Hyperbranched polyphosphates (HBPPs) are newly emerged polymeric biomaterials with repeating phosphate bonds in a highly branched framework over the past 5 years. Due to the integration of the ...advantages of both hyperbranched polymers and polyphosphates, HBPPs are versatile in chemical structure, flexible in physicochemical properties, water soluble, biocompatible and biodegradable in biological features. On the basis of their excellent water solubility, biocompatibility, biodegradability and potential functionalization as well as their simple preparation in one-pot synthesis, HBPPs have fascinating biomedical applications, especially for drug delivery. In this tutorial review, the recent advances of HBPPs are summarized. HBPPs with different topological structures and various functionalities were synthesized
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adjusting the side group of cyclic phosphate monomers, which have shown promising biomedical applications, for example, using as a macromolecular anticancer agent and constructing advanced drug delivery systems, including site-specific delivery systems, self-delivery systems, and stimuli-responsive delivery systems. Such progress may promote the further development of interdisciplinary research between polymer chemistry, material science and biomedicine.
This review covers the recent development of hyperbranched polyphosphates, including synthesis, functionalization and biomedical applications, that may promote the interdiscipline research among dendritic polymers, functional material, and biomedicine.
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Sodium polyphosphate is a linear polymer formed from phosphate units linked together by sharing oxygen atoms. Addition of calcium to a solution of sodium polyphosphate results in ...phase separation and formation of a polyphosphate coacervate best described as a polymeric rich viscoelastic material. Polyphosphate coacervate is an interesting candidate as a biomaterial based on its ability to bind with different cations and to be loaded with drugs. Here, in vitro degradation and hemostatic properties of polyphosphate coacervates are comprehensively evaluated. We show that polyphosphate coacervates degrade and dissolve at a fast rate, losing half of their original mass in a week and transforming to mainly pyrophosphate after 4weeks. This burst dissolution phase happens earlier for the coacervate prepared from very short chain polyphosphate but overall using longer polyphosphate chains does not increase the coacervate longevity significantly. Substitution of Ca with Sr or Ba does not affect the hydrolysis of coacervates but slows down their dissolution into the media. In a whole blood clotting assay, coacervates profoundly decrease the clotting time especially when very long chain polyphosphates are used. While coacervate chain length and divalent cation type were found to significantly affect prothrombin time and thromboplastin time compared to the control, no discernible trends were observed. Platelets adhere in large numbers to coacervates, especially those containing long chain polyphosphate, but the cell morphology observed suggests that they might not to be fully activated. Overall, the long chain polyphosphate coacervate holds a great potential as a resorbable hemostatic agent.
Divalent cation additions to a sodium polyphosphate solution result in polyphosphate coacervates, or highly viscous gel-like materials, having great potential in bio-applications such as drug delivery and hemostasis. As these coacervates degrade in aqueous environments, we undertook a comprehensive evaluation to better understand the impact of polyphosphate chain length and divalent cation substitution on this hydrolytic response in order to better predict degradation behavior in the body. Furthermore, there is great interest in the role of polyphosphates in hemostasis following recent publications showing that platelets secrete polyphosphates upon thrombin stimulation. In this paper, we evaluate the hemostatic potential of polyphosphate coacervates as bulk constructs, demonstrating that indeed these materials hold great potential as a degradable hemostatic agent.
The diphosphoinositol polyphosphates (PP‐IPs) represent a novel class of high‐energy phosphate‐containing messengers which control a wide variety of cellular processes. It is thought that PP‐IPs ...exert their pleiotropic effects as allosteric regulators and through pyrophosphorylation of protein substrates. However, most details of PP‐IP signaling have remained elusive because of a paucity of suitable tools. We describe the synthesis of PP‐IP bisphosphonate analogues (PCP‐IPs), which are resistant to chemical and biochemical degradation. While the two regioisomers 1PCP‐IP5 and 5PCP‐IP5 inhibited Akt phosphorylation with similar potencies, 1PCP‐IP5 was much more effective at inhibiting its cognate phosphatase hDIPP1. Furthermore, the PCP analogues inhibit protein pyrophosphorylation because of their inability to transfer the β‐phosphoryl group, and thus enable the distinction between PP‐IP signaling mechanisms. As such, the PCP analogues will find widespread applications for the structural and biochemical characterization of PP‐IP signaling properties.
Stable analogues of high‐energy messengers: Bisphosphonate analogues of the diphosphoinositol polyphosphate (PP‐IP) messengers are resistant to chemical and biochemical degradation. The compounds mimic the natural counterparts well when proteins are regulated allosterically by PP‐IPs, but have an opposing effect in protein pyrophosphorylation. Thus, the compounds can be used to elucidate PP‐IP signaling properties.
PAGE is often used to resolve inorganic polyphosphates (polyP), but unfortunately polyP size ladders are not commercially available. Since several dyes that are commonly used to detect nucleic acids ...in gels also stain polyP, we examined the utility of commercially available DNA size ladders for estimating polyP polymer lengths by gel electrophoresis. Narrow size fractions of polyP were prepared and their polymer lengths were quantified using NMR. Commercially available DNA ladders and these polyP fractions were then subjected to PAGE to determine the relationship between migration of DNA vs polyP, which was found to be: log10(dsDNA length in bp) = 1.66 × log10(polyP length in phosphate units) − 1.97. This relationship between DNA and polyP size held for a variety of different polyacrylamide concentrations, indicating that DNA size ladders can readily be employed to estimate polyP polymer lengths by PAGE.
Probiotics exhibit beneficial effects on human health, particularly in the maintenance of intestinal homeostasis in a complex manner notwithstanding the diversity of an intestinal flora between ...individuals. Thus, it is highly probable that some common molecules secreted by probiotic and/or commensal bacteria contribute to the maintenance of intestinal homeostasis and protect the intestinal epithelium from injurious stimuli. To address this question, we aimed to isolate the cytoprotective compound from a lactobacillus strain, Lactobacillus brevis SBC8803 which possess the ability to induce cytoprotective heat shock proteins in mouse small intestine. L. brevis was incubated in MRS broth and the supernatant was passed through with a 0.2-µm filter. Caco2/bbe cells were treated with the culture supernatant, and HSP27 expression was evaluated by Western blotting. HSP27-inducible components were separated by ammonium sulfate precipitation, DEAE anion exchange chromatography, gel filtration, and HPLC. Finally, we identified that the HSP27-inducible fraction was polyphosphate (poly P), a simple repeated structure of phosphates, which is a common product of lactobacilli and other bacteria associated with intestinal microflora without any definitive physiological functions. Then, poly P was synthesized by poly P-synthesizing enzyme polyphosphate kinase. The synthesized poly P significantly induced HSP27 from Caco2/BBE cells. In addition, Poly P suppressed the oxidant-induced intestinal permeability in the mouse small intestine and pharmacological inhibitors of p38 MAPK and integrins counteract its protective effect. Daily intrarectal administration of poly P (10 µg) improved the inflammation grade and survival rate in 4% sodium dextran sulfate-administered mice. This study, for the first time, demonstrated that poly P is the molecule responsible for maintaining intestinal barrier actions which are mediated through the intestinal integrin β1-p38 MAPK.
Summary
The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein‐kinin system and the procoagulant intrinsic coagulation pathway. ...Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy‐associated increase in bleeding, renewing interest in the FXIIa‐driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross‐road of inflammation, coagulation, and innate immunity.
The mechanisms of heavy metal resistance in microbial cells involve multiple pathways. They include the formation of complexes with specific proteins and other compounds, the excretion from the cells ...via plasma membrane transporters in case of procaryotes, and the compartmentalization of toxic ions in vacuoles, cell wall and other organelles in case of eukaryotes. The relationship between heavy metal tolerance and inorganic polyphosphate metabolism was demonstrated both in prokaryotic and eukaryotic microorganisms. Polyphosphates, being polyanions, are involved in detoxification of heavy metals through complex formation and compartmentalization. The bacteria and fungi cultivated in the presence of some heavy metal cations contain the enhanced levels of polyphosphate. In bacteria, polyphosphate sequesters heavy metals; some of metal cations stimulate an exopolyphosphatase activity, which releases phosphate from polyphosphates, and MeHPO
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ions are then transported out of the cells. In fungi, the overcoming of heavy metal stresses is associated with the accumulation of polyphosphates in cytoplasmic inclusions, vacuoles and cell wall and the formation of cation/polyphosphate complexes. The effects of knockout mutations and overexpression of the genes encoding polyphosphate-metabolizing enzymes on heavy metal resistance are discussed.
Graphical abstract
In the process of tumorigenesis and development, cancer cells must integrate and respond to complex and dynamic signals in the tumor microenvironment. Nevertheless, simulating the original ...biomechanical and biochemical microenvironment of different cells in vitro is a fundamental challenge in studying synergistic effects. To address this issue, we have proposed a biomimetic multi-factor stimulation platform, which conveniently creates a two-dimensional matrix environment with controllable stiffness as biomechanical factor and can smoothly introduce biochemical cue. Our results indicated that the extracellular matrix (ECM) stiffness could enhance the cell stretching, which further lead to the amplification of cell-matrix adhesion and proliferation. And there existed obvious differences of endocytosis efficiency response of cells on matrix stiffness. Nanoparticles (NPs) with the same size and shape, but differs in electrical charges showed more uptake on harder matrix. Besides, the inorganic polyphosphates (polyP), which acts as energy storage and producer in the in-extracellular space, was proven to synergistically promote aforementioned cell biomechanical behaviors by increasing ATP metabolism for the first time. These results explored the impact of microenvironmental performance on the glioma mechanoresponses, and we believe this biomimetic multifactor stimulation method would exhibit a profound impact on researches of in vitro biomimetic cell culture and NPs-like drug phagocytosis.
Matrix stiffness and inorganic polyphosphates have been identified to jointly promote some behaviors of glioma for the first time. Display omitted
•Introduction of a biomimetic multi-factor stimulation platform.•Simulation of near-physiological glioma tumor microenvironment on PAA platform.•Stiffer matrix could enhance glioma response to stretch, ATP metabolism and cell endocytosis of nanoparticles.•The precise collaboration of substrate stiffness and inorganic polyphosphates (polyP) are highlighted.
Abstract The covalently modified ureido-conjugated chitosan/TPP multifunctional nanoparticles have been developed as targeted nanomedicine delivery system for eradication of Helicobacter pylori. ...H. pylori can specifically express the urea transport protein on its membrane to transport urea into cytoplasm for urease to produce ammonia, which protects the bacterium in the acid milieu of stomach. The clinical applicability of topical antimicrobial agent is needed to eradicate H. pylori in the infected fundal area. In this study, we designed and synthesized two ureido-conjugated chitosan derivatives UCCs-1 and UCCs-2 for preparation of multifunctional nanoparticles. The process was optimized in order to prepare UCCs/TPP nanoparticles for encapsulation of amoxicillin. The results showed that the amoxicillin-UCCs/TPP nanoparticles exhibited favorable pH-sensitive characteristics, which could procrastinate the release of amoxicillin at gastric acids and enable the drug to deliver and target to H. pylori at its survival region effectively. Compared with unmodified amoxicillin-chitosan/TPP nanoparticles, a more specific and effective H. pylori growth inhibition was observed for amoxicillin-UCCs/TPP nanoparticles. Drug uptake analysis tested by flow cytometry and confocal laser scanning microscopy verified that the uptake of FITC-UCCs-2/TPP nanoparticles was associated with urea transport protein on the membrane of H. pylori and reduced with the addition of urea as competitive transport substrate. These findings suggest that the multifunctional amoxicillin-loaded nanoparticles have great potential for effective therapy of H. pylori infection. They may also serve as pharmacologically effective nanocarriers for oral targeted delivery of other therapeutic drugs to treat H. pylori.
In wastewater treatment plants (WWTPs), aeration is the major energetic cost, thus its minimisation will improve the cost-effectiveness of the process. This study shows that both the dissolved oxygen ...(DO) concentration and aerobic hydraulic retention time (HRT) affect the competition between polyphosphate accumulating organisms (PAOs) and glycogen accumulating organisms (GAOs). At low DO levels, Accumulibacter PAOs were shown to have an advantage over Competibacter GAOs, as PAOs had a higher oxygen affinity and thus largely maintained their aerobic activity at low DO levels, while GAO activity decreased. Bioreactor operation at low DO levels was found to increase the PAO fraction of the sludge. Furthermore, an increase in aerobic HRT (at a DO level of 2 mg O2/L), promoted the proliferation of GAOs over PAOs, decreasing the EBPR efficiency. Overall, this study shows that low aeration can be beneficial for EBPR performance through selecting for PAOs over GAOs, which should be incorporated into WWTP models in order to minimise energetic costs and improve WWTP sustainability.
•DO concentration and aerobic hydraulic retention time affect the PAO–GAO competition.•PAOs present an advantage over GAOs at low aeration inputs.•PAOs have a significantly higher affinity for oxygen than GAOs.•Low aeration can be used as an operational strategy to reduce GAOs.
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