simultaneous short-course nitrification, denitrification and fermentation process: bio-enhanced phenol degradation and denitrification in a single reactor.

The feasibility of a simultaneous nitrification, denitrification and fermentation process (SNDF) under electric stirrer agitation conditions was verified in a single reactor. Enhanced activated sludge for phenol degradation and denitrification in pharmaceutical phenol-containing wastewater under low dissolved oxygen conditions, additional inoculation with Comamonas sp. BGH and optimisation of co-metabolites were investigated. At a hydraulic residence time (HRT) of 28 h, 15 mg/L of substrate as strain BGH co-metabolised substrate degraded 650 ± 50 mg/L phenol almost completely and was accompanied by an incremental increase in the quantity of strain BGH. Strain BGH showed enhanced phenol degradation. Under trisodium citrate co-metabolism, strain BGH combined with activated sludge treated phenol wastewater and degraded NO2--N from 50 ± 5 to 0 mg/L in only 7 h. The removal efficiency of this group for phenol, chemical oxygen demand (COD) and TN was 99.67%, 90.25% and 98.71%, respectively, at an HRT of 32 h. The bioaugmentation effect not only promotes the degradation of pollutants, but also increases the abundance of dominant bacteria in activated sludge. Illumina MiSeq sequencing research showed that strain BGH promoted the growth of dominant genera (Acidaminobacter, Raineyella, Pseudarcobacter) and increased their relative abundance in the activated sludge system. These genera are resistant to toxicity and organic matter degradation. This paper provides some reference for the activated sludge to degrade high phenol pharmaceutical wastewater under the action of biological enhancement.

[Quality control method for phenolic acid components in abandoned stems and leaves of Artemisia selengensis based on UPLC fingerprint combined with quantitative analysis of multi-components by single marker (QAMS)].

This study established an ultra-performance liquid chromatography(UPLC) fingerprint of abandoned stems and leaves of Artemisia selengensis and quantitative analysis of multi-components by single marker(QAMS) for five phenolic acid components. Waters Acquity UPLC BEH C_(18) chromatography column(2.1 mm×100 mm, 1.7 µm) was used. The gradient elution was carried out with the mobile phase composed of 0.1% phosphoric acid water and acetonitrile at a flow rate of 0.3 mL·min~(-1) and a column temperature at 30 ℃. The detection wavelength was 330 nm, and the injection volume was 2 µL. Similarity evaluation and cluster analysis were conducted on the fingerprint data, and 15 common components in 13 batches of abandoned stems and leaves of A. selengensis were identified. The relative correction factors of ferulic acid, isochlorogenic acid A, isochlorogenic acid B, and isochlorogenic acid C were calculated using chlorogenic acid as the internal reference. The QAMS for determining five components in the abandoned stems and leaves of A. selengensis was established. At the same time, the content of these five components was determined using the external standard method(ESM), and the results showed that there were no significant differences in their content determined by the QAMS and the ESM. The results indicated that the content of phenolic acid components in the abandoned stems and leaves of A. selengensis from different varieties and different origins had obvious differences. In addition, the content of phenolic acid components in the abandoned stems and leaves of lignified A. selengensis was significantly higher than that of non-lignified A. selengensis. In summary, QAMS established in this study can be quickly, accurately, and economically used to determine the content of five phenolic acid components in abandoned stems and leaves of A. selengensis, laying a foundation for the resource development and utilization of abandoned stems and leaves of A. selengensis.

Isopimaric acid, an ion channel regulator, regulates calcium and oxidative phosphorylation pathways to inhibit breast cancer proliferation and metastasis.

Breast cancer is the globally most common malignant tumor and the biggest threat to women. Even though the diagnosis and treatment of breast cancer are progressing continually, a large number of breast cancer patients eventually develop a metastatic tumor, especially triple-negative breast cancer (TNBC). Recently, metal ion homeostasis and ion signaling pathway have become important targets for cancer therapy. In this study, We analyzed the effects and mechanisms of isopimaric acid (IPA), an ion channel regulator, on the proliferation and metastasis of breast cancer cells (4 T1, MDA-MB-231and MCF-7) by cell functional assay, flow cytometry, western blot, proteomics and other techniques in vitro and in vivo. Results found that IPA significantly inhibited the proliferation and metastasis of breast cancer cells (especially 4 T1). Further studies on the anti-tumor mechanism of IPA suggested that IPA might affect EMT and Wnt signaling pathways by targeting mitochondria oxidative phosphorylation and Ca2+ signaling pathways, and then inducing breast cancer cell cycle arrest and apoptosis. Our research reveals the therapeutic value of IPA in breast cancer and provides a theoretical basis for the new treatment of breast cancer.

LncRNA CYP4A22-AS1 promotes the progression of lung adenocarcinoma through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

OBJECTIVES: Lung adenocarcinoma (LUAD) exhibits a higher fatality rate among all cancer types worldwide, yet the precise mechanisms underlying its initiation and progression remain unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) exert significant regulatory roles in cancer development and progression. Nevertheless, the precise involvement of lncRNA CYP4A22-AS1 in LUAD remains incompletely comprehended. METHODS: Bioinformatics analyses evaluated the expression level of CYP4A22-AS1 in lung adenocarcinoma and paracancer. The LUAD cell line with a high expression of CYP4A22-AS1 was constructed to evaluate the role of CYP4A22-AS1 in the proliferation and metastasis of LUAD by CCK8, scratch healing, transwell assays, and animal experiments. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. Luciferase reporter gene analyses, west-blotting, and qRT-PCR were carried out to reveal the interaction between CYP4A22-AS1, miR-205-5p/EREG, and miR-34c-5p/BCL-2 axes. RESULTS: CYP4A22-AS1 expression was significantly higher in LUAD tissues than in the adjacent tissues. Furthermore, we constructed a LUAD cell line with a high expression of CYP4A22-AS1 and noted that the high expression of CYP4A22-AS1 significantly enhanced the proliferation and metastasis of LUAD. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. CYP4A22-AS1 increased the expression of EREG and BCL-2 by reducing the expression of miR-205-5p and miR-34-5p and activating the downstream signaling pathway of EGFR and the anti-apoptotic signaling pathway of BCL-2, thereby triggering the proliferation and metastasis of LUAD. The transfection of miR-205-5p and miR-34-5p mimics inhibited the role of CYP4A22-AS1 in enhancing tumor progression. CONCLUSION: This study elucidates the molecular mechanism whereby CYP4A22-AS1 overexpression promotes LUAD progression through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

Endophytic bacterial community diversity in genetically related hybrid rice seeds.

The Food and Agriculture Organization of the United Nations (FAO) has identified hybrid rice as ideal for addressing food scarcity in poor nations. A comprehensive investigation of the endophytic bacteria in hybrid rice seeds is essential from a microecological perspective to illuminate the mechanisms underlying its high yield, high quality, and multi-resistance. The endophytic bacterial diversity and community structures of 11 genetically correlated hybrid rice seeds with different rice blast resistance levels were studied using high-throughput sequencing (HTS) on the Illumina MiSeq platform to reveal their "core microbiota" and explore the effect of genotypes, genetic relationships, and resistance. Proteobacteria (78.15-99.15%) represented the most abundant group in the 11 hybrid rice cultivars, while Pantoea, Pseudomonas, and Microbacterium comprised the "core microbiota." Hybrid rice seeds with different genotypes, genetic correlations, and rice blast resistance displayed endophytic bacterial community structure and diversity variation. In addition, the network relationships between the rice seed endophytic bacteria of "the same female parent but different male parents" were more complex than those from "the same male parent but different female parents." Matrilineal inheritance may be the primary method of passing on endophytic bacteria in rice from generation to generation. The endophytic bacterial interaction network in rice blast-resistant hybrid rice seed varieties was more complicated than in susceptible varieties. In summary, this study demonstrated that the genotype, genetic relationship, and rice blast resistance were important factors affecting the community structures and diversity of endophytic bacteria in hybrid rice seeds, which was vital for revealing the interaction between endophytic bacteria and the host. KEY POINTS: • Pantoea, Pseudomonas, and Microbacterium represent the main endophytic bacteria in hybrid rice seeds. • Genotype is the primary factor affecting endophytic bacterial diversity in hybrid rice seeds. • The diversity of the endophytic bacterial community in hybrid rice seeds is related to their genotypes, genetic relationships, and rice blast resistance.

Synthesis and Evaluation of 2-Amine-4-oxyphosaniline Pyrimidine Derivatives as EGFR L858R/T790M/C797S Mutant Inhibitors.

Epidermal growth factor receptor (EGFR) C797S mutation leads to Osimertinib drug resistance by disturbing the covalent biding of Michael acceptor group to the Cys797 residue in the ATP biding cleft. In this manuscript, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were designed, synthesized and evaluated as new noncovalent reversible EGFR inhibitors against L858R/T790M/C797S (CTL) triple mutant. The kinases inhibitiory activity evaluation showed that four compounds exhibited significant inhibitory activities against CTL (IC50 < 30 nM). In particularly, the most promising compound 7a showed excellent enzymatic inhibitory activity against CTL with IC50 value of 9.9 nM, which was more potent than control compound Osimertinib. Moreover, cell proliferation assays indicated that 7a effectively inhibited H1975-EGFR L858R/T790M/C797S with IC50 value of 0.33 µM. Furthermore, compound 7a displayed good metabolic stabilities in human, rat and mouse liver microsomes, and the putative biding mode of compound 7a with ATP was revealed by molecular docking study. These findings strongly indicated that compound 7a was a promising L858R/T790M/C797S mutant EGFR inhibitor.

Comparison of buttress plate and cannulated screw in the treatment of anteromedial coronoid fracture with elbow posteromedial rotatory instability.

PURPOSE: The purpose of this study is to compare the effect of buttress plate and cannulated screw in the treatment of anteromedial coronoid fracture with posteromedial rotatory instability (PMRI). METHODS: We retrospectively evaluated patients who were diagnosed with O'Driscoll type 2 fractures combined with elbow posteromedial rotatory instability and underwent surgery for anteromedial coronoid fracture between August 2014 and March 2019. They were divided into buttress plate (n=16) and cannulated screw (n=11) groups. The elbow range of motion, visual analog scale (VAS), Mayo elbow performance score (MEPS), and disabilities of the arm, shoulder, and hand score (DASH) were used for clinical outcome assessment. RESULT: There were no significant differences in clinical outcomes. However, the surgical time was significantly shorter in cannulated screw group (85.45±4.156) compared to the buttress plate group (93.81±8.863, P=0.008), and the surgical time was associated with internal fixation (P=0.008). CONCLUSION: Although there was selection of cases in that small fragments were treated with buttress plate and large fragments with cannulated screw, the buttress plate and cannulated screw have comparable functional outcomes on fixation of the anteromedial coronoid fracture with elbow PMRI. The fixation of the anteromedial coronoid fracture with large fragments using the cannulated screw has a shorter operation time.

Controllable 3D Porous Ni Current Collector Coupled with Surface Phosphorization Enhances Na Storage of Ni3 S2 Nanosheet Arrays.

3D porous Ni is fabricated via an easily scalable electroless plating method using a dynamic template formed through in-situ hydrogen bubbles. The pore size in the range of several micrometers is controllable through adjusting the Ni2+ depositing rate and hydrogen bubbles releasing rate. The Ni3 S2 nanosheet arrays anode is then grown on the unique 3D porous Ni current collector followed by subsequent surface phosphorization. The tremendous interconnected pores and rich voids between the Ni3 S2 nanosheet arrays cannot only provide rapid transferring channels for Na+ , but also accommodate volumetric changes of the Ni3 S2 electrode during cycling, guaranteeing the integrity of the active material. In addition, the surface phosphorized layer enhances the electronic conductivity through providing an electron transport highway along the 3D Ni3 S2 , NiP2 layer, and 3D porous Ni current collector, and simultaneously stabilizes the electrode/electrolyte interphase as a protecting layer. Because of these merits, the phosphorized 3D porous Ni3 S2 (3D P-Ni3 S2 ) electrode is capable of delivering an ultra-stable capacity of 387.5 mAh g-1 at 0.1 A g-1 , and a high capacity retention of 85.3% even at a high current density of 1.6 A g-1 .

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer.

Colorectal cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 µM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 µM). Furthermore, compound 10 exhibited strong in vivo anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.

Mechanistic insights on cytotoxicity of KOLR, Cinnamomum pauciflorum Nees leaf derived active ingredient, by targeting signaling complexes of phosphodiesterase 3B and rap guanine nucleotide exchange factor 3.

Protein signaling complexes play important roles in prevention of several cancer types and can be used for development of targeted therapy. The roles of signaling complexes of phosphodiesterase 3B (PDE3B) and Rap guanine nucleotide exchange factor 3 (RAPGEF3), which are two important enzymes of cyclic adenosine monophosphate (cAMP) metabolism, in cancer have not been fully explored. In the current study, a natural product Kaempferol-3-O-(3'',4''-di-E-p-coumaroyl)-α-L-rhamnopyranoside designated as KOLR was extracted from Cinnamomum pauciflorum Nees leaves. KOLR exhibited higher cytotoxic effects against BxCP-3 pancreatic cancer cell line. In BxPC-3 cells, the KOLR could enhance the formation of RAPGEF 3/ PDE3B protein complex to inhibit the activation of Rap-1 and PI3K-AKT pathway, thereby promoting cell apoptosis and inhibiting cell metastasis. Mutation of RAPGEF3 G557A or low expression of PDE3B inactivated the binding action of KOLR resulting in KOLR resistance. The findings of this study show that PDE3B/RAPGEF3 complex is a potential therapeutic cancer target.

Lipid Profiles of the Heads of Four Shrimp Species by UPLC-Q-Exactive Orbitrap/MS and Their Cardiovascular Activities.

Lipids are key factors in nutrition, structural function, metabolic features, and other biological functions. In this study, the lipids from the heads of four species of shrimp (Fenneropenaeus chinensis (FC), Penaeus japonicus (PJ), Penaeus vannamei (PV), and Procambarus clarkia (PCC)) were compared and characterized based on UPLC-Q-Exactive Orbitrap/MS. We compared the differences in lipid composition of four kinds of shrimp head using multivariate analysis. In addition, a zebrafish model was used to evaluate pro-angiogenic, anti-inflammatory, anti-thrombotic, and cardioprotective activities of the shrimp head lipids. The lipids from the four kinds of shrimp head had different degrees of pro-angiogenic activities, and the activities of PCC and PJ shrimp lipids were more significant than those of the other two species. Four lipid groups displayed strong anti-inflammatory activities. For antithrombotic activity, only PCC (25 µg/mL) and PV (100 µg/mL) groups showed obvious activity. In terms of cardioprotective activity, the four kinds of lipid groups significantly increased the zebrafish heart rhythms. The heart distances were shortened, except for those of the FC (100 µg/mL) and PJ (25 µg/mL) groups. Our comprehensive lipidomics analysis and bioactivity study of lipids from different sources could provide a basis for the better utilization of shrimp.

High prevalence of tryptophan-truncated S quasispecies in treatment-naïve chronic hepatitis B patients.

Hepatitis B virus surface antigen (HBsAg) encoded by the S gene is highly expressed during the replication cycle of hepatitis B virus (HBV). However, the frequent usage of tryptophan in HBsAg, which leads to a high cost of biosynthesis, is inconsistent with the high expression level of this protein. Tryptophan-truncated mutation of HBsAg, that is, a tryptophan to stop codon mutation resulting in truncated HBsAg, might help to maintain its high expression with lower biosynthetic cost. We aimed to investigate the prevalence of tryptophan-truncated S quasispecies in treatment-naïve patients with chronic hepatitis B (CHB) by applying CirSeq as well as a site-by-site algorithm developed by us to identify variants at extremely low frequencies in the carboxyl terminus of HBsAg. A total of 730 mutations were identified in 27 patients with CHB, varying from seven to 56 mutations per sample. The number of synonymous mutations was much higher than that of nonsynonymous mutations in the reverse transcriptase (RT) coding region and vice versa in the S coding region, implying that the evolutionary constraints on the RT and S genes might be different. We showed that 25 (92.6 %) of 27 patients had at least one S-truncated mutation, most of which were derived from tryptophan, indicating a high prevalence of tryptophan-truncated S mutations in treatment-naïve patients with CHB. In terms of the RT gene, 21 (77.8 %) patients had pre-existing drug-resistant mutations, while no truncated mutations were detected. Our findings that tryptophan-truncated S quasispecies and drug-resistant RT mutants were highly prevalent in treatment-naïve patients with CHB provide new insights into the composition of the HBV population, which might help optimize the treatment and management of patients with CHB.

Extraordinary diversity of viruses in deep-sea sediments as revealed by metagenomics without prior virion separation.

Our current knowledge of the virosphere in deep-sea sediments remains rudimentary. Here we investigated viral diversity at both gene and genomic levels in deep-sea sediments of Southwest Indian Ocean. Analysis of 19 676 106 non-redundant genes from the metagenomic DNA sequences revealed a large number of unclassified viral groups in these samples. A total of 1106 high-confidence viral contigs were obtained after two runs of assemblies, and 217 of these contigs with sizes up to ~120 kb were shown to represent complete viral genomes. These contigs are clustered with no known viral genomes, and over 2/3 of the ORFs on the viral contigs encode no known functions. Furthermore, most of the complete viral contigs show limited similarity to known viral genomes in genome organization. Most of the classified viral contigs are derived from dsDNA viruses belonging to the order Caudovirales, including primarily members of the families Myoviridae, Podoviridae and Siphoviridae. Most of these viruses infect Proteobacteria and, less frequently, Planctomycetes, Firmicutes, Chloroflexi, etc. Auxiliary metabolic genes (AMGs), present in abundance on the viral contigs, appear to function in modulating the host ability to sense environmental gradients and community changes, and to uptake and metabolize nutrients.

Multi-band terahertz resonant absorption based on an all-dielectric grating metasurface for chlorpyrifos sensing.

Perfect metasurface absorbers play a significant role in imaging, detecting, and manipulating terahertz radiation. We utilize all-dielectric gratings to demonstrate tunable multi-band absorption in the terahertz region. Simulation reveals quad-band and tri-band absorption from 0.2 to 2.5 THz for different grating depths. Coupled-mode theory can explain the absorption phenomenon. The absorption amplitude can be precisely controlled by changing the pump beam fluence. Furthermore, the resonant frequency is sensitive to the medium's refractive index, suggesting the absorber may be of great potential in the sensor detection field. The experimental results exhibit a high detectivity of pesticides.

High-throughput sequencing-based analysis of the composition and diversity of endophytic bacterial community in seeds of upland rice.

Upland rice is an ecotype crop resulting from the long-term domestication and evolution of rice in dry land without a water layer. Generally, the stems and leaves are thick and luxuriant, while the leaves also typically broad and light. The root system is developed with abundant root hair, and the osmotic pressure of the root and cell juice concentration in the leaves is high, while this plant is drought-resistant, heat-resistant, and water absorbent. This study aims to reveal the "core flora" of the endophytes in upland rice seeds by examining their diversity and community structures. It further intends to reveal the impact of the soil environment on the formation of endophyte community structures in upland rice seeds by comparing the environmental soil microorganisms in upland rice habitats. In this study, high-throughput sequencing technology based on the Illumina Hiseq 2500 platform was used to investigate the structure and diversity of endophytic bacterial communities using upland rice varieties collected from different locations and soil samples from unified planting sites as materials. Here, 42 endophytic OTUs were found to coexist in the 14 samples. At the phylum level, the first dominant phyla in all the samples were Proteobacteria (93.81-99.99%). At the genus level, Pantoea (8.77-87.77%), Pseudomonas (1.15-61.58%), Methylobacterium (0.40-4.64%), Sphingomonas (0.26-3.85%), Microbacterium (0.01-4.67%) and Aurantimonas (0.04-4.34%), which represent the core microflora in upland rice seeds, served as the dominant genera that coexisted in all the upland rice seeds tested. This study significant for the isolation, screening, functional evaluation, and re-action of various functional microorganisms in upland rice to improve its agronomic traits. It also provides a specific reference for the interaction between microorganisms and plants.

Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors.

Valine-containing protein (VCP) is a member of the adenosine triphosphate family involved in a variety of cellular activities. VCP/p97 is capable of maintaining protein homeostasis and mediating the degradation of misfolded polypeptides by the ubiquitin-proteasome system (UPS). In this manuscript, a series of novel p97 inhibitors with pyrimidine as core structure were designed, synthesized and biologically evaluated. Based on the enzymatic results, a detailed structure-activity relationship discussion of the synthesized compounds was carried out. Furthermore, cellular activities of the compounds with enzymatic potency of less than 200 nM were investigated by using A549 and RPMI8226 cell lines. Among the screened inhibitors, compound 17 (IC50, 54.7 nM) showed good enzymatic activity. Investigation of cellular activities with non-small cell lung cancer A549 and multiple myeloma (MM) RPMI8226 further confirmed the potency of 17 with the IC50 values of 2.80 µM and 0.86 µM, respectively. Compound 17 is now being developed as a candidate. Finally, docking studies were carried out to explore the possible binding mode between the active inhibitor 17 and p97.

Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma.

The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.

Myxadazoles, Myxobacterium-Derived Isoxazole-Benzimidazole Hybrids with Cardiovascular Activities.

There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.