A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori.

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 µg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

The functions of triple gene block proteins and coat protein of apple stem pitting virus in viral cell-to-cell movement.

Apple stem pitting virus is a species in the genus Foveavirus in the family Betaflexiviridae. Apple stem pitting virus (ASPV) commonly infects apple and pear plants grown worldwide. In this study, by integrating bimolecular fluorescence complementation, split-ubiquitin-based membrane yeast two-hybrid, and Agrobacterium-mediated expression assays, the interaction relationships and the subcellular locations of ASPV proteins TGBp1-3 and CP in Nicotiana benthamiana leaf cells were determined. Proteins CP, TGBp1, TGBp2, and TGBp3 were self-interactable, and TGBp2 played a role in the formation of perinuclear viroplasm and enhanced the colocalization of TGBp3 with CP and TGBp1. We found that the plant microfilament and endoplasmic reticulum structures were involved in the production of TGBp3 and TGBp2 vesicles, and their disruption decreased the virus accumulation level in the systemic leaves. The TGBp3 motile vesicles functioned in delivering the viral ribonucleoprotein complexes to the plasma membrane. Two cysteine residues at sites 35 and 49 of the TGBp3 sorting signal were necessary for the diffusion of TGBp3-marked vesicles. Furthermore, our results revealed that TGBp1, TGBp2, and CP could increase plasmodesmal permeability and move to the adjacent cells. This study demonstrates an interaction network and a subcellular location map of four ASPV proteins and for the first time provides insight into the functions of these proteins in the movement of a foveavirus.

Evaluation and mechanism study of Pien Tze Huang against EV-A71 infection.

Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) infection, currently lacks specific preventive and therapeutic interventions. Here, we demonstrated that Pien Tze Huang (PZH) could dose-dependently inhibit EV-A71 replication at the cellular level, resulting in significant reductions in EV-A71 virus protein 1 (VP1) expression and viral yields in Vero and human rhabdomyosarcoma cells. More importantly, we confirmed that PZH could protect mice from EV-A71 infection for the first time, with Ribavirin serving as a positive control. PZH treatment reduced EV-A71 VP1 protein expression, viral yields in infected muscles, and improved muscle pathology. Additionally, we conducted a preliminary mechanism study using quantitative proteomics. The results suggested that the suppression of the PI3K/AKT/mTOR and NF-κB signaling pathways may contribute to the anti-EV-A71 activity of PZH. These findings provide strong evidence supporting the potential therapeutic application of PZH for EV-A71 infection management.

Multi-Modular Design of Stable Pore-Space-Partitioned Metal-Organic Frameworks for Gas Separation Applications.

Pore space partition (PSP) is an effective materials design method for developing high-performance small-pore materials for storage and separation of gas molecules. The continued success of PSP depends on broad availability and judicious choice of pore-partition ligands and better understanding of each structural module on stability and sorption properties. Here, by using substructural bioisosteric strategy (sub-BIS), a dramatic expansion of pore-partitioned materials is targeted by using ditopic dipyridyl ligands with non-aromatic cores or extenders, as well as by expanding heterometallic clusters to uncommon nickel-vanadium and nickel-indium clusters rarely known before in porous materials. The dual-module iterative refinement of pore-partition ligands and trimers leads to remarkable enhancement of chemical stability and porosity. Here a family of 23 pore-partitioned materials synthesized from five pore-partition ligands and seven types of trimeric clusters is reported. New materials with such compositionally and structurally diverse framework modules reveal key factors that dictate stability, porosity, and gas separation properties. Among these, materials based on heterometallic vanadium-nickel trimeric clusters give rise to the highest long-term hydrolytic stability and remarkable uptake capacity for CO2 , C2 H2 /C2 H4 /C2 H6 , and C3 H6 /C3 H8 hydrocarbon gases. The breakthrough experiment shows the potential application of new materials for separating gas mixtures such as C2 H2 /CO2 .

Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1).

A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.

Trehalose hydrolysis and transport-related genes promote Bombyx mori nucleopolyhedrovirus proliferation through the phosphoinositide 3-kinase-Akt signalling pathway in BmN cell.

The reprogramming of host physiology has been considered an essential process for baculovirus propagation. Trehalose, the main sugar in insect blood, plays a crucial role as an instant energy source. Although the trehalose level is modulated following infection with Bombyx mori nucleopolyhedrovirus (BmNPV), the mechanism of trehalose metabolism in response to BmNPV infection is still unclear. In this study, we demonstrated that the trehalose level tended to be lower in BmNPV-infected hemolymph and higher in the midgut. The omics analysis revealed that two trehalose transporters, BmTret1-1 and BmTret1-2, and trehalase, BmTRE1 and BmTRE2, were differentially expressed in the midgut after BmNPV infection. BmTret1-1 and BmTret1-2 had the ability to transport trehalose into the cell and promoted cellular absorption of trehalose. Furthermore, the functions of BmTret1-1, BmTret1-2, BmTRE1 and BmTRE2 in BmNPV infection were analyzed. These genes were upregulated in the midgut after BmNPV infection. Virus amplification analysis revealed that these genes could promote BmNPV proliferation in BmN cells. In addition, these genes could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO in the phosphoinositide 3-kinase (PI3K)-Akt signalling pathway. Similarly, the increased trehalose level in BmN cells could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO. Taken together, BmNPV infection promote the expression of trehalose hydrolysis and transport-related genes. These changes affect the PI3K-Akt signalling pathway to facilitate BmNPV proliferation. These findings help clarify the relationship between trehalose metabolism and BmNPV infection.

NiCrBSi Coatings Fabricated on 45 Steel Using Large Spot Laser Cladding.

Ni35 coatings were fabricated on 45 steel using a CO2 laser at various parameters. A relatively large spot (10 mm diameter) was adopted, which was beneficial to the coating quality and the cladding efficiency. The cross-sectional geometry, phase constituent, and microstructure of the coatings were investigated. With a lower specific energy, coating height increased, while coating width, melted depth, dilution rate, width to height ratio and contact angle decreased. Ni35 coating primarily consisted of γ-Ni, FeNi3, Ni3B, Cr23C6, and Cr5B3. Dendrites with flower-like, fishbone-like, pearl-like, and column-like morphologies were observed. The fraction of flower-like dendrites increased gradually with the decrease in scanning velocity due to the dendrite growth direction evolution. With the decrease in scanning velocity, the microstructure of the heat-affected zone transformed from martensite to martensite + sorbite and finally sorbite. The maximum microhardness of the Ni35 coating reached 451.8 HV0.2, which was about double that of the substrate (220 HV0.2).

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation.

Sixty palmatine (PMT) derivatives were synthesized and evaluated for antiplatelet aggregation taking berberine as the lead, and the structure-activity relationship was first systematically described. Among them, compound 2v showed the best potency in reducing adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent manner. It greatly suppressed ADP-induced platelet aggregation, activation, and Akt phosphorylation in vitro and ex vivo after oral administration to mice. It also effectively inhibited carrageenan-induced thrombus formation in the mouse tail and lung, as well as reduced the serum P-selectin level. Compound 2v might simultaneously bind to protein kinase G to improve vasodilator-stimulated phosphoprotein phosphorylation and bind to phosphatidylinositol 3-kinase to inhibit Akt phosphorylation, which synergically reduced platelet aggregation, thereby achieving antithrombotic efficacy. Therefore, PMT derivatives constituted a novel family of antiplatelet aggregation agents with the advantage of a good safety profile, worthy of further investigation.

Salivary Fusobacterium nucleatum serves as a potential biomarker for colorectal cancer.

Fusobacterium nucleatum (Fn) is primarily colonized in the oral cavity. Recently, Fn has been closely associated with the tumorigenesis of colorectal cancer (CRC). Here, we showed that the relative level of Fn DNA was increased in the saliva of the CRC group compared with the normal colonoscopy, hyperplastic polyp, and adenoma groups. Receiver operating characteristic curve analysis illustrated that Fn DNA was superior to carcinoembryonic antigen and carbohydrate antigen 19-9 in CRC diagnosis. Moreover, levels of Fn DNA were associated with the overall survival and disease-free survival of CRC patients, which was an independent factor for prognostic prediction. Transcriptome sequencing identified 1,287 differentially expressed mRNAs in tumor tissues between CRC patients with high-Fn and low-Fn infection. Kyoto encyclopedia of genes and genomes analysis showed that ECM-receptor interaction and focal adhesion were the top two significant pathways. Overall, salivary Fn DNA may be a noninvasive diagnostic and prognostic biomarker for CRC patients.

A novel Actinidia cytorhabdovirus characterized using genomic and viral protein interaction features.

A novel cytorhabdovirus, tentatively named Actinidia virus D (AcVD), was identified from kiwifruit (Actinidia chinensis) in China using high-throughput sequencing technology. The genome of AcVD consists of 13,589 nucleotides and is organized into seven open reading frames (ORFs) in its antisense strand, coding for proteins in the order N-P-P3-M-G-P6-L. The ORFs were flanked by a 3' leader sequence and a 5' trailer sequence and are separated by conserved intergenic junctions. The genome sequence of AcVD was 44.6%-51.5% identical to those of reported cytorhabdoviruses. The proteins encoded by AcVD shared the highest sequence identities, ranging from 27.3% (P6) to 44.5% (L), with the respective proteins encoded by reported cytorhabdoviruses. Phylogenetic analysis revealed that AcVD clustered together with the cytorhabdovirus Wuhan insect virus 4. The subcellular locations of the viral proteins N, P, P3, M, G, and P6 in epidermal cells of Nicotiana benthamiana leaves were determined. The M protein of AcVD uniquely formed filament structures and was associated with microtubules. Bimolecular fluorescence complementation assays showed that three proteins, N, P, and M, self-interact, protein N plays a role in the formation of cytoplasm viroplasm, and protein M recruits N, P, P3, and G to microtubules. In addition, numerous paired proteins interact in the nucleus. This study presents the first evidence of a cytorhabdovirus infecting kiwifruit plants and full location and interaction maps to gain insight into viral protein functions.

The p23 of Citrus Tristeza Virus Interacts with Host FKBP-Type Peptidyl-Prolylcis-Trans Isomerase 17-2 and Is Involved in the Intracellular Movement of the Viral Coat Protein.

Citrus tristeza virus is a member of the genus Closterovirus in the family Closteroviridae. The p23 of citrus tristeza virus (CTV) is a multifunctional protein and RNA silencing suppressor. In this study, we identified a p23 interacting partner, FK506-binding protein (FKBP) 17-2, from Citrus aurantifolia (CaFKBP17-2), a susceptible host, and Nicotiana benthamiana (NbFKBP17-2), an experimental host for CTV. The interaction of p23 with CaFKBP17-2 and NbFKBP17-2 were individually confirmed by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Subcellular localization tests showed that the viral p23 translocated FKBP17-2 from chloroplasts to the plasmodesmata of epidermal cells of N. benthamiana leaves. The knocked-down expression level of NbFKBP17-2 mRNA resulted in a decreased CTV titer in N. benthamiana plants. Further, BiFC and Y2H assays showed that NbFKBP17-2 also interacted with the coat protein (CP) of CTV, and the complexes of CP/NbFKBP17-2 rapidly moved in the cytoplasm. Moreover, p23 guided the CP/NbFKBP17-2 complexes to move along the cell wall. To the best of our knowledge, this is the first report of viral proteins interacting with FKBP17-2 encoded by plants. Our results provide insights for further revealing the mechanism of the CTV CP protein movement.

[Effect of ligustilide on oxygen and glucose deprivation/reperfusion-induced mitochondria fission in PC12 cells].

This study aimed to investigate the effect and mechanism of ligustilide, the main active ingredient in Ligusticum wallichii, on mitochondria fission after PC12 cell injury induced by oxygen and glucose deprivation/reperfusion(OGD/R). In the experiment, an OGD/R model was established in vitro, and PC12 cells were pre-treated with ligustilide for 3 h, and then the cell viability was detected by CCK-8 method. The effect of different concentrations of ligustilide on the morphology of PC12 cells after OGD/R injury was observed under an inverted microscope. Transmission electron microscopy was used to observe the mitochondrial fission of PC12 cells after OGD/R injury. DCFH-DA immunofluorescence staining method was used to detect intracellular reactive oxygen species(ROS) changes. Changes in mitochondria membrane potential(MMP) were detected by flow cytometry. Hochest 33258 was used to observe the apoptosis of PC12 cells. Western blot was used to detect changes in cytochrome C(Cyt C) content in mitochondria and cytoplasm, and mitochondrial fission-related proteins Drp 1 and Fis 1. All results showed that compared with the model group, ligustilide significantly increased the survival rate of PC12 cells and the number of cells. Further experiments showed that ligustilide inhibited the release of ROS and decline of mitochondrial membrane potential in PC12 cells after OGD/R injury. Moreover, ligustilide reduced the release of Cyt C and promoted the expressions of Drp1 and Fis1 in mitochondrial fission proteins. Verification experiments showed that mitochondrial fission inhibitor mdivi-1 decreased cell survival rate and inhibited fission. The results indicated that ligustilide exerted neuro-protective effects by promoting mitochondrial fission and reducing cell damage. It preliminary proves that the mechanism of ligustilide on ischemic brain injury may be related to the promotion of mitochondrial fission and the maintenance of cell homeostasis.

Structure-activity relationship and hypoglycemic activity of tricyclic matrines with advantage of treating diabetic nephropathy.

Forty-three tricyclic matrinic derivatives with a unique scaffold were prepared and evaluated for their stimulation effects on glucose consumption in HepG2 cells. The structure-activity relationship was systematically elucidated for the first time. Among them, compound 17a exhibited the most promising potency, and dose-dependently increased glucose consumption in L6 myotubes. It significantly lowered blood glucose, glucosylated haemoglobin and AGE level, and improved glucose tolerance and insulin resistance in KK-Ay mice as well. More importantly, 17a effectively ameliorated diabetic nephropathy (DN), as indicated by the improvement of renal function and pathological changes, and decrease of urinary protein. Furthermore, 17a could induce glycolysis but suppressed aerobic oxidation of glucose, in a similar mechanism to Metform. Our results indicated that in addition to hyperglycemia, 17a may be developed to treat diabetic complication such as DN.

Pore-Space-Partition-Enabled Exceptional Ethane Uptake and Ethane-Selective Ethane-Ethylene Separation.

An ideal material for C2H6/C2H4 separation would simultaneously have the highest C2H6 uptake capacity and the highest C2H6/C2H4 selectivity. But such material is elusive. A benchmark material for ethane-selective C2H6/C2H4 separation is peroxo-functionalized MOF-74-Fe that exhibits the best known separation performance due to its high C2H6/C2H4 selectivity (4.4), although its C2H6 uptake capacity is moderate (74.3 cm3/g). Here, we report a family of pore-space-partitioned crystalline porous materials (CPMs) with exceptional C2H6 uptake capacity and C2H6/C2H4 separation potential (i.e., C2H4 recovered from the mixture) despite their moderate C2H6/C2H4 selectivity (up to 1.75). The ethane uptake capacity as high as 166.8 cm3/g at 1 atm and 298 K, more than twice that of peroxo-MOF-74-Fe, has been achieved even though the isosteric heat of adsorption (21.9-30.4 kJ/mol) for these CPMs is as low as about one-third of that for peroxo-MOF-74-Fe (66.8 kJ/mol). While the overall C2H6/C2H4 separation potentials have not yet surpassed peroxo-MOF-74-Fe, these robust CPMs exhibit outstanding properties including high thermal stability (up to 450 °C) and aqueous stability, low regeneration energy, and a high degree of chemical and geometrical tunability within the same isoreticular framework.

Synthesis and biological evaluation of berberine derivatives as a new class of broad-spectrum antiviral agents against Coxsackievirus B.

A series of novel berberine (BBR) analogues were prepared and tested for their antiviral potencies against six different genotype Coxsackievirus B (CVB1-6) strains, taking BBR core for structural modification. Structure-activity relationship (SAR) research revealed that introduction of a primary amine through a linker at position 3 might be beneficial for both antiviral activity and safety. Compound 14c displayed most promising inhibitory potency with IC50 values of 3.08-9.94 µM against tested CVBs 2-6 strains and satisfactory SI value of 34.3 on CVB3, better than that of BBR. Also, 14c could inhibit CVB3 replication through down-regulating the expression of VP1 protein and VP1 RNA. The mechanism revealed that 14c could suppress host components JNK-MAPK, ERK-MAPK and p38-MAPK activation. Therefore, BBR derivatives were considered to be a new class of anti-CVB agents with an advantage of broad-spectrum anti-CVB potency.

Massilia atriviolacea sp. nov., a dark purple-pigmented bacterium isolated from soil.

A bacterial strain, designated SODT, with Gram-stain-negative and motile rod-shaped cells, was isolated from soil in Hefei, PR China, and was characterized using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SODT belonged to the genus Massilia and showed the highest similarities to Massilia violaceinigra B2T (99.3 %), followed by Massilia glaciei B448-2T (98.7 %), Massilia eurypsychrophila CGMCC 1.12828T (98.6 %) and Rugamonas rubra CCM3730T (97.8 %). Average nucleotide identity and digital DNA-DNA hybridization values between genome sequences of strain SODT and the closely related species ranged from 77.1 to 89.3% and from 22.2 to 34.7 %. The DNA G+C content of strain SODT was 65.4 mol%. Strain SODT contained Q-8 as the major ubiquinone and the dominant fatty acids were summed feature 3 (C16 : 1ω7c and/or C15 : 0iso 2-OH; 58.5 %), C16 : 0 (26.8 %) and C18 : 1ω7c (5.0 %). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. On the basis of the evidence presented in this study, strain SODT represents a novel species of the genus Massilia, for which the name Massiliaatriviolacea sp. nov. is proposed. The type strain is SODT (=KCTC 62720T=LMG 30840T).

MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-ß-activated kinase 1-dependent activation of the transcription factor EB.

Lysosome has a crucial role in clearance of endocytosed pathogens from the cell. Small molecules that can boost lysosome function and bactericidal ability to cope with subsequent infection are urgently needed. Here, we report that MPB, a novel berberine derivative, induced lysosome-based degradation and clearance of methicillin-resistant Staphylococcus aureus and enteroinvasive Escherichia coli in macrophages. MPB caused nuclear translocation of transcription factor EB (TFEB), which boosted expression of lysosome genes. TFEB silencing repressed the MPB-mediated enhancements in degradation and bacterial eradication. MPB switched on TFEB nuclear translocation by coupling 2 parallel signaling pathways. MPB-triggered JNK activation led to 14-3-3δ being released from TFEB, which, in turn, caused TFEB nuclear translocation. In addition, MPB induced AMPK activation and subsequent inhibition of mechanistic target of rapamycin activity, which also contributed to TFEB nuclear translocation. Importantly, genetical or pharmaceutical inhibition of TGF-ß-activated kinase 1 (TAK1) reduced MPB action remarkably. MPB acted through TAK1 at lysine 158 to activate JNK and AMPK and, thus, induced TFEB-dependent bactericidal activity in macrophages. Therefore, our study reveals a novel mechanism by which MPB controls JNK and AMPK phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158-dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection.-Liu, X., Zhang, N., Liu, Y., Liu, L., Zeng, Q., Yin, M., Wang, Y., Song, D., Deng, H. MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-ß-activated kinase 1-dependent activation of the transcription factor EB.

Urethane-based low-temperature curing, highly-customized and multifunctional poly(glycerol sebacate)-co-poly(ethylene glycol) copolymers.

Poly (glycerol sebacate) (PGS), a tough elastomer, has been widely explored in tissue engineering due to the desirable mechanical properties and biocompatibility. However, the complex curing procedure (high temperature and vacuum) and limited hydrophilicity (∼90° of wetting angle) greatly impede its functionalities. To address these challenges, a urethane-based low-temperature setting, PEGylated PGS bioelastomer was developed with and without solvent. By simultaneously tailoring PEG and hexamethylene diisocyanate (HDI) contents, the elastomers X-P-mUs (X referred to the PEG content and m referred to HDI content) with a broad ranging mechanical properties and customized hydrophilicity were constructed. The X-P-mUs synthesized exhibited adjustable tensile Young's modulus, ultimate tensile strength and elongation at break in the range of 1.0 MPa-14.2 MPa, 0.3 MPa-7.6 MPa and 53.6%-272.8%, with the water contact angle varying from 28.6° to 71.5°, respectively. Accordingly, these elastomers showed favorable biocompatibility in vitro and mild host response in vivo. Furthermore, the potential applications of X-P-mU elastomers prepared with solvent-base and solvent-free techniques in biomedical fields were investigated. The results showed that these X-P-mU elastomers with high molding capacity at mild temperature could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity, demonstrating that the X-P-mU elastomers could be tailored as potential building blocks for diverse applications in biomedical research. STATEMENT OF SIGNIFICANCE: Poly(glycerol sebacate) (PGS), a tough biodegradable elastomer, has received great attentions in biomedical field. But the complex curing procedure and limited hydrophilicity greatly hamper its functionality. Herein, a urethane-based low-temperature setting, PEGylated PGS (PEGS-U) bioelastomer with highly-customized mechanical properties, hydrophilicity and biodegradability was first explored. The synthesized PEGS-U showed favorable biocompatibility both in vitro and in vivo. Furthermore, the PEGS-U elastomer could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity. This versatile, user-tunable bioelastomers should be a promising biomaterials for biomedical applications.

Self-assembled filomicelles prepared from polylactide-poly(ethylene glycol) diblock copolymers for sustained delivery of cycloprotoberberine derivatives.

Polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers were synthesized by ring opening polymerization of l-lactide using a monomethoxy PEG (mPEG) as macroinitiator and zinc lactate as catalyst. The resulting diblock copolymers were characterized by 1H NMR and GPC. Polymeric micelles were prepared by self-assembly of copolymers in distilled water using co-solvent evaporation or membrane hydration methods. The resulting micelles are worm-like in shape as shown by TEM measurements. A hydrophobic anticancer drug, cycloprotoberberine derivative A35, was successfully loaded in PLA-PEG filomicelles with high encapsulation efficiency (above 88%). Berberine (BBR) was studied for comparison. In both methods, PLA-PEG filomicelles were prepared with a theoretical loading of 5%, 10% and 20%. Physical stability studies indicated that BBR/A35-loaded filomicelles were more stable when stored at 4 °C than at 25 °C. Compared with BBR-loaded filomicelles, A35-loaded filomicelles exhibited higher antitumor activity. Importantly, the in vitro cytotoxicity and stability of A35-loaded filomicelles evidenced the potential of drug-loaded filomicelles in the development of drug delivery systems.

Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1.

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.