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Apoptotic effect of sulfated galactofucan from marine macroalga Turbinaria ornata on hepatocellular and ductal carcinoma cells

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Abstract

Tumor protein or cellular tumor antigen p53, is considered a critical transcriptional regulation factor, which can suppress the growth of tumor cells by activating other functional genes. The current study appraised the p53 activation pathways, which could be used as an alternative therapeutic strategy for the treatment of hepatocellular and ductal carcinoma. Algal polysaccharides have been used as emerging sources of bioactive natural pharmacophores. A sulfated galactofucan characterized as [→1)-O-4-sulfonato-α-fucopyranose-(3 → 1)-α-fucopyranose-(3→] as the main branch with [→1)-6-O-acetyl-β-galactopyranose-(4→] as side chain isolated from marine macroalga Turbinaria ornata exhibited prospective apoptosis on HepG2 (hepatocellular carcinoma) and MCF7 (ductal carcinoma) cells. Annexin V-fluorescein isothiocyanate-propidium iodide study displayed higher early apoptosis in MCF7 and HepG2 cell lines (56 and 24.2%, respectively) treated with TOP-3 (at IC50 concentration) than those administered with standard camptothecin. Upregulation of the p53 gene expression was perceived in TOP-3 treated HepG2 and MCF7 cells.

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In this study, a novel heteropolysaccharide named SP90–1 with immunostimulatory and antitumor activity was purified and characterized from Spirulina platensis. SP90–1 has a molecular weight of 63.92 kDa and mainly consists of rhamnose (Rha), glucose (Glc), galactose (Gal) and glucuronic acid (GlcA), followed by the minor components Fuc and Xyl. The backbone of SP90–1 was determined to be →2)-α-d-Rhap-(1 → 2,3)-α-d-Rhap-(1 → 4)-β-d-Glcp-(1 → [3)-β-d-Rhap-(1→]3, with branches at the O-3 of Rha, consisting of the side chains 4-Galp and 4-GlcpA. SP90–1 was found to significantly enhance phagocytic capacity, promote the secretion of nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in RAW264.7 cells, and remarkably inhibit the growth of A549 lung cancer cells. These findings demonstrate that SP90–1 could potentially be further explored for immunomodulatory biomedical applications.
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Consumption of marine alga-based polysaccharides as additional functional foods can endow with health benefits by diminishing the risk of chronic diseases. A polygalacto-fucopyranose characterized as [→1)-2, 4-SO3-α-Fucp-(3 → 1)-{2-SO3-α-Fucp-(3→}] with [(4 → 1)-6-OAc-β-Galp-(4→] side chain isolated from marine alga Sargassum wightii exhibited potential antihypertensive activity. Upon treatment with studied polygalactofucan (50 mg/kg BW), serum hypertension biomarkers troponin-T (1.3 pg/mL), troponin-I (1.2 μg/dL) and angiotensin-II converting enzyme (0.18 pg/mL) were significantly recovered in hypertensive rats compared to disease control. Serum cardiovascular risk indices of diseased rats were significantly decreased (< 10%, p < 0.05) after administration of the studied galactofucan (50 mg/kg BW) related to hypertension group (> 17%), and were comparable with standard antihypertensive agent telmisartan (8.3–10.2% at 2 mg/kg BW). The studied compound was safe for consumption as obvious from the high LD50 value (>5 g/kg), and could be developed as a prospective functional food ingredient attenuating the pathophysiological attributes causing hypertension-related conditions.
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Fucoidans from brown seaweed shows various bioactive properties and promising prospects in biomedical field. Here, a novel fucoidan (F-4) was extracted and purified from Durvillaea antarctica. The structure of F-4 was characterized by HPLC, HPGPC, GC-MS, together with IR and NMR spectral analysis. F-4 is a sulfated polysaccharide mainly composed of fucose (Fuc), galactose (Gal), and glucose (Glc) in a molar ratio of 26.4: 7.1: 1.0. The backbone of F-4 is composed of (1→3) and (1→4)-linked-α-L-Fucp residues, which sulfated at C-4 or C-2 positions and branched with α-L-Fuc, β-D-Gal, and β-D-Glc residues. Furthermore, F-4 can effectively promote the growth of leukocyte in a mouse model induced by cyclophosphamide, possibly by activating hematopoietic progenitor cells and regulating the hematopoietic microenvironment of bone marrow. Our data provide useful information for further investigation of fucoidan in the treatment of chemotherapy-induced leukopenia.
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Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87–0.96] at baseline and 0.98 [95% CI 0.97–1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
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To investigate and compare the effects of different extraction methods on the structure and anti-tumor activity of Ecklonia kurome polysaccharides (EP), three techniques, namely hot water extraction (HW), ultrasonic-assisted extraction (UA) and enzyme-assisted extraction (EA), were used to extract EP, and three crude EPs were purified by DEAE-cellulose and gel filtration chromatography. The significant antitumor active components in each method were screened by MTT assay and named as HW-EP5, UA-EP4 and EA-EP3, respectively. The molecular weight, FT-IR assay and NMR showed that HW-EP5, UA-EP4 and EA-EP3 were pyran polysaccharides with a molecular weight of 14466, 15922 and 16947 Da, respectively. HW-EP5 contained the most monosaccharides and the highest content of sulfate and uronic acid. HW-EP5 had an even and smooth sheet-like appearance, while UA-EP4 and EA-EP3 exhibited irregular and rough fragments. All three polysaccharides can inhibit the migration of human breast cancer cells (MCF-7) and promote its apoptosis. All three polysaccharides promoted caspase activity during apoptosis. HW-EP5 and UA-EP4 up-regulated the expression of proapoptotic proteins Bax and p53, while EA-EP3 only up-regulated the expression of p53. These experimental results indicate that Ecklonia kurome polysaccharides, especially HW-EP5, have great potential as a natural medicine for the treatment of breast cancer.
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Poor pancreatic cancer (PC) prognosis has been attributed to its resistance to apoptosis and propensity for early systemic dissemination. Existing therapeutic strategies are often circumvented by the molecular crosstalk between cell-signalling pathways. p53 is mutated in more than 50% of PC and NFκB is constitutively activated in therapy-resistant residual disease; these mutations and activations account for the avoidance of cell death and metastasis. Recently, we demonstrated the anti-PC potential of fucoidan extract from marine brown alga, Turbinaria conoides (J. Agardh) Kützing (Sargassaceae). In this study, we aimed to characterize the active fractions of fucoidan extract to identify their select anti-PC efficacy, and to define the mechanism(s) involved. Five fractions of fucoidan isolated by ion exchange chromatography were tested for their potential in genetically diverse human PC cell lines. All fractions exerted significant dose-dependent and time-dependent regulation of cell survival. Fucoidans induced apoptosis, activated caspase -3, -8 and -9, and cleaved Poly ADP ribose polymerase (PARP). Pathway-specific transcriptional analysis recognized inhibition of 57 and 38 nuclear factor κB (NFκB) pathway molecules with fucoidan-F5 in MiaPaCa-2 and Panc-1 cells, respectively. In addition, fucoidan-F5 inhibited both the constitutive and Tumor necrosis factor-α (TNFα)-mediated NFκB DNA-binding activity in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB-dependent luciferase activity further substantiate the inhibitory potential of seaweed fucoidans on NFκB. Moreover, fucoidan(s) treatment increased cellular p53 in PC cells and reverted NFκB forced-expression-related p53 reduction. The results suggest that fucoidan regulates PC progression and that fucoidans may target p53-NFκB crosstalk and dictate apoptosis in PC cells.
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Background: Turbinaria conoides, a brown seaweed, is a rich source of oxygenated fucosterols which are capable of suppressing the proliferation of cancer cells. Their specific therapeutically significant biological activity is directly related to the unique structural features of the molecule. This study specifically focuses on extracting unconventional sterol molecules (side chain extension) from this seaweed which can be used as a lead molecule to evolve therapeutical agents. Materials and Methods: To isolate unconventional sterol molecule, for structural elucidation and bioactivity study, sufficient amount of T. conoides was collected from Mandapam, an unique biodiverse environment along the Southeast coast of India. State-of-the-art methods available for the purification and characterization of molecule (High-resolution fast-atom bombardment mass spectrometry, ultraviolet-visible spectroscopy, attenuated total reflection–fourier transform infra-red, One-dimensional nuclear magnetic resonance, and two-dimensional nuclear magnetic resonance) were put in. In vitro bioassays (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide, double staining, and flowcytometry) were carried out against A549 and human liver cancer cell line (HepG2) malignant cells to assess the cytostatic potential. Data were statistically validated. Results: A unique unconventional sterol molecule (Turbiconol) with ethyl and methyl group at C-27 was isolated. This molecule induced apoptosis in A549 and HepG2. However, cell cycle assessment revealed G0/G1 cell cycle arrest in Hep G2 and G2/M checkpoint was responsible for the suppression of A549 cell line. Conclusion: A novel unconventional compound, turbiconol, is reported in this study. In vitro results highlight the potential of this molecule in developing therapeutical combination which can be used for novel treatment methods.
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Marine sponge alkaloid aaptamine is a promising anti-bacterial and anti-cancer drug against ESBL producing Gram negative bacteria and HepG 2 human liver carcinoma cell line. The antibacterial activity of aaptamine against selected ESBL producing Gram negative bacteria was inhibited at the concentration of 55 µg/mL. At the minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) of 50 µg/mL, the aaptamine was significantly effective against all the ESBL positive uropathogens. Importantly, the inhibition was much high compared to other marine compounds through intracellular damage and morphological modification by confocal laser scanning electron microscope (CLSM) and scanning electron microscope (SEM). Further, the cytotoxic efficacy of aaptamine against HepG 2 cells was showed at 75 µg/mL very effectively and this concentration was indicated as IC50 dose. The morphological and intracellular nuclear damage of aaptamine treated HepG 2 cell was detected by florescence microscope using acridine orange/ethidium bromide (AO/EB) combination and Hoechst 33342 staining assays. The nuclear fragmentation of aaptamine treated HepG 2 cells were confirmed by expression of Caspase-9, Caspase-8, Caspase-3 cleavage, which provide the suggestion for the induction of intrinsic and extrinsic apoptosis pathways. In addition, the western blot analysis of appatamine treated HepG 2 cells also confirmed that the expression genes were damaged and the aaptamine showed dose and time dependent relationship. Hence, our findings suggest, the marine natural compounds aaptamine might be a potential alternative agents for ESBL producing uropathogens and human liver cancer therapy.
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Sulfated polysaccharides owe important space in therapeutics, since they exhibit promising biological activities. Their role in cancer alleviation was described in various literatures, but most of them failed to explain the molecular mechanism behind. In the present study, we determined the elemental composition, purity and molecular weight of sulfated polysaccharides, ESPs-CP, isolated and purified from the brown marine algae Padina tetrastromatica. The elemental analysis proved the presence of essential elements, UV visible spectroscopy revealed the absence of any impurities and GPC analysis showed the existence of both high and low molecular weight fractions in ESPs-CP. The anticancer potency of ESPs-CP was evaluated in Human cervical cancer cells, HeLa. IC50 value of ESPs-CP was 1.2 mg/ml and at this concentration, they could induce prominent apoptosis in the cells. There was also an obvious ROS generation and mitochondrial membrane depolarization imparted by ESPs-CP. The expression of genes in the apoptotic cascade such as p53, PUMA, PMAIP, BAX, BCL2, CASP9, CASP3 showed unique alterations in the presence of ESPs-CP. The results substantiated that the mechanism behind the anticancer effect of ESPs-CP is the induction of ROS mediated intrinsic pathway of apoptosis.
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Hydrocolloids from seaweeds (phycocolloids) have interesting functional properties like antiproliferative activity. Marine algae consumptions are linked to law cancer incidences in countries that traditionally consume marine products. In this study, we have investigated water-soluble sulfated polysaccharides isolated from the red seaweed Laurencia papillosa and determined their chemical characteristics and biological activities on the human breast cancer cell line MCF-7. Total polysaccharides were extracted and fractionated from L. papillosa and characterized using FTIR-ATR and NMR spectrometry. In addition, their approximate molar mass was determined by GPC method. The chemical characterization of purified polysaccharides reveals the presence of sulfated polysaccharides differentially dispersed in the algal cell wall. They are the three types of carrageenan, kappa, iota and lambda carrageenans, named LP-W1, -W2 and -W3 respectively. Biological effects and cytotoxicity of the identified of the three sulfated polysaccharide fractions were evaluated in MCF-7 cell line. Our results showed a significant inhibition of MCF-7 cell viability by dose-dependent manner for cells exposed to LP-W2 and LP-W3 polysaccharides for 24hrs. The mechanistic of LP fractions-mediated apoptosis in MCF-7 cells was demonstrated. The biological effects of L. papillosa SPs indicate that it may be a promising candidate for breast cancer prevention and therapy.
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The ocean contains numerous marine organisms, including algae, animals, and plants, from which diverse marine polysaccharides with useful physicochemical and biological properties can be extracted. In particular, fucoidan, carrageenan, alginate, and chitosan have been extensively investigated in pharmaceutical and biomedical fields owing to their desirable characteristics, such as biocompatibility, biodegradability, and bioactivity. Various therapeutic efficacies of marine polysaccharides have been elucidated, including the inhibition of cancer, inflammation, and viral infection. The therapeutic activities of these polysaccharides have been demonstrated in various settings, from in vitro laboratory-scale experiments to clinical trials. In addition, marine polysaccharides have been exploited for tissue engineering, the immobilization of biomolecules, and stent coating. Their ability to detect and respond to external stimuli, such as pH, temperature, and electric fields, has enabled their use in the design of novel drug delivery systems. Thus, along with the promising characteristics of marine polysaccharides, this review will comprehensively detail their various therapeutic, biomedical, and miscellaneous applications.
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Antioxidant potential, total phenolic content, and high performance liquid chromatography-based solvent extract fingerprints of phenolic constituents of brown seaweeds, Turbinaria conoides, and Turbinaria ornata were evaluated. The ethyl acetate (EtOAc) fraction of the seaweeds registered greater phenolic content and antioxidant activities. Salicylic acid, gallic acid, quercetin, and syringic acid were predominant in the EtOAc fraction of T. conoides, while the main components in EtOAc fraction of T. ornata were quercetin and salicylic acid. This study demonstrated the candidacy of Turbinaria sp as potential source of antioxidant phenolics for use as food supplements and nutraceuticals to deter deleterious free radical-induced disorders and diseases.
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Laminaran and three fractions of fucoidan were isolated from brown alga Alaria angusta. The laminaran AaL was characterized as a typical 1,3;1,6-β-D-glucan (ratio of bonds 1,3:1,6=10:1). Fucoidans AaF1 and AaF2 are sulfated heteropolysaccharides, containing fucose, galactose, mannose and xylose. The fraction AaF3 is sulfated and acetylated galactofucan with the main chain represented by a repeating unit →3)-α-L-Fucp-(2,4-SO3(-))-(1→. According the data of methylation analysis, AaF3 contains mainly 1,3-linked fucose, less 1,4-linked and 1,4,6-linked galactose residues. The autohydrolysis (37°C) of fucoidan AaF3 allowed to obtain selectively 2-desulfaled polysaccharide fraction, built up of fucose only, and low molecular weight (LMW) fraction. The negative-ion tandem mass spectrometry of LMW fraction, further hydrolyzed by acid hydrolysis identified the following fragments: Gal-2-SO3(-)-(1→4)-Gal, Gal-4-SO3(-)-(1→4)-Gal, Gal-(1→2)-Gal-4-SO3(-), Fuc-2-SO3(-)-(1→4)-Gal, Gal-2-SO3(-)-(1→3)-Fuc-(1→3)-Fuc, Fuc-2-SO3(-)-(1→3)-Fuc-(1→4)-Gal. The laminaran AaL and the fucoidan AaF3 exhibited no cytotoxicity in vitro for HT 29, T-47D, and SK-MEL-28 cell lines. The AaF3 fraction suppressed colony formation of HT 29 and T-47D cells, AaL-only HT 29 cells. Copyright © 2015. Published by Elsevier Ltd.
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Carrageenans are sulfated galactan isolated from marine red algae with different disaccharide forms. There are also some hybrid carrageenan-like oligomers, which are reported to possess a number of bioactivities. Here, we describe a method to study the structural characterization of a carrageenan-like sulfated galactan FB1 extracted from the red seaweed Furcellaria lumbricalis. We show the process of the general analysis of FB1, including the molecular weight, sulfate content, total sugar content, protein content, and 3,6-anhydrogalactose (3,6-AnG) content analyses. The fine structure identification methods, including desulfation and methylation, nuclear magnetic resonance (NMR), and electrospray ionization collision induced dissociation tandem mass spectrometry (ES-CID-MS/MS), are also described in detail.
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Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway. Cancer Res; 74(24); 1-7. ©2014 AACR. ©2014 American Association for Cancer Research.
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New methylation procedures and the combined application of gas-liquid chromatography and mass spectrometry for the qualitative and quantitative analysis of mixtures of methylated sugars permit methylation analysis of polysaccharides to be performed more accurately, faster, and with less material than previously.
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Clostridium difficile is an anaerobic, spore-forming, gram-positive bacillus that can produce severe colitis resulting in death. There has been an overall increase in the incidence of Clostridium difficile-associated disease and, particularly, an increase in the more virulent forms of the disease. Treatment of severe C difficile infection includes management of severe sepsis and shock, pathogen-directed antibiotic therapy, and, in selected cases, surgical intervention. Ultimately, prevention is the key to limiting the devastating effects of this microorganism.