Songshan Shi

Mechanisms underlying the effect of polysaccharides in the treatment of type 2 diabetes: A review

Type 2 diabetes mellitus, a common metabolic and endocrine disorder worldwide, causes severe health and economic problems. At present, pharmacotherapy involving synthetic diabetic agents is clinically administered for diabetic therapy, which has certain side effects. Fortunately, various natural polysaccharides have anti-diabetic activity and use of these polysaccharides as adjuncts to conventional therapies is increasing in developing countries. A literature search was conducted to obtain relevant information of anti-diabetic polysaccharide from electronic databases, namely PubMed, Web of Science, ScienceDirect, and Springer, for the period 2011-2015. In total, 114 types of polysaccharides from 78 kinds of natural sources, namely plants, fungi, algae, animals, and bacteria, have shown anti-diabetic properties. In vivo and in vitro experiments have shown that administering these polysaccharides has hypoglycaemic effects and alleviates β-cell dysfunction in addtion to eliciting other anti-diabetic activities which are equally efficient to even more efficient than those of synthetic diabetic agents.

Structure characterization of an arabinogalactan from green tea and its anti-diabetic effect

A water-soluble polysaccharide, 7WA, with an average molecular mass of 7.1×10(4)Da, was isolated from the leaves of green tea. Monosaccharide composition analysis indicated that 7WA mainly contained Arabinose and Galactose in the molar ratio of 1.0:0.96. By using the methods of methylation analysis, partial hydrolysis, and NMR, 7WA was characterized to possess a backbone consisting of 1,3- and 1,6-linked galactopyranosyl residues, with branches attached to O-3 of 1,6-linked galactose residues, and O-4 and O-6 of 1,3-linked galactose residues. The results of glucose-stimulated insulin secretion (GSIS) showed that 7WA significantly augmented insulin secretion at high glucose level (25mM), however, such effect was not seen at low glucose level (5mM). The mechanism study results indicated 7WA, a type II arabinogalactan from Green Tea, enhances GSIS through cAMP-PKA pathway.

A RG-II type polysaccharide purified from Aconitum coreanum alleviates lipopolysaccharide-induced inflammation by inhibiting the NF-κB signal pathway.

Korean mondshood root polysaccharides (KMPS) isolated from the root of Aconitum coreanum (Lévl.) Rapaics have shown anti-inflammatory activity, which is strongly influenced by their chemical structures and chain conformations. However, the mechanisms of the anti-inflammatory effect by these polysaccharides have yet to be elucidated. A RG-II polysaccharide (KMPS-2E, Mw 84.8 kDa) was isolated from KMPS and its chemical structure was characterized by FT-IR and NMR spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The backbone of KMPS-2E consisted of units of [→6) -β-D-Galp (1→3)-β-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-Galp-(1→] with the side chain →5)-β-D-Arap (1→3, 5)-β-D-Arap (1→ attached to the backbone through O-4 of (1→3,4)-L-Rhap. T-β-D-Galp is attached to the backbone through O-6 of (1→3,6)-β-D-Galp residues and T-β-D-Ara is connected to the end group of each chain. The anti-inflammatory effects of KMPS-2E and the underlying mechanisms using lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages and carrageenan-induced hind paw edema were investigated. KMPS-2E (50, 100 and 200 µg/mL) inhibits iNOS, TLR4, phospho-NF-κB–p65 expression, phosphor-IKK, phosphor-IκB-α expression as well as the degradation of IκB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS and IL-6) mediated by the NF-κB signal pathways in macrophages. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) in a dose-dependent manner and it reduced NF-κB DNA binding affinity by 62.1% at 200µg/mL. In rats, KMPS-2E (200 mg/kg) can significantly inhibit carrageenan-induced paw edema as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation.

Homogalacturonans from Preinfused Green Tea: Structural Characterization and Anticomplementary Activity of Their Sulfated Derivatives

Two homogeneous water-soluble polysaccharides (TPSR4-2B and TPSR4-2C) were obtained from preinfused green tea. Their average molecular weights were estimated to be 41 kDa and 28 kDa, respectively. A combination of composition, methylation, and configuration analysis, as well as NMR spectroscopy, indicated that both TPSR4-2B and TPSR4-2C were poly-(1-4)-α-d-galactopyranosyluronic acid in which 30.5 ± 0.3% and 28.3 ± 0.5%, respectively, of uronic acid existed as methyl ester. Two sulfated derivatives (Sul-R4-2B and Sul-R4-2C) from TPSR4-2B and TPSR4-2C were prepared after sulfation with a 2:1 chlorosulfonic acid-pyridine ratio. The anticomplementary assay showed that Sul-R4-2B and Sul-R4-2C demonstrated a stronger inhibitory effect on the complement activation through the classic pathway, compared to that of heparin. Preliminary mechanism studies by using complement component depleted-sera indicated that both Sul-R4-2B and Sul-R4-2C selectively interact with C1q, C1r, C1s, C2, C5, and C9 but not with C3 and C4. The relationship between DS and the anticomplementary activity of sulfated derivatives of homogalacturonans showed that low sulfated derivatives of homogalacturonans also exhibited potent anticomplementary effect, which might greatly reduce the side effects related to heparin and oversulfated chondroitin sulfate, such as anticoagulant activity and allergic-type reaction. These results suggested that sulfated derivatives of homogalacturonans might be promising drug candidates for therapeutic complement inhibition.

Structure analysis of a heteropolysaccharide from Taraxacum mongolicum Hand.-Mazz. and anticomplementary activity of its sulfated derivatives.

A homogenous water-soluble polysaccharide, DPSW-A, with a deduced chemical structure was extracted from the herb Taraxacum mongolicum Hand.-Mazz. Moreover, 80.813-kDa DPSW-A is composed of three types of monosaccharide, namely rhamnose, arabinose, and galactose, at a molar ratio of 1.0:10.7:11.9. The main chain of DPSW-A contains Terminal-Galp, 1,3-Galp, 1,6-Galp, 1,3,6-Galp, and 1,2,4-Rhap; the branched chain contains Terminal-Araf, 1,5-Araf, and 1,3,5-Araf. The sulfated derivatives prepared from DPSW-A showed inhibitory effects on complement activation through the classical pathway (CH50: Sul-DPSW-A, 3.94±0.43μg/mL; heparin, 104.40±3.82μg/mL) and alternative pathway (AP50: Sul-DPSW-A, 42.76±0.46μg/mL; heparin, 43.42±0.22μg/mL). Mechanism studies indicated that Sul-DPSW-A inhibited complement activation by blocking C1q, C1r, C1s, and C9, but not C2, C3, C4, and C5. In addition, Sul-DPSW-A displayed limited anticoagulant effects. These results suggest that Sul-DPSW-A prepared from DPSW-A is valuable for treating diseases caused by excessive complement system activation.

Structure of a homofructosan from Saussurea costus and anti-complementary activity of its sulfated derivatives.

A homogeneous water-soluble polysaccharide APS-W1, (2→1)-β-d-fructofuranosan, with an average molecular weight of 3.9kDa, was isolated and characterized from the roots of Saussurea costus. Five sulfated derivatives of APS-W1 with different degrees of sulfation were prepared and they showed strong inhibitory effect on the complement activation through the classical pathway (CP50: 2.2-18.9μg/mL; 8.3μg/mL for heparin) and alternative pathway (AP50: 11.4-115.8μg/mL; 89.2μg/mL for heparin). Mechanism studies by using complement-depleted sera indicated that sulfated derivatives with different positions of sulfation targeted to different complement proteins. Meanwhile the sulfated derivatives have limited anticoagulant effect based on re-calcification time and thrombin time. These results suggested that the sulfated derivatives prepared from APS-W1 could be promising potential complement inhibitors for the treatment of diseases caused by an over-activated complement system.

Neutral monosaccharide composition analysis of plant-derived oligo- and polysaccharides by high performance liquid chromatography.

A novel analytical method for neutral monosaccharide composition analysis of plant-derived oligo- and polysaccharides was developed using hydrophilic interaction liquid chromatography coupled to a charged aerosol detector. The effects of column type, additives, pH and column temperature on retention and separation were evaluated. Additionally, the method could distinguish potential impurities in samples, including chloride, sulfate and sodium, from sugars. The results of validation demonstrated that this method had good linearity (R(2) ≥ 0.9981), high precision (relative standard deviation ≤ 4.43%), and adequate accuracy (94.02-103.37% recovery) and sensitivity (detection limit: 15-40 ng). Finally, the monosaccharide compositions of the polysaccharide from Eclipta prostrasta L. and stachyose were successfully profiled through this method. This report represents the first time that all of these common monosaccharides could be well-separated and determined simultaneously by high performance liquid chromatography without additional derivatization. This newly developed method is convenient, efficient and reliable for monosaccharide analysis.

Structural Features and Anti-Complement Activity of an Acidic Polysaccharide from Forsythia suspensa

Background: The complement system is an important host defence mechanism against the invasion of foreign materials. However, excessive or uncontrolled activation of the complement system might lead to severe complement-mediated disorders which are harmful to human bodies. There are still no desirable therapeutic compounds available on the market for complement inhibition. In recent years, researches have been focused on natural polysaccharides to modulate of the immune system because of their immunomodulatory activities and safety. In this study, Fs-8-ba2, a homogeneous acidic polysaccharide (MW ca. 7.2 kDa) was isolated from Forsythia suspensa and its anti-complementary effect was investigated. Method: The major primary structural features of Fs-8-ba2 were elucidated using HPGPC, IR, absolute configuration, component analysis and methylation analysis, periodate oxidation, carboxyl reduction partial acid hydrolysis, and NMR spectroscopy, etc. To identify the anti-complementary activity of Fs-8-ba2, the hemolytic assays through the classical pathway (CP) and the alternative pathway (AP) of complement system in vitro were taken. Results: The backbone of Fs-8-ba2 was composed of 7 homogalacturonan (HG) and 2 rhamnogalacturonan (RG-I) moieties with the side chains attached at O-4 of 1,2,4-linked α-L-Rha in the RG-I moieties. The anti-complement assay showed that the native acidic polysaccharide (Fs-8-ba2) possessed stronger inhibitory effect on the complement activation than the carboxyl-reduced polysaccharide (Fs-8-ba2re) through the classical (IC50: 0.311 ± 0.020 mg/mL vs. 3.292 ± 0.032 mg/mL) and alternative pathways (IC50: 0.218 ± 0.015 mg/mL vs. no activity). It indicated that the anti-complement effect of pectic polysaccharide was related to GalA content (carboxyl group). Preliminary mechanism studies by using complement-depleted sera indicated that Fs-8-ba2 selectively interacted with C1q, C1r, C1s, C2, C3 and C9, but not C4 and C5. Conclusion: These results suggested that Fs-8-ba2, an acidic polysaccharide, could be of potential benefits in the treatment of the complement-mediated diseases.

Hypoglycemic effect and mechanism of a pectic polysaccharide with hexenuronic acid from the fruits of Ficus pumila L. in C57BL/KsJ db/db mice

In this study, a particular pectic polysaccharide (FPLP) was extracted and purified from the fruits of Ficus pumila Linn. through boiling water extraction, alcohol precipitation, diethylaminoethyl-Sepharose Fast Flow chromatography and Superdex™ G-75 gel filtration chromatography. Analysis of high-performance gel permeation chromatography, FTIR, GC-MS, methylation and 1D/2D NMR spectroscopy revealed that FPLP (Mw: 34.69kDa) is a linear (1,4)-α-d-galacturonic acid binding 1.30% branched chain hexenuronic acid with 23.34% methyl esterification. Treatment with FPLP ameliorated hyperglycaemia in association with an improvement in hepatic glycogen metabolism in C57BL/KsJ db/db mice. The activation of IRS-1/PI3K/Akt/GSK3β/GS insulin signalling pathway and AMPK/GSK3β/GS signalling pathway and the regulation of glucokinase, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expressions involved in hepatic glycogenesis and glycogenolysis were considered the therapeutic mechanisms of FPLP. These results provide a new insight for investigating the effects of pectic polysaccharides on blood glucose control and suggest that FPLP is a promising nutraceutical for treatment of T2DM.

Can highly cited herbs in ancient Traditional Chinese medicine formulas and modern publications predict therapeutic targets for diabetes mellitus

ETHNOPHARMACOLOGICAL RELEVANCE The prevalence of diabetes among all age groups worldwide was estimated to be more than 382 million in 2013. Traditional Chinese medicine (TCM) has been practiced for thousands of years, and substantial valuable experience and prescriptions have been accumulated in the TCM system for the treatment of diabetes. In recent decades, a large amount of experimental and clinical data has been published on the use of herbal medicines related to these ancient TCM prescriptions. AIM OF THE STUDY This study aimed to discover a method for the investigation of potential antidiabetic herbs from the large amount of data in ancient TCM formulas and modern publications and to verify this method through an in vitro bioactivity study. MATERIALS AND METHODS In our review, the most frequently cited TCM herbs were selected as potential antidiabetic herb candidates on the basis of TCM philosophical theory (ancient TCM formulas) and Western medicine philosophical theory (modern publications). The ethanol and aqueous extracts of the selected herbs were screened for their α-glucosidase inhibitory, glucose-stimulated insulin secretion (GSIS), and intestinal glucose transport inhibitory effects. RESULTS Twelve herbs [Terminalia chebula Retz., fructus immaturus, dried; Poria cocos (Schw) Wolf., sclerotium, dried; Zea mays L., stigma, dried; Pueraria lobata (Willd.) Ohwi, radix, dried; Cucurbita moschata (Duch. ex Lam.) Duch. ex Poiret, fructus, dried; Lycium barbarum L., fructus, dried; Glycine max (L.) Merr., semen, fermented; Glycyrrhiza uralensis Fisch., radix and rhizoma, dried; Dioscorea opposita Thunb., rhizoma, dried; Morus alba L., folium, dried, Morus alba L., fructus, dried; and Polygonatum odoratum (Mill.) Druce, rhizoma, dried] were finally selected as candidates with potential glucose-lowering effects after a review was performed of herbs that are frequently cited in ancient TCM formulas and modern publications. The bioactive study results demonstrated that both the ethanol extracts and crude polysaccharides of M. alba L., fructus, dried, and M. alba L., folium, dried, and the crude polysaccharides of T. chebula Retz., fructus immaturus, dried, exhibited α-glucosidase inhibitory effects. Moreover, the crude polysaccharides of P. cocos (Schw) Wolf., sclerotium, dried; Z. mays L., stigma, dried; and T. chebula Retz., fructus immaturus, dried, exhibited favorable GSIS effects, and the ethanol extracts of P. odoratum (Mill.) Druce, rhizoma, dried; T. chebula Retz., fructus immaturus, dried; and G. uralensis Fisch., radix and rhizoma, dried, significantly decreased glucose transport across the cell monolayer. CONCLUSIONS Our review and the preliminary bioactive study revealed that 10 of the 12 recommended edible TCM herbs had favorable antidiabetic effects, demonstrating that TCM herbs with a high prescription and publication frequency may provide insights into the potential therapeutic targets of diabetes mellitus and may aid in the discovery of effective compounds complementary to currently used medicines. Such a literature and medicine review is a useful method of exploring potential antidiabetic herbs by using the wealth of information in ancient TCM formulas and modern publications.