A Novel PTP1B Inhibitor-Phosphate of Polymannuronic Acid Ameliorates Insulin Resistance by Regulating IRS-1/Akt Signaling.

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). Low-molecular-weight polymannuronic acid phosphate (LPMP) was found to be a selective PTP1B inhibitor with an IC50 of 1.02 ± 0.17 µM. Cellular glucose consumption was significantly elevated in insulin-resistant HepG2 cells after LPMP treatment. LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Western blot and polymerase chain reaction (PCR) analysis demonstrated that LPMP could enhance insulin sensitivity through the PTP1B/IRS/Akt transduction pathway. Furthermore, animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. Taken together, LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed.

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an In Situ Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer.

Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRASG12V). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo. This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.

Sodium alginate and alginic acid as pharmaceutical excipients for tablet formulation: Structure-function relationship.

Alginic acid and its sodium salt are well-accepted pharmaceutical excipients fulfilling several roles in the development of solid oral dosage forms. Although they have attractive advantages as safety, abundance, relatively low cost and biodegradability, these natural polysaccharides possess a high variability that may limit their use as excipients for tablet formulation. Thus, to obtain robust formulations and high-quality drug products with consistent performance a complete understanding of the structure-property relationship becomes necessary as the structure of alginates affects both, technological and biopharmaceutical properties. This review compiles the compaction studies carried out that relate the structure of alginates to their mechanical and dissolution performances. The different analytical methods used to determine the chemical composition, primary structure and molecular weight distribution, major factors affecting the behavior of alginates in direct compression, are also exposed. Finally, different strategies reported to improve the properties of alginic acid as direct compression excipient are discussed.

A bone replacement-type calcium phosphate cement that becomes more porous in vivo by incorporating a degradable polymer.

This study investigated whether mixing low viscosity alginic acid with calcium phosphate cement (CPC) causes interconnected porosity in the CPC and enhances bone replacement by improving the biological interactions. Furthermore, we hypothesized that low viscosity alginic acid would shorten the setting time of CPC and improve its strength. CPC samples were prepared with 0, 5, 10, and 20% low viscosity alginic acid. After immersion in acetate buffer, possible porosification in CPC was monitored in vitro using scanning electron microscopy (SEM), and the setting times and compressive strengths were measured. In vivo study was conducted by placing CPC in a hole created on the femur of New Zealand white rabbit. Microcomputed tomography and histological examination were performed 6 weeks after implantation. SEM images confirmed that alginic acid enhanced the porosity of CPC compared to the control, and the setting time and compressive strength also improved. When incorporating a maximum amount of alginic acid, the new bone mass was significantly higher than the control group (P = 0.0153). These biological responses are promising for the translation of these biomaterials and their commercialization for clinic applications.

Fermentation of alginate and its derivatives by different enterotypes of human gut microbiota: Towards personalized nutrition using enterotype-specific dietary fibers.

Alginate and its derivatives are widely used as food additives and dietary fibers. Previous studies indicated that alginate, polyguluronate (PG) and polymannuronate acid (PM) could be fermented by human gut microbiota. However, how different compositions of the microbiota may affect the fermentation outcomes of these polysaccharides remains unknown. Here we show that Bacteroides-dominated microbiota (Bacteroides enterotype) is more proficient at degrading and utilizing PG and PM as compared to Prevotella-dominated (Prevotella enterotype) and Escherichia-dominated microbiota (Escherichia enterotype). Enterotype dictates the fermentation outcomes of the three fibers and the amount of short-chain fatty acids (SCFAs) that are produced. Fermentation of alginate and PM by Bacteroides-dominated microbiota produced the highest amount of total SCFAs and butyrate. Our study demonstrates an enterotype-specific effect of microbiota on the fermentation of alginate and its derivatives and highlights that personalized nutrition using dietary fibers should be tailored according to individual's composition of the gut microbiome.

Identification of a polyphenol and its antioxidant properties from the roasting reaction of alginic acid.

The radical scavenging activity of marine polysaccharides was enhanced by their high-temperature treatment (roasting reaction model). The product obtained from alginic acid exhibited maximum activity, and a radical scavenger, alginetin, was identified in the product. Its antioxidant activities were examined by chemical methods, which confirmed that it possessed a stoichiometrically greater antioxidant capacity than that of Trolox.

Preparation and evaluation of conjugate nanogels of glycyl-prednisolone with natural anionic polysaccharides as anti-arthritic delivery systems.

Although prednisolone (PD) is used as an anti-arthritis drug due to its rapid and strong anti-inflammatory potential, its frequent and large dosing often brings about adverse effects. Therefore, targeting therapy has attracted increasing attention to overcome such adverse effects. In the present study, nanogels (NGs) composed of macromolecule-PD conjugates were developed as a novel targeting delivery system, and their anti-inflammatory potential was examined. Conjugates were prepared by carbodiimide coupling between glycyl-prednisolone (GP) and the natural anionic polysaccharides, alginic acid (AL) and hyaluronic acid (HA). NGs were produced by the evaporation of organic solvent from the conjugate solution. The obtained NGs, named AL-GP-NG and HA-GP-NG, respectively, were examined for particle characteristics, in vitro release, pharmacokinetics, and in vivo efficacy. Both NGs were several hundred nanometers in size, had negative zeta potentials, and several % (w/w) drug contents. They released PD gradually at pH 7.4 and 6. They exhibited fairly good retention in the systemic circulation. In the efficacy examination using rats with adjuvant-induced arthritis, both NGs showed the stronger and more prolonged suppression of paw inflammation than PD alone. These suggested that the present NGs should be possibly useful as anti-arthritis targeting therapeutic systems.

Bioactivity of alginetin, a caramelization product of pectin: Cytometric analysis of rat thymic lymphocytes using fluorescent probes.

Alginetin is the major product formed from pentoses and hexurionic acids. Alginetin is producted by cooking process of food including pection, a naturally-occurring polysacharride found in many plants. However, the biological interaction and toxicity of alginetin are not known at all. The aim of the present study was to investigate the cellular actions of alginetin on rat thymic lymphocytes. The effects of alginetin on the cell were examined using flow cytometry with fluorescent probes. Alginetin increased cellular content of non-protein thiols ([NPT]i) and elevated intracellular Zn2+ levels ([Zn2+]i). Chelation of intracellular Zn2+ reduced the effect of alginetin on [NPT]i, and chelation of external Zn2+ almost completely diminished alginetin-induced elevation of [Zn2+]i, indicating that alginetin treatment increased Zn2+ influx. Increased [NPT]i and [Zn2+]i levels in response to alginetin were positively correlated. Alginetin protected cells against oxidative stress induced by hydrogen peroxide and Ca2+ overload by calcium ionophore. It is considered that the increases in [NPT]i and [Zn2+]i are responsible for the cytoprotective activity of alginetin because NPT attenuates oxidative stress and Zn2+ competes with Ca2+. Alginetin may be produced during manufacturing of jam, which may provide additional health benefits of jam.

Bioinspired adenine-dopamine immobilized polymer hydrogel adhesives for tissue engineering.

Nontoxic adhesive hydrogels are of great importance in tissue engineering. Herein, we report a simple synthesis of a few biocompatible hydrogels from adenine and dopamine immobilized polyacrylic acid (PAA) and alginic acid (Alg) polymers. The adenine-dopamine adduct incorporated hydrogels showed enhanced adhesiveness, transparency and biocompatibility, and induced cell proliferation in 2D and 3D-cell culture models within 24 h. Moreover, blending the modified PAA and Alg polymers (P2P4) further increased the stability and bioactivity of the hydrogel. Such biogels can be developed as smart materials for biomedical applications.

Microencapsulation of immunoglobulin Y: optimization with response surface morphology and controlled release during simulated gastrointestinal digestion.

Immunoglobulin Y (IgY) is an effective orally administered antibody used to protect against various intestinal pathogens, but which cannot tolerate the acidic gastric environment. In this study, IgY was microencapsulated by alginate (ALG) and coated with chitooligosaccharide (COS). A response surface methodology was used to optimize the formulation, and a simulated gastrointestinal (GI) digestion (SGID) system to evaluate the controlled release of microencapsulated IgY. The microcapsule formulation was optimized as an ALG concentration of 1.56% (15.6 g/L), COS level of 0.61% (6.1 g/L), and IgY/ALG ratio of 62.44% (mass ratio). The microcapsules prepared following this formulation had an encapsulation efficiency of 65.19%, a loading capacity of 33.75%, and an average particle size of 588.75 µm. Under this optimum formulation, the coating of COS provided a less porous and more continuous microstructure by filling the cracks on the surface, and thus the GI release rate of encapsulated IgY was significantly reduced. The release of encapsulated IgY during simulated gastric and intestinal digestion well fitted the zero-order and first-order kinetics functions, respectively. The microcapsule also allowed the IgY to retain 84.37% immune-activity after 4 h simulated GI digestion, significantly higher than that for unprotected IgY (5.33%). This approach could provide an efficient way to preserve IgY and improve its performance in the GI tract.

Structures, properties and application of alginic acid: A review.

Alginic acid is a natural polysaccharide, which has been widely concerned and applied due to its excellent water solubility, film formation, biodegradability and biocompatibility. This paper briefly describes the source, properties, structure and application of sodium alginate by summarizing and analyzing the current literature. This paper reviews the application of sodium alginate in the fields of food industry, catalyst, health, water treatment, packaging, immobilized cells, and looks forward to its application prospects.

Dual Release Model to Evaluate Dissolution Profiles from Swellable Drug Polyelectrolyte Matrices.

BACKGROUND: Mathematical modeling in modified drug release is an important tool that allows predicting the release rate of drugs in their surrounding environment and elucidates the transport mechanisms involved in the process. OBJECTIVE: The aim of this work was to develop a mathematical model that allows evaluating the release profile of drugs from polymeric carriers in which the swelling phenomenon is present. METHODS: Swellable matrices based on ionic complexes of alginic acid or carboxymethylcellulose with ciprofloxacin were prepared and the effect of adding the polymer sodium salt on the swelling process and the drug release was evaluated. Experimental data from the ciprofloxacin release profiles were mathematically adjusted, considering the mechanisms involved in each stage of the release process. RESULTS: A proposed model, named "Dual Release" model, was able to properly fit the experimental data of matrices presenting the swelling phenomenon, characterized by an inflection point in their release profile. This entails applying the extended model of Korsmeyer-Peppas to estimate the percentage of drug released from the first experimental point up to the inflection point and then a model called Lumped until the final time, allowing to adequately represent the complete range of the drug release profile. Different parameters of pharmaceutical relevance were calculated using the proposed model to compare the profiles of the studied matrices. CONCLUSION: The "Dual Release" model proposed in this article can be used to predict the behavior of complex systems in which different mechanisms are involved in the release process.

Structure-Properties Relationship in the Evaluation of Alginic Acid Functionality for Tableting.

The aim of this study is to investigate the relationship between the structural, molecular, and particulate properties of alginic acid and its functional characteristics in direct compression (tabletability, compressibility, elasticity, deformation mechanism, and disintegration ability). Therefore, accurate characterization of two different batches of alginic acid was executed (X-ray powder diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, 1H nuclear magnetic resonance, size exclusion chromatography - multi angle light scattering, viscosimetry, carboxylic acid titration, powder flowability, true density, laser granulometry). Results showed that molecular weight seems to affect tablet properties and that the alginic acid with the lowest molecular weight provides the hardest tablets with the lowest elastic recovery. Furthermore, these results show the potential interest of exploiting alginic acid as filler excipient in tablet formulation. Finally, disintegration properties of tested materials were found to be close to that of commercial superdisintegrants (Glycolys® and Kollidon Cl®) but not correlated to their swelling force. It can be concluded, for the first time, that the determination of alginic acid molecular weight seems key for applications in direct compression and in particular for obtaining tablets with reproducible strength.

Amido-amine derivative of alginic acid (AmAA) for enhanced adsorption of Pb(II) from aqueous solution.

The present work reports the alternate synthesis of amido-amine derivative of alginic acid (AmAA) with high degree of functionalization. The AmAA have been characterized for percentage functionalization, functional group change, surface morphology and thermal decomposition behavior. The results indicate that the amido-amine derivatisation of alginic acid (AA) with >95% functionalization, significantly improves its Pb(II) adsorption efficiency (395.72 mg/g to 535.87 mg/g) over the AA. The equilibrium and kinetic studies showed that Langmuir and Freundlich adsorption isotherm models fitted well to the experimental data, and these followed pseudo-second order kinetic model. The FTIR (Fourier transform infrared spectroscopy) and 13C CP-MAS NMR (Cross-polarization magic angle spinning carbon-13 solid state nuclear magnetic resonance spectroscopy) analysis revealed that Pb(II) binds to the carboxyl group in case of AA and to the carbonyl & amine group in case of AmAA, which leads to increase in its adsorption efficiency. The study concludes that the functionalization of amido-amine on AA improves its adsorptive efficiency for Pb(II) from aqueous medium.

Synthesis of a novel magnetic starch-alginic acid-based biomaterial for drug delivery.

The magnetic composite hydrogel was fabricated by the graft copolymerization of itaconic acid (IA) onto starch and Alginic acid in the presence graphene sheets (Gr) and Fe3O4 nanoparticles (Fe3O4@Gr-IA/St-Alg) for Guaifenesin (GFN) delivery and wound healing. The Fe3O4@Gr-IA/St-Alg biomaterial is a hydrogel network endowed the material with magnetic property. In addition, GFN not only achieved effectively bound to the magnetic hydrogel, but also released in a controlled manner. The using external magnetic field has significantly positive influence on the drug release rate. To close, these hydrogel drug carriers offer a favorable platform for magnetically targeted drug delivery as well as a dress for wound healing.

Composition, isolation, purification and biological activities of Sargassum fusiforme polysaccharides: A review.

Sargassum fusiforme polysaccharides, acidic water-soluble polysaccharides extract from Sargassum fusiforme, are mainly composed of alginic acid, fucoidan and laminaran. Alginic acid is carboxyl-containing polysaccharide formed by joining ß-D-mannuronic acid and α-L-guluronic acid through ß-(1→4)/α-(1→4) glycosidic bond. Fucoidan, a natural water-soluble sulfated heteropolysaccharide with fucose and sulfuric acid groups as the core structure, is mainly linked by L-fucose through α-(1→3) glycosidic bond and has the strongest biological activity. Laminaran is mainly composed of ß-D-glucose through ß-(1→3) glycosidic bond linkage. Sargassum fusiforme polysaccharides have a variety of pharmacological activities, including antioxidant, anti-tumor, promoting immunity, anti-aging, prompting bone growth, lowering blood glucose, anti-coagulation, anti-virus, anti-bacteria, anti-fatigue, promoting growth and development, and skin protection. These activities are closely related to the functions of fucoidan in Sargassum fusiforme polysaccharides, which fucoidan is able to strengthen immune system and antioxidation in human body. In this review, the composition, the isolation and purification, and the biological activities of Sargassum fusiforme polysaccharides are discussed and can bereference for further study.

Microencapsulation of immunoglobulin Y: optimization with response surface morphology and controlled release during simulated gastrointestinal digestion / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Immunoglobulin Y (IgY) is an effective orally administered antibody used to protect against various intestinal pathogens, but which cannot tolerate the acidic gastric environment. In this study, IgY was microencapsulated by alginate (ALG) and coated with chitooligosaccharide (COS). A response surface methodology was used to optimize the formulation, and a simulated gastrointestinal (GI) digestion (SGID) system to evaluate the controlled release of microencapsulated IgY. The microcapsule formulation was optimized as an ALG concentration of 1.56% (15.6 g/L), COS level of 0.61% (6.1 g/L), and IgY/ALG ratio of 62.44% (mass ratio). The microcapsules prepared following this formulation had an encapsulation efficiency of 65.19%, a loading capacity of 33.75%, and an average particle size of 588.75 μm. Under this optimum formulation, the coating of COS provided a less porous and more continuous microstructure by filling the cracks on the surface, and thus the GI release rate of encapsulated IgY was significantly reduced. The release of encapsulated IgY during simulated gastric and intestinal digestion well fitted the zero-order and first-order kinetics functions, respectively. The microcapsule also allowed the IgY to retain 84.37% immune-activity after 4 h simulated GI digestion, significantly higher than that for unprotected IgY (5.33%). This approach could provide an efficient way to preserve IgY and improve its performance in the GI tract.

Structural and biochemical characterisation of a novel alginate lyase from Paenibacillus sp. str. FPU-7.

A novel alginate lyase, PsAly, with a molecular mass of 33 kDa and whose amino acid sequence shares no significant similarity to other known proteins, was biochemically and structurally characterised from Paenibacillus sp. str. FPU-7. The maximum PsAly activity was obtained at 65 °C, with an optimum pH of pH 7-7.5. The activity was enhanced by divalent cations, such as Mg2+, Mn2+, or Co2+, and inhibited by a metal chelator, ethylenediaminetetraacetic acid. The reaction products indicated that PsAly is an endolytic enzyme with a preference for polymannuronate. Herein, we report a detailed crystal structure of PsAly at a resolution of 0.89 Å, which possesses a ß-helix fold that creates a long cleft. The catalytic site was different from that of other polysaccharide lyases. Site-directed mutational analysis of conserved residues predicted Tyr184 and Lys221 as catalytic residues, abstracting from the C5 proton and providing a proton to the glycoside bond, respectively. One cation was found to bind to the bottom of the cleft and neutralise the carboxy group of the substrate, decreasing the pKa of the C5 proton to promote catalysis. Our study provides an insight into the structural basis for the catalysis of alginate lyases and ß-helix polysaccharide lyases.

Recent progress in nanoformulations of silver nanoparticles with cellulose, chitosan, and alginic acid biopolymers for antibacterial applications.

Nanotechnology presents the new aspect of material as nanomaterials (NMs) with unique properties such as the large surface area to the volume ratio compared to bulk types. Metal and polymer nanoparticles (NPs) are two major groups of NMs with various medicinal and non-medicinal applications. The rise of antibiotic resistance in microorganisms in general, and bacteria in particular, has necessitated the use of these NMs as novel antibacterial agents. In this regard, medicinal usage of natural polymers particularly cellulose, chitosan, and alginic acid are increasing due to their higher biocompatibility, biodegradability, and accessibility than to other biopolymers or synthetic polymers. Antibacterial activities of these polysaccharides can be improved by incorporation of silver NPs as nanocomposite (NC) forms. Therefore, in this review, recent advances related to nanoformulations of silver NPs with three biopolymers having antibacterial and biocompatibility properties have been discussed.

Oxidized alginate/gelatin decorated silver nanoparticles as new nanocomposite for dye adsorption.

In the current article di-aldehyde alginate (DAA) crosslinking gelatin (Ge) hydrogel was prepared and investigated for stabilizing silver nanoparticles. DAA/Ge decorated silver nanoparticles hydrogel was characterized by IR, XRD, TGA, SEM and AFM. The outcomes demonstrate that silver nanoparticles with uniform sizes were homogenously distributed through DAA/Ge hydrogel. DAA/Ge decorated silver nanocomposite was examined for the rejection of methylene blue (MB) from aqueous solutions. Comparing with DAA/Ge hydrogel, the nanocomposite has high efficiency for removal of MB. The highest MB removal efficiency was observed at pH 7 and the adsorption process is well described by pseudo-second order and Langmuir adsorption model with adsorption capacity of 625 mg/g. Our results proved that the DAA/Ge/Ag nanocomposite could be used for removal of MB from decontaminated solutions.