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The carrageenans isolated from red algae demonstrated a variety of activities from antiviral and immunomodulatory to antitumor. The diverse structure and sulfation profile of carrageenans provide a great landscape for drug development. In this study, we isolated, purified and structurally characterized κo- and λo- oligosaccharides from the marine algae Chondrus armatus . We further examined the tumor suppressive activity of both carrageenans in gastrointestinal cancer models. Thus, using MTT assay, we could demonstrate a pronounced antiproliferative effect of the carrageenans in KYSE-30 and FLO-1 as well as HCT-116 and RKO cell lines with IC 50 184~405 μg/mL, while both compounds were less active in non-cancer epithelial cells RPE-1. This effect was stipulated by the inhibition of cell cycle progression in the cancer cells. Specifically, flow cytometry revealed an S phase delay in FLO-1 and HCT-116 cells under κo-carrageenan treatment, while KYSE-30 demonstrated a pronounced G 2 /M cell cycle delay. In line with this, western blotting revealed a reduction of cell cycle markers CDK2 and E2F2. Interestingly, κo-carrageenan inhibited cell cycle progression of RKO cells in G 1 phase. Finally, isolated κo- and λo- carrageenans induced apoptosis on adenocarcinomas, specifically with high apoptosis induction in RKO cells. Overall, our data underline the potential of κo- and λo- carrageenans for colon and esophageal carcinoma drug development.

Neurodegenerative diseases are growing to become one of humanity's biggest health problems, given the number of individuals affected by them. They cause enough mortalities and severe economic impact to rival cancers and infections. With the current diversity of pathophysiological mechanisms involved in neurodegenerative diseases, on the one hand, and scarcity of efficient prevention and treatment strategies, on the other, all possible sources for novel drug discovery must be employed. Marine pharmacology represents a relatively uncharted territory to seek promising compounds, despite the enormous chemodiversity it offers. The current work discusses one vast marine region-the Northwestern or Russian Pacific-as the treasure chest for marine-based drug discovery targeting neurodegenerative diseases. We overview the natural products of neurological properties already discovered from its waters and survey the existing molecular and cellular targets for pharmacological modulation of the disease. We further provide a general assessment of the drug discovery potential of the Russian Pacific in case of its systematic development to tackle neurodegenerative diseases.

Photodynamic therapy (PDT) represents a powerful avenue for anticancer treatment. PDT relies on the use of photosensitizers-compounds accumulating in the tumor and converted from benign to cytotoxic upon targeted photoactivation. We here describe (3 S ,4 S )-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (ETPA) as a major metabolite of the North Pacific brittle stars Ophiura sarsii . As a chlorin, ETPA efficiently produces singlet oxygen upon red-light photoactivation and exerts powerful sub-micromolar phototoxicity against a panel of cancer cell lines in vitro. In a mouse model of glioblastoma, intravenous ETPA injection combined with targeted red laser irradiation induced strong necrotic ablation of the brain tumor. Along with the straightforward ETPA purification protocol and abundance of O. sarsii , these studies pave the way for the development of ETPA as a novel natural product-based photodynamic therapeutic.

Triple-negative breast cancer (TNBC) represents the deadliest form of gynecological tumors currently lacking targeted therapies. The ethanol extract of the North Pacific brittle star Ophiura sarsii presented promising anti-TNBC activities. After elimination of the inert material, the active extract was submitted to a bioguided isolation approach using high-resolution semipreparative HPLC-UV, resulting in one-step isolation of an unusual porphyrin derivative possessing strong cytotoxic activity. HRMS and 2D NMR resulted in the structure elucidation of the compound as (3 S ,4 S )-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid. Never identified before in Ophiuroidea, porphyrins have found broad applications as photosensitizers in the anticancer photodynamic therapy. The simple isolation of a cytotoxic porphyrin from an abundant brittle star species we describe here may pave the way for novel natural-based developments of targeted anti-cancer therapies.

This review is devoted to the medical application of tetrodotoxin (TTX), a potent non-protein specific blocker of voltage-gated sodium (NaV) channels. The selectivity of action, lack of affinity with the heart muscle NaV channels, and the inability to penetrate the blood⁻brain barrier make this toxin an attractive candidate for anesthetic and analgesic drug design. The efficacy of TTX was shown in neuropathic, acute and inflammatory pain models. The main emphasis of the review is on studies focused on the improvement of TTX efficacy and safety in conjunction with additional substances and drug delivery systems. A significant improvement in the effectiveness of the toxin was demonstrated when used in tandem with vasoconstrictors, local anesthetics and chemical permeation enhancers, with the best results obtained with the encapsulation of TTX in microparticles and liposomes conjugated to gold nanorods.

Antitumor efficiency of fascaplysin synthetic derivatives (7-phenylfascaplysin, 3-chlorofascaplysin, 3-bromofascaplysin, and 10-bromofascaplysin) was compared out in vitro on C6 glioma cells. The cytotoxic efficiency of all tested compounds was higher than that of unsubstituted fascaplysin; 3-bromofascaplysin and 7-phenylfascaplysin exhibited the best capacity to kill glioma C6 cells. Apoptosis was the main mechanism of glioma cell death. The cytotoxic activity of these compounds increased with prolongation of exposure to the substance and increase of its concentration. Fascaplysin derivatives modified all phases of glioma cell vital cycle. The count of viable tumor cell in G0 phase remained minimum by the end of experiment under the effects of 3-bromofascaplysin and 7-phenylfascaplysin.

Pro-proliferative oncogenic signaling is one of the hallmarks of cancer. Specific targeting of such signaling pathways is one of the main approaches to modern anti-cancer drug discovery, as opposed to more traditional search for general cytotoxic agents. Natural products, especially from marine sources, represent a largely untapped source of chemical diversity, which so far have mostly been screened for cytotoxicity. Here we present a pioneering pipeline of high-throughput screening of marine-based activities targeted against the Wnt signaling pathway, which is one of the key factors in oncogenic transformation, growth and metastasis in different cancers, including the devastating triple-negative breast cancer (TNBC) currently lacking any targeted therapies. This pipeline consisted of collection and characterization of numerous invertebrates during the SokhoBio expedition to the Kuril Basin in North Pacific, preparation of extracts from these specimen, and their screening in dedicated assays monitoring Wnt signaling in TNBC cells. This approach yielded a number of promising hits, including highly specific anti-Wnt activities targeting multiple levels within the Wnt pathway from Ophiura irrorata and other Pacific brittle stars.

Glioblastoma multiforme is an aggressive malignant brain tumor with terminal consequences. A primary reason for its resistance to treatment is associated with cancer stem cells (CSCs), of which there are currently no effective ways to destroy. It remains unclear what cancer cells become a target of stem cell migration, what the role of this process is in oncogenesis and what stem cell lines should be used in developing antitumor technologies. Using modern post‑genome technologies, the present study investigated the migration of human stem cells to cancer cells in vitro, the comparative study of cell proteomes of certain stem cells (including CSCs) was conducted and stem cell migration in vivo was examined. Of all glioblastoma cells, CSCs have the stability to attract normal stem cells. Critical differences in cell proteomes allow the consideration of hematopoietic stem cells (HSCs) as an instrument for interaction with glioblastoma CSCs. Following injection into the bloodstream of animals with glioblastoma, the majority of HSCs migrated to the tumor‑containing brain hemisphere and penetrated the tumor tissue. HSCs therefore are of potential use in the development of methods to target CSCs.

Multiform glioblastoma is the most common primary, highly invasive, malignant tumor of the central nervous system, with an extremely poor prognosis. The median survival of patients following surgical resection, radiation therapy and chemotherapy does not exceed 12-15 months and thus, novel approaches for the treatment of the disease are required. The phenomenon of the directed migration of stem cells in tumor tissue presents a novel approach for the development of technologies that facilitate the targeted delivery of drugs and other therapeutic agents to the tumor foci. Hematopoietic cluster of differentiation (CD)34 + /CD133 + stem cells possess significant reparative potential and are inert with respect to normal neural tissue. The aim of the present study was to investigate the substantiation ability of adult hematopoietic progenitors to the directed migration of glioma cells. A C6 glioma cell line, a culture of hematopoietic CD34 + /CD133 + stem cells and primary cultures of rat astrocytes and fibroblasts were used. The cells were co-cultured for five days. The results revealed the formation of cell shaft hematopoietic stem cells on the perimeter of the culture inserts containing the glioma culture. However, this was not observed in the wells with fibroblast and astrocyte cultures. The results indicated that hematopoietic stem cells exhibit a high potential for the directional migration of C6 glioma cells, which allows them to be considered as a promising cell line for the development of novel anticancer biomedical technologies and increases our understanding with regard to previously unclear aspects of glial tumor carcinogenesis.

The mechanisms of therapeutic resistance of human glioblastoma multiforme are analyzed. The authors make an attempt at systematization and scientific theoretical validation of new approaches to creation of biomedical cellular preparations, based on the oncoproteomic technologies, for personified therapy of the glial tumors. A new approach to the treatment of glioblastoma multiforme with due consideration for the molecular biological characteristics of the tumor stem cells is suggested. It is shown that the tumor stem cell proteome can be regarded as the main target for cell therapy.

Lead (Pb) exposure, even at low levels, causes a variety of health problems. The aims of this study were to investigate the tissue distribution of lead in the bodies of rats, to evaluate lead removal from the internal organs and bones using calcium alginate in doses of 500, 200 and 100 mg/kg per day for 28 days and to assess the impact of calcium alginate on the level of essential elements. Lead (Pb), calcium (Ca), manganese (Mn), iron (Fe), copper (Cu) and zinc (Zn) levels in the blood, hearts, kidneys, livers and femurs of the experimental animals were measured using mass spectrometry with inductively coupled plasma. The results revealed that lead acetate exposure increased the levels of Pb in the blood and organs of the animals and significantly reduced contents of Ca, Mn, Fe, Cu and Zn. Treatment with calcium alginate in dose 500 mg/kg contributed to significant decreases in the amount of lead in the kidney, heart and bones of animals and a slight increase in the content of essential elements in the liver, kidneys and heart, although these changes were not significant. Decreasing of lead was not significant in the internal organs, bones and blood of animals treated with calcium alginate 200 and 100 mg/kg. Consequently, calcium alginate dose of 500 mg/kg more efficiently removes lead accumulated in the body. Calcium alginate does not have negative effect on level of essential elements quite the contrary; reducing the levels of lead, calcium alginate helps normalize imbalances of Ca, Mn, Fe, Cu and Zn. The results of this study suggest that calcium alginate may potentially be useful for the treatment and prevention of heavy metal intoxications.

The effects of nonstarch polysaccharides with different molecular weights on the development of Lewis' lung carcinoma and efficiency of cyclophosphamide therapy in mice were studied. Treatment with these substances with low molecular weights (<30 kDa) caused no changes in the primary tumor growth, but inhibited its metastasizing, while nonstarch polysaccharides with high molecular weights (>400 kDa) inhibited the growth of Lewis' lung carcinoma node. Antimetastatic effects of cyclophosphamide were stimulated by low and high molecular weight polysaccharides.

The effects of various alginate forms on the development of transplanted tumors in mice and efficiency of cytostatic therapy were studied. High-molecular-weight Ca and Na alginates, acid-soluble hydrolysate, and sodium alginate fraction inhibited the growth of Ehrlich adenocarcinoma. The use of acid-insoluble sodium alginate in chemotherapy protocol improved the treatment efficiency. All alginate forms inhibited metastasizing of Lewis pulmonary carcinoma; in combination with cyclophosphamide they potentiated its antimetastatic effect.

In vitro experiments showed that calcium pectate added to the culture medium produces a dose-dependent prebiotic effect on lacto-and bifidobacteria cultures and on non-pathogenic strain of Escherichia coli. Calcium pectate produced a pronounced bacteriostatic effect on Candida albicans strain; the effects was more pronounced in a concentration of 4%.

Cerium binding activity of different water soluble pectin compounds varying according to their degree of esterification and insoluble calcium pectate beads in aqueous solution was studied in a batch sorption system. The cerium uptake by all pectin compounds was highest within the pH range from 4.0 to 6.0. The binding capacities and rates of cerium ions by pectin compounds were evaluated. The Langmuir, Freundlich and BET sorption models were applied to describe the isotherms and constants. Sorption isothermal data could be well interpreted by the Langmuir equation. The results obtained through the study suggest that pectin compounds are favorable sorbents. The largest amount of cerium ions is bound by pectin with the degree of esterification close to zero. Therefore, it can be concluded that low esterified pectins are more effective substances for elimination of cerium ions from aqueous disposals., (2010 Elsevier B.V. All rights reserved.)

Carrageenans are abundant and safe non-starch polysaccharides exerting their biological effects in living organisms. Apart from their known pro-inflammation properties and some pharmacological activity, carrageenans can also strongly bind and hold metal ions. This property can be used for creation of the new drugs for elimination of metals from the body or targeted delivery of these metal ions for healing purposes. Metal binding activity of different carrageenans in aqueous solutions containing Y(3+) or Pb(2+) ions was studied in a batch sorption system. The metal uptake by carrageenans is not affected by the change of the pH within the range from 2.0 to 6.0. The rates and binding capacities of carrageenans regarding metal ions were evaluated. The Langmuir, Freundlich and BET sorption models were applied to describe the isotherms and constants, and the sorption isothermal data could be explained well by the Langmuir equation. The results obtained through the study suggest that kappa-, iota-, and lambda-carrageenans are favorable sorbents. The largest amount of Y(3+) and Pb(2+) ions are bound by iota-carrageenan. Therefore, it can be concluded that this type of polysaccharide is the more appropriate substance for elaboration of the drugs with high selective metal binding properties.

The zinc-binding activity of different water-soluble pectin compounds varying according to their degree of esterification and of insoluble calcium pectate beads in aqueous solution was studied in a batch sorption system. The zinc uptake by all pectin compounds was highest within the pH range from 4.0 to 7.0. The binding capacities and rates of zinc ions by pectin compounds were evaluated. The Langmuir, Freundlich, and BET sorption models were applied to describe the isotherms and constants. Sorption isotherm data could be well interpreted by the Langmuir equation. The results obtained through the study suggest that pectin compounds are favorable sorbents. The largest number of zinc ions are bound by pectin with the degree of esterification close to zero. Therefore, it can be concluded that low-esterified pectins are more effective substances for elimination of zinc ions from aqueous disposals.

Experiments on mice and rats with modeled neurogenic and indomethacin-induced injuries to the gastric mucosa showed that preventive courses of calcium alginate, calcium pectate, and low-esterified pectin improved the resistance of the gastroduodenal mucosa to the destructive effect of the above factors.

We studied the effects of low-esterified pectin, calcium pectate, and alginate on the development of transplanted Ehrlich adenocarcinoma and Lewis pulmonary carcinoma and on the efficiency of cyclophosphamide treatment in mice.

We studied the effects of low-esterified pectin and antistrumin in rats with hypofunction of the thyroid gland modeled by enteral administration of lead acetate. Pectin more rapidly recovered thyroid function than iodine.

We studied in vitro effects of charged polysaccharides on the classic and alternative pathways of complement activation. The complement system was affected by substances having different charges. Our findings suggest that the conformation of polysaccharide molecules, but not their charge, plays a primary role in the interaction with C1 and C3 complement components followed by initiation of cascade enzymatic reactions.

We studied the effects of aqueous knotweed extracts in alkeran-induced experimental pathozoospermia. Therapeutic effect of knotweed extract in experimental cytostatic hypogonadism was demonstrated (the preparation improved spermatozoon motility).