Isosteviol derivatives as protein tyrosine Phosphatase-1B inhibitors: Synthesis, biological evaluation and molecular docking.

Protein tyrosine phosphatase (PTP1B) antagonizes insulin signaling and acts as a potential therapeutic target for insulin resistance associated with obesity and type II diabetes. In this work, a series of isosteviol derivatives 1-28 was synthesized and the inhibitory activity on PTP1B was evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Most isosteviol derivatives showed moderate PTP1B inhibitory activities. Among them, derivatives 10, 13, 24, 27 showed remarkable bioactivities with IC50 values ranging from 0.24 to 0.40 µM. Particularly, derivative 24 exhibited the best inhibitory activity against PTP1B (IC50 = 0.24 µM) in vitro; moreover, it showed 7-fold selectivity to PTP1B over T-cell protein tyrosine phosphatase (TCPTP) and 14-fold selectivity to PTP1B over cell division cycle 25 homolog B (CDC25B). Molecular docking studies demonstrated the hydrogen bond interaction between 24 and LYS-116 residue in PTP1B might be essential for the inhibitory activity. The results suggested that derivative 24 has great potential to be employed as drug candidate for the treatment of obesity and type II diabetes.

Real-Time Fluorescence Screening Platform for Meat Freshness.

Meat's freshness is closely related to food safety and human health and has received increasing attention nowadays. To on-site visually screen meat freshness in a fast and non-destructive manner, we rationally constructed a series of fluorescent probes (JDCN, JDNS, and JDPY) with distinct electron-withdrawing substitution groups based on julolidine-fused coumarin. These probes underwent an aza-Michael addition followed by an elimination reaction with cadaverine to generate a colorimetric and ratiometric fluorescence response, and their sensing performance was rationally enhanced by improving the electron-withdrawing strength of substitution groups. Particularly, JDCN with a dicyanovinyl group as the reaction site exhibited outstanding sensing performance including rapid response (∼60 s), high selectivity, and low detection limit (14 nM). Furthermore, JDCN was fabricated into test kits to detect cadaverine vapor with a high-contrast fluorescence change from red to green. Based on two-color visualization of cadaverine vapor, on-site non-contact and non-destructive monitoring of meat freshness was successfully achieved. The good sensing performance rendered JDCN test kits a promising real-time fluorescence screening platform for rapid, non-destructive, and accurate evaluation of meat freshness.

A smartphone-adaptable fluorescent sensing tag for non-contact and visual monitoring of the freshness of fish.

Fish-based food products play important roles in our daily diet. The related food safety is vitally essential for human health, thus it is very necessary to screen the freshness of fish-based foods. In this work, we presented a ratiometric fluorescent probe PTCN for the determination of cadaverine, a metabolic biomarker of the spoilage of fish. PTCN displayed a ratiometric fluorescence response towards cadaverine with good specificity, high sensitivity (LOD = 46 nM) and ultra-fast response (<15 s), and thus has been successfully utilized to determine cadaverine from the spoilage of fish. PTCN was fabricated into cheap and portable sensing tags, which can visually detect gaseous cadaverine with obvious fluorescence color transformation from red to green and a low detection limit (8.65 ppm). Moreover, the PTCN tags were used as smart fluorescent tags for non-contact and visual monitoring of cadaverine in fish. Furthermore, the ratiometric fluorescence signals were utilized to create a smartphone-adaptable digital sensing profile for indicating cadaverine in fish products.

Progress in Isoindolone Alkaloid Derivatives from Marine Microorganism: Pharmacology, Preparation, and Mechanism.

Compound 1 (SMTP-7, also FGFC1), an isoindolone alkaloid from marine fungi Starchbotrys longispora FG216 and fungi Stachybotrys microspora IFO 30018, possessed diverse bioactivities such as thrombolysis, anti-inflammatory and anti-oxidative properties, and so on. It may be widely used for the treatment of various diseases, including cerebral infarction, stroke, ischemia/reperfusion damage, acute kidney injury, etc. Especially in cerebral infarction, compound 1 could reduce hemorrhagic transformation along with thrombolytic therapy, as the traditional therapies are accompanied with bleeding risks. In the latest studies, compound 1 selectively inhibited the growth of NSCLC cells with EGFR mutation, thus demonstrating its excellent anti-cancer activity. Herein, we summarized pharmacological activities, preparation of staplabin congeners-especially compound 1-and the mechanism of compound 1, with potential therapeutic applications.

Daphnetin, a Coumarin in Genus Stellera Chamaejasme Linn: Chemistry, Bioactivity and Therapeutic Potential.

Coumarins is a huge family of phenolic compounds containing a common structure of 2H-1-benzopyran-2-one. Nowadays, more than 1,300 natural-based coumarins have been identified in a variety of plants, bacteria and fungi, many of them exhibited promising biomedical performance. Daphnetin (7,8-dihydroxycoumarin), a typical coumarin, showed a couple of bioactivities such as anti-cancer, antibacterial, anti-inflammatory and anti-arthritis. In the treatment of diseases, it has been verified that daphnetin has outstanding therapeutic effects on diabetes, arthritis, transplant rejection, cancer and even on central nervous system diseases. In China, it is being used for clinical applications, about 93 patent publications were associated with daphnetin. Due to its wide therapeutic potentials in clinical applications, numerous research on the action mechanisms and synthetic methods of daphnetin have been performed to support the future developments. Herein, we summarized the chemical synthetic methodologies, bioactivities, therapeutic potentials and structure-activity relationships of daphnetin and its derivatives. Moreover, the state-of-the-arts in current daphnetin study and future perspective in this field were discussed. Hopefully, this review would be beneficial for the discovery of new coumarin-based biomedicine in the near future.

Microfluidic-Based Cationic Cholesterol Lipid siRNA Delivery Nanosystem: Highly Efficient In Vitro Gene Silencing and the Intracellular Behavior.

Safe and efficient delivery of small interfering RNA (siRNA) is essential to gene therapy towards intervention of genetic diseases. Herein, we developed a novel cationic cholesterol lipid derivative (CEL) in which cholesterol hydrophobic skeleton was connected to L-lysine cationic headgroup via a hexanediol linker as the non-viral siRNA delivery carrier. Well-organized CEL/siRNA nanocomplexes (100-200 nm) were prepared by microfluidic-assisted assembly of CEL and siRNA at various N/P ratios. The CEL and CEL/siRNA nanocomplexes have lower cytotoxicity compared with bPEI25k. Delightfully, we disclosed that, in Hela-Luc and H1299-Luc cell lines, the micro-fluidic-based CEL/siRNA nanocomplexes exhibited high siRNA transfection efficiency under both serum-free condition (74-98%) and low-serum circumstances (80-87%), higher than that of lipofectamine 2000. These nanocomplexes also showed high cellular uptake through the caveolae/lipid-raft mediated endocytosis pathway, which may greatly contribute to transfection efficiency. Moreover, the time-dependent (0-12 h) dynamic intracellular imaging demonstrated the efficient delivery to cytoplasm after lysosomal co-localization. The results indicated that the microfluidic-based CEL/siRNA nanosystems possessed good stability, low cytotoxicity, high siRNA delivery efficiency, rapid cellular uptake and caveolae/lipid raft-dependent internalization. Additionally, this study provides a simple approach for preparing and applying a "helper lipid-free" cationic lipid siRNA delivery system as potential nanotherapeutics towards gene silencing treatment of (tumor) diseases.

Alginate Lyases from Marine Bacteria: An Enzyme Ocean for Sustainable Future.

The cell wall of brown algae contains alginate as a major constituent. This anionic polymer is a composite of ß-d-mannuronate (M) and α-l-guluronate (G). Alginate can be degraded into oligosaccharides; both the polymer and its products exhibit antioxidative, antimicrobial, and immunomodulatory activities and, hence, find many commercial applications. Alginate is attacked by various enzymes, collectively termed alginate lyases, that degrade glycosidic bonds through ß-elimination. Considering the abundance of brown algae in marine ecosystems, alginate is an important source of nutrients for marine organisms, and therefore, alginate lyases play a significant role in marine carbon recycling. Various marine microorganisms, particularly those that thrive in association with brown algae, have been reported as producers of alginate lyases. Conceivably, the marine-derived alginate lyases demonstrate salt tolerance, and many are activated in the presence of salts and, therefore, find applications in the food industry. Therefore, this review summarizes the structural and biochemical features of marine bacterial alginate lyases along with their applications. This comprehensive information can aid in the expansion of future prospects of alginate lyases.

Synthesis and Bioactivities of Marine Pyran-Isoindolone Derivatives as Potential Antithrombotic Agents.

2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-teraahydro-6H-pyran[a]isoindol-2-yl]-pentanoic acid (FGFC1) is a marine pyran-isoindolone derivative isolated from a rare marine microorganism Stachybotrys longispora FG216, which showed moderate antithrombotic(fibrinolytic) activity. To further enhance its antithrombotic effect, a series of new FGFC1 derivatives (F1-F7) were synthesized via chemical modification at C-2 and C-2' phenol groups moieties and C-1″ carboxyl group. Their fibrinolytic activities in vitro were evaluated. Among the derivatives, F1-F4 and F6 showed significant fibrinolytic activities with EC50 of 59.7, 87.1, 66.6, 82.8, and 42.3 µM, respectively, via enhancement of urokinase activity. Notably, derivative F6 presented the most remarkable fibrinolytic activity (2.72-fold than that of FGFC1). Furthermore, the cytotoxicity of derivative F6 was tested as well as expression of Fas/Apo-1 and IL-1 on HeLa cells. The results showed that, compared to FGFC1, derivative F6 possessed moderate cytotoxicity and apoptotic effect on HeLa cells (statistical significance p > 0.1), making F6 a potential antithrombotic agent towards clinical application.

Syntheses and evaluation of daphnetin derivatives as novel G protein-coupled receptor inhibitors and activators.

A series of daphnetin (7,8-dihydroxycoumarin) derivatives 1-22 were synthesized including sixteen new compounds (1-5, 7-14, 18, 21 and 22) and six known compounds (6, 15-17, 19 and 20). Their pharmacological activities on G protein-coupled receptors (GPCRs) were evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Daphnetin derivatives with various substitution patterns/groups were obtained from inhibitors to activators on GPCRs. Derivatives 2-5, 8, 15, 16 and 18-20 possessed moderate activation potency on GPCRs. Among them, derivatives 3-5, 16 and 19 presented significant activation potency on GPCRs with EC50 values in the range of 1.18-1.91 nM. Derivatives 6, 11, 14 and 18 showed significant inhibitory potency on GPCRs with IC50 values in the range of 1.26-1.38 nM. Moreover, the structure-activity relationships (SARs) of daphnetin derivatives were discussed in detail. The new daphnetic-based GPCRs activators and inhibitors have potentials as future drug candidates for the treatment of metabolic diseases.

Rationally assembled albumin/indocyanine green nanocomplex for enhanced tumor imaging to guide photothermal therapy.

Herein, a novel phototheranostic nanocomplex that is self-assembled from bovine serum albumin (BSA) and indocyanine green (ICG) is developed for enhanced near-infrared (NIR) fluorescence imaging, which benefits the guidance on in vivo cancer photothermal therapy (PTT). The study confirms that the binding of ICG with the bind sits on the albumin will result in improved hydrolytic stability and high photoluminescence quantum yield (PLQY). The ICG loading ratio in the nanocomplex is optimized and confirms the loading ratio of 0.5% ICG to be the optimal content. The optimized ICG-BSA nanocomplex (ICG-BSA NC) possesses a higher PLQY of 16.8% than that of free ICG (2.7%). The high PLQY and efficient passive targeting ability of ICG-BSA NC help improve its in vivo tumor accumulation and NIR fluorescence imaging significantly. Under laser irradiation, efficient PTT with obvious tumor growth suppression on a triple negative breast tumor model can be observed in the ICG-BSA NC treated group.

Novel Bioactive Polyketides Isolated from Marine Actinomycetes: An Update Review from 2013 to 2019.

Marine organism-associated actinobacteria represent a valuable resource for marine drugs due to their abundant secondary metabolites. The special environments in the ocean, for instance, high salt, high pressure, low temperature and oligotrophy, not only adapt to survival of actinomycetes but also enhance molecular diversity of actinomycete secondary metabolites production, thus making marine actinomycetes important sources of marine-based bioactive compounds, especially polyketides. Herein, we summarized the structures and pharmacological activities of polyketides from actinobacteria associated with marine organisms from 2013 to 2019; moreover, the main source species of actinomycetes were discussed as well. We expected that this review would be helpful for future in-depth research and development of marine-based bioactive polyketides.

Colorimetric and Ratiometric Chemosensor for Visual Detection of Gaseous Phosgene Based on Anthracene Carboxyimide Membrane.

In this work, we reported an anthracene carboxyimide-based chemosensor (AC-Phos) for colorimetric and ratiometric fluorescence detection of highly toxic phosgene, which displayed rapid response (<5 min) toward phosgene with a high selectivity and a low detection limit (2.3 nM). Furthermore, a facile testing membrane with a polystyrene immobilizing chemosensor has been fabricated for real-time visualizing of gaseous phosgene.

99m Tc-labeled rHuEpo for imaging of the erythropoietin receptor in tumors.

To analyze erythropoietin receptor (EpoR) status in tumors, recombinant human erythropoietin (rHuEpo) was labeled with 99m Tc by 99m Tc-centered 1-pot synthesis, resulting in high radiochemical purity, stability, and biological activity. Both in vitro cell culture experiments and biodistribution studies of normal rats demonstrated successful EpoR targeting. The biodistribution of labeled rHuEpo in a NCI-H1975 xenograft model showed tumor accumulation (tumor-to-muscle ratio, 4.27 ± 1.77), confirming the expression of active EpoR in tumors. Thus, as a novel single positron emission computerized tomography tracer for the imaging of EpoR expression in vivo, 99m Tc-rHuEpo is effective for exploring the role of EpoR in cancer growth, metastasis and angiogenesis.

Skeleton-Controlled pDNA Delivery of Renewable Steroid-Based Cationic Lipids, the Endocytosis Pathway Analysis and Intracellular Localization.

Using renewable and biocompatible natural-based resources to construct functional biomaterials has attracted great attention in recent years. In this work, we successfully prepared a series of steroid-based cationic lipids by integrating various steroid skeletons/hydrophobes with (l-)-arginine headgroups via facile and efficient synthetic approach. The plasmid DNA (pDNA) binding affinity of the steroid-based cationic lipids, average particle sizes, surface potentials, morphologies and stability of the steroid-based cationic lipids/pDNA lipoplexes were disclosed to depend largely on the steroid skeletons. Cellular evaluation results revealed that cytotoxicity and gene transfection efficiency of the steroid-based cationic lipids in H1299 and HeLa cells strongly relied on the steroid hydrophobes. Interestingly, the steroid lipids/pDNA lipoplexes inclined to enter H1299 cells mainly through caveolae and lipid-raft mediated endocytosis pathways, and an intracellular trafficking route of "lipid-raft-mediated endocytosis→lysosome→cell nucleic localization" was accordingly proposed. The study provided possible approach for developing high-performance steroid-based lipid gene carriers, in which the cytotoxicity, gene transfection capability, endocytosis pathways, and intracellular trafficking/localization manners could be tuned/controlled by introducing proper steroid skeletons/hydrophobes. Noteworthy, among the lipids, Cho-Arg showed remarkably high gene transfection efficacy, even under high serum concentration (50% fetal bovine serum), making it an efficient gene transfection agent for practical application.

Amphiphilic Diblock Terpolymer PMAgala-b-P(MAA-co-MAChol)s with Attached Galactose and Cholesterol Grafts and Their Intracellular pH-Responsive Doxorubicin Delivery.

In this work, a series of diblock terpolymer poly(6-O-methacryloyl-D-galactopyranose)-b-poly(methacrylic acid-co-6-cholesteryloxy hexyl methacrylate) amphiphiles bearing attached galactose and cholesterol grafts denoted as the PMAgala-b-P(MAA-co-MAChol)s were designed and prepared, and these terpolymer amphiphiles were further exploited as a platform for intracellular doxorubicin (DOX) delivery. First, employing a sequential RAFT strategy with preliminarily synthesized poly(6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose) (PMAIpGP) macro-RAFT initiator and a successive trifluoroacetic acid (TFA)-mediated deprotection, a series of amphiphilic diblock terpolymer PMAgala-b-P(MAA-co-MAChol)s were prepared, and were further characterized by NMR, Fourier transform infrared spectrometer (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and a dynamic contact angle testing instrument (DCAT). In aqueous media, spontaneous micellization of the synthesized diblock terpolymer amphiphiles were continuously examined by critical micellization concentration assay, dynamic light scattering (DLS), and transmission electron microscopy (TEM), and the efficacies of DOX loading by these copolymer micelles were investigated along with the complexed nanoparticle stability. Furthermore, in vitro DOX release of the drug-loaded terpolymer micelles were studied at 37 °C in buffer under various pH conditions, and cell toxicities of as-synthesized diblock amphiphiles were examined by MTT assay. Finally, with H1299 cells, intracellular DOX delivery and localization by the block amphiphile vectors were investigated by invert fluorescence microscopy. As a result, it was revealed that the random copolymerization of MAA and MAChol comonomers in the second block limited the formation of cholesterol liquid-crystal phase and enhanced DOX loading efficiency and complex nanoparticle stability, that ionic interactions between the DOX and MAA comonomer could be exploited to trigger efficient DOX release under acidic condition, and that the diblock terpolymer micellular vector could alter the DOX trafficking in cells. Hence, these suggest the pH-sensitive PMAgala-b-P(MAA-co-MAChol)s might be further exploited as a smart nanoplatform toward efficient antitumor drug delivery.

Radical-mediated divergent cyclization of benzamides toward perfluorinated or cyanated isoquinolinediones.

A simple and efficient copper-controlled divergent cyclization of benzamides, which leads to perfluorinated or cyanated isoquinolinediones, is developed. In the presence of AIBN, methacryloyl benzamides with perfluoroalkyl iodides undergo cascade radical addition/cyclization to afford perfluoroinated isoquinolinediones as the major product under metal-free conditions, whereas the use of CuI (10 mol%) is able to redirect the cyclization to yield isoquinolinediones bearing an α-cyano quaternary carbon center. The cyclization features controllable divergent synthesis and a broad substrate scope as well as highly practical reaction conditions, thereby making this strategy a highly attractive means to fluorinate or cyanate isoquinolinediones.

Synthesis of Perfluorinated Isoquinolinediones through Visible-Light-Induced Cyclization of Alkenes.

A novel visible-light-induced carboperfluoroalkylation of alkenes using perfluoroalkyl iodides and bromides as Rf sources, leading to isoquinoline-1,3-diones, was developed. This method offers rapid entry to perfluorinated isoquinoline-1,3(2H,4H)-diones from N-alkyl-N-methacryloyl benzamides under mild reaction conditions, allowing for the incorporation of a wide variety of perfluorinated groups such as CF3, C3F7, C4F9, C6F13, C8F17, C10F21, and CF2CO2Et.

Metal-free cascade cyclization of alkenes toward perfluorinated oxindoles.

A simple AIBN-mediated cyclization reaction of activated alkenes toward perfluorinated oxindoles is developed. In the presence of readily available AIBN, N-arylacrylamide and perfluoroalkyl iodides underwent perfluorination reaction to give perfluorinated oxindoles in good to excellent yields under metal-free conditions.

Smart stimuli-responsive strategies for titanium implant functionalization in bone regeneration and therapeutics.

With the increasing and aging of global population, there is a dramatic rise in the demand for implants or substitutes to rehabilitate bone-related disorders which can considerably decrease quality of life and even endanger lives. Though titanium and its alloys have been applied as the mainstream material to fabricate implants for load-bearing bone defect restoration or temporary internal fixation devices for bone fractures, it is far from rare to encounter failed cases in clinical practice, particularly with pathological factors involved. In recent years, smart stimuli-responsive (SSR) strategies have been conducted to functionalize titanium implants to improve bone regeneration in pathological conditions, such as bacterial infection, chronic inflammation, tumor and diabetes mellitus, etc. SSR implants can exert on-demand therapeutic and/or pro-regenerative effects in response to externally applied stimuli (such as photostimulation, magnetic field, electrical and ultrasound stimulation) or internal pathology-related microenvironment changes (such as decreased pH value, specific enzyme secreted by bacterial and excessive production of reactive oxygen species). This review summarizes recent progress on the material design and fabrication, responsive mechanisms, and in vitro and in vivo evaluations for versatile clinical applications of SSR titanium implants. In addition, currently existing limitations and challenges and further prospective directions of these strategies are also discussed.

Natural alkaloids from Dicranostigma leptopodum (Maxim.) Fedde and their G5. NHAc-PBA dendrimer-alkaloid complexes for targeting chemotherapy in breast cancer MCF-7 cells.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.