|Angiotensin-I-converting enzyme (ACE) inhibitors from marine resources: prospects in the pharmaceutical industry.|
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|PMID: 20479968 Owner: NLM Status: MEDLINE|
|Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 184.108.40.206; ACE) plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS) and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.|
|Isuru Wijesekara; Se-Kwon Kim|
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|Type: Journal Article; Research Support, Non-U.S. Gov't; Review Date: 2010-03-31|
|Title: Marine drugs Volume: 8 ISSN: 1660-3397 ISO Abbreviation: Mar Drugs Publication Date: 2010|
|Created Date: 2010-05-18 Completed Date: 2010-08-18 Revised Date: 2013-05-29|
Medline Journal Info:
|Nlm Unique ID: 101213729 Medline TA: Mar Drugs Country: Switzerland|
|Languages: eng Pagination: 1080-93 Citation Subset: IM|
|Marine Biochemistry Laboratory, Department of Chemistry, Pukyong National University, Busan 608-737, Korea. email@example.com|
|APA/MLA Format Download EndNote Download BibTex|
Angiotensin-Converting Enzyme Inhibitors
isolation & purification,
Biological Agents / adverse effects, isolation & purification, pharmacology*
Drug Industry / methods
Hypertension / drug therapy
Oligosaccharides / adverse effects, isolation & purification, pharmacology
Peptides / adverse effects, isolation & purification, pharmacology
Tannins / adverse effects, isolation & purification, pharmacology
|0/Angiotensin-Converting Enzyme Inhibitors; 0/Biological Agents; 0/Oligosaccharides; 0/Peptides; 0/Tannins|
Journal ID (nlm-ta): Mar Drugs
Journal ID (publisher-id): MD
Publisher: Molecular Diversity Preservation International
? 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland
Received Day: 19 Month: 2 Year: 2010
Revision Received Day: 8 Month: 3 Year: 2010
Accepted Day: 29 Month: 3 Year: 2010
collection publication date: Year: 2010
Electronic publication date: Day: 31 Month: 3 Year: 2010
Volume: 8 Issue: 4
First Page: 1080 Last Page: 1093
PubMed Id: 20479968
Publisher Id: marinedrugs-08-01080
|Angiotensin-I-Converting Enzyme (ACE) Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry|
1 Marine Biochemistry Laboratory, Department of Chemistry, Pukyong National University, Busan 608-737, Korea; E-Mail:
2 Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Korea
|Correspondence: *Author to whom correspondence should be addressed; E-Mail:
firstname.lastname@example.org; Tel.: +82-51-629-7094; Fax: +82-51-629-7099.
Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases [1,2] and it is a major health issue, estimated to be affecting about 20% of the world?s adult population . Among processes related to hypertension, angiotensin-I-converting enzyme (ACE) plays an important role in the regulation of blood pressure. ACE is a dipeptidyl carboxypeptidase (EC. 220.127.116.11) and was originally isolated from horse blood . It plays a crucial role in the regulation of blood pressure as it promotes the conversion of angiotensin-I to the potent vasoconstrictor angiotensin-II as well as inactivates the vasodilator bradykinin, which has a depressor action in the renin-angiotensin system. This potent vasoconstrictor is also involved in the release of a Na-retaining steroid, aldosterone from the adrenal cortex, which has a tendency to increase blood pressure .
Inhibition of ACE is considered to be a useful therapeutic approach in the treatment of hypertension. Therefore, in the development of drugs to control high blood pressure, ACE inhibition has become an important activity. Many studies have been attempted in the synthesis of ACE inhibitors such as captopril, enalapril, alcacepril and lisinopril, which are currently used in the treatment of essential hypertension and heart failure in humans . However, these synthetic drugs are believed to have certain side effects such as cough, taste disturbances, skin rashes or angioneurotic edema all of which might be intrinsically linked to synthetic ACE inhibitors . Therefore, the research and development to find safer, innovative, and economical ACE inhibitors is necessary for the prevention and remedy of hypertension [8,9]. Many research groups have combed for novel ACE inhibitors from natural products , microbial sources  and food proteins .
Marine organisms are rich sources of structurally diverse bioactive compounds. Hence, a great interest has been developed nowadays to isolate bioactive compounds, which act as ACE inhibitors from marine resources because of their numerous health beneficial effects. According to the researches, it has reported that marine-derived bioactive peptides, chitooligosaccharide derivatives (COS) and phlorotannins have potent ACE inhibitory activity. This review discusses the above three groups of marine-derived ACE inhibitors and their inhibitory properties, emphasizing their potential application as future pharmaceuticals to prevent hypertension.
Components of proteins in food are containing sequences of bioactive peptides, which could exert a physiological effect in the body. These short chains of amino acids are inactive within the sequence of the parent protein, but can be released during gastrointestinal digestion, food processing, or fermentation. Marine-derived bioactive peptides have been obtained widely by enzymatic hydrolysis of marine proteins [13?17]. In fermented marine food sauces such as blue mussel sauce and oyster sauce, enzymatic hydrolysis has already been done by microorganisms, and bioactive peptides can be purified without further hydrolysis [18,19]. In addition, several bioactive peptides have been isolated from marine processing by-products or wastes [20?23]. Marine by-products generated during marine food processing, have low commercial value, but the detection of in vitro ACE inhibitory activity in these products might provide significant environmental and cost benefits. Marine-derived bioactive peptides have been shown to possess many physiological functions, including antihypertensive or ACE inhibition , antioxidant [25,26], anticoagulant [27,28], and antimicrobial [29,30] activities. Moreover, some of these bioactive peptides have identified to possess nutraceutical potentials that are beneficial in human health promotion  and recently the possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular diseases has been shown .
Marine-derived antihypertensive peptides have shown potent ACE inhibitory activities (Table 1). The potency of these marine-derived peptides to inhibit ACE activity has been expressed as an IC50 value, which is the ACE inhibitor concentration, leading to 50% inhibition of ACE activity. Moreover, the inhibition modes of ACE-catalyzed hydrolysis of these antihypertensive peptides have been determined by Lineweaver-Burk plots.
According to Lineweaver-Burk plot studies, competitive ACE inhibitory peptides have most frequently reported [18,36,40]. These inhibitors can bind to the active site to block it or to the inhibitor binding site that is remote from the active site to alter the enzyme conformation such that the substrate no longer binds to the active sites. Moreover, tryptophan, tyrosine, proline or phenylalanine at the C-terminal and branched-chain aliphatic amino acids at the N-terminal is suitable for peptides to act as competitive inhibitors by binding with ACE . In addition, a non-competitive mechanism has also been observed in some peptides [35,52] and this means that the peptide can combine with an enzyme molecule to produce a dead-end complex, regardless of whether a substrate molecule is bound or not. The hydrophobicity of the N-terminus, which is one of the common features of ACE inhibitory peptides, may contribute to the inhibitory activity . ACE inhibitory peptides are generally short chain peptides, often carrying polar amino acid residues like proline. Furthermore, structure-activity relationships among various peptide inhibitors of ACE indicate that binding to ACE is strongly influenced by the C-terminal tripeptide sequence of the substrate, and it is suggested that peptides, which contain hydrophobic amino acids at these positions, are potent inhibitors .
Numerous in vivo studies of marine-derived antihypertensive peptides in spontaneously hypertensive rats have shown potent ACE inhibition activity [35,36,40,50] and their systolic blood pressure has reduced significantly after oral administration of peptides. According to Lee et al. , a single oral administration (10 mg/kg of body weight) of peptide has shown a strong suppressive effect on systolic blood pressure of spontaneously hypertensive rats and this antihypertensive activity was similar with captopril, a commercial antihypertensive drug. Furthermore, they have reported that no side effect observed on rats after administration of antihypertensive peptide. In addition, these marine bioactive peptides exhibit antihypertensive activity in vivo than in vitro. The exact mechanisms underlying this phenomenon have not yet been identified. However, it was suggested that bioactive peptides have higher tissue affinities and are subject to a slower elimination than captopril . The antihypertensive peptide isolated from bonito fish hydrolysate product, has found to be hydrolyzed by ACE to produce a smaller peptide than the initial one, which had 8-fold ACE inhibitory activity compared with the initial peptide .
Therefore, marine-derived bioactive peptides have a potential in use as functional ingredients in nutraceuticals and pharmaceuticals due to their effectiveness in both prevention and treatment of hypertension in addition to the nutritive value. Some antihypertensive synthetic commercial drugs are known to produce side effects such as an abnormal elevation of the blood pressure after administration. However, marine-derived bioactive peptides are well tolerated by the body, are not expected to exert any harmful side effects. In addition, cost effective and safe drugs can be produced from marine bioactive peptides, but further studies are needed with clinical trials for these marine-derived antihypertensive peptides.
Chitin is the second most abundant biopolymer on earth after cellulose and one of the most abundant polysaccharide . It is a glycan of ? (1?4)-linked N-acetylglucosamine units and it is widely distributed in crustaceans and insects as the protective exo-skeleton and cell walls of most fungi. Chitin is usually prepared from the shells of crabs and shrimps. Chitosan, a partially deacetylated polymer of N-acetylglucosamine, is prepared by alkaline deacetylation of chitin . Chitooligosaccharides (COS) are chitosan derivatives (polycationic polymers comprised principally of glucosamine units) and can be generated via either chemical or enzymatic hydrolysis of chitosan [57?59]. Recently, COS have been the subject of increased attention in terms of their pharmaceutical and medicinal applications , due to their missing toxicity and high solubility as well as their positive physiological effects such as ACE enzyme inhibition , antioxidant , antimicrobial , anticancer [64,65], immuno-stimulant , antidiabetic , hypocholesterolemic , hypoglycemic , anti-Alzheimer?s , anticoagulant  properties and adipogenesis inhibition .
Researches on chitosan and its derivative oligomers have identified their potential to inhibit ACE activity. Even though enough studies have not been carried out, it is presumed that COS may have desirable properties to inhibit ACE activity. Recently, marine-derived chitooligosaccharide (COS) derivatives such as hetero-chitooligosaccharides, aminoethyl chitooligosaccharides, chitin derivatives, chitosan trimer oligomers and carboxylated chitooligosaccharides have been reported as potent ACE inhibitors. They are briefly discussed below as well as summarized in Table 2.
Hong et al.  studied ACE inhibitory activity of different COS and identified that chitosan trimer is more effective in lowering blood pressure compared to other oligomers. Specifically, the trimer has a lower IC50 value (0.9 ?M) than most of the other molecular weight COS. In addition, Park et al.  reported the ACE inhibitory activities of different molecular weight COS or hetero-COS. ACE inhibitory activity of hetero-COS was dependent on the degree of deacetylation of chitosan. They have tested nine kinds of hetero-COS derivatives; prepared by 90%, 75% and 50% N-deacetylated of crab chitin with 40% NaOH solution and then each chitosan in to hetero-COS derivatives with relatively high molecular masses (5,000?10,000 Dalton), medium molecular masses (1,000?5,000 Dalton) and low molecular masses (below 1,000 Dalton) by ultrafiltration membrane bioreactor system. Among these hetero-COS, 50% deacetylated and medium molecular weight (1,000?5,000 Dalton) hetero-COS has exhibited the highest ACE inhibitory activity with the IC50 value of 1.22 mg/mL (Table 2.) and the inhibition pattern is competitive according to the Lineweaver-Burk plots. These findings suggested that molecular weight and degree of deacetylation of COS are important factors for the ACE inhibitory activity.
To develop ACE inhibitory chitin derivatives, chitin with different degrees of deacetylation have been chemically modified by grafting 2-chloroethylamino hydrochloride on to chitin at the C-6 position . Among three chitin derivatives, such as aminoethyl-chitin with 10% deacetylation (AEC), aminoethyl-chitin with 50% deacetylation (AEC50), and aminoethyl chitin with 90% deacetylation (AEC90), the strongest ACE inhibitor is aminoethyl-chitin with 50% deacetylation (IC50 value, 0.038 ?M) and the inhibition is competitive. Captopril was used as the positive control (IC50 value, 0.1 ?M) in this study. Moreover, in vivo studies have shown that it effectively decreased the systolic blood pressure of spontaneously hypertensive rats in a dose-dependent manner. When comparing with the IC50 values of previous studies, these three water-soluble chitin derivatives have superior ACE inhibitory activity than that of chitosan oligosaccharide derivatives and captopril .
Furthermore, the structural properties of chitosan also can be improved by chemical modification to obtain higher active COS derivatives. For example, aminoethyl-COS were synthesized by grafting aminoethyl functional group to improve its ACE inhibitory activity . Hydroxyl groups of the pyranose ring structure at different positions are different chemical attractions and hydroxyl group in the C-6 position was successfully replaced by the aminoethyl group because the structure of COS was maintained due to the C-6 hydroxyl group, which shows the highest reactivity for aminoethylation. Here, another advantage they acquired is that the aminoethyl COS derivatives are easily soluble in water. According to Ngo et al. , ACE inhibitory activity of aminoethyl-COS (AE-COS) has increased more than that of original COS. At the 2.5 ?g/mL concentration, COS and aminoethyl-COS exhibited ACE inhibitory activities of 18.6% and 89.3% respectively. Further, a marked dose-dependent inhibitory effect has been reported in both COS and aminoethyl-COS treatment groups.
Similarly, Huang et al.  have modified COS by carboxylation with ?COCH2CH2COO? groups to obtain specific structural features similar to captopril. ACE inhibitory activity of carboxylated COS enhances its activity with increased substitution degree and competitive inhibition has been observed. Further, improvement in ACE inhibitory activity of carboxylated-COS compared to COS might be due to the electrostatic interactions between positively charged sites of enzymatic and negatively charged carboxyl groups similar to captopril.
In addition to the ACE, it has shown that renin also plays a vital role in the renin-angiotensin system. Renin (or angiotensinogenase), is a rate-limiting enzyme in the renin-angiotensin system. It cleaves plasma angiotensinogen to angiotensin-I, which is further converted by ACE to angiotensin-II. Therefore, the inhibition of renin activity is also an attractive target in hypertension therapy. Park et al.  reported that COS have greater potential to inhibit renin activity. According to them, 90% deacetylated and medium molecular weight (1,000?5,000 Dalton) COS has the strongest renin inhibition (IC50 value, 0.51 mg/mL) and act as a competitive inhibitor. Collectively, it can be suggested that COS derivatives are potent drug candidates for treat hypertension and their therapeutic role in pharmaceutical industry are assured.
Phlorotannins are phenolic compounds formed by the polymerization of phloroglucinol or defined as 1,3,5-trihydroxybenzene monomer units and biosynthesized through the acetate-malonate pathway. They are highly hydrophilic components with a wide range of molecular sizes ranging between 126?650,000 Dalton . Marine brown algae and red algae accumulate a variety of phloroglucinol-based polyphenols, as phlorotannins of low, intermediate and high molecular weight containing both phenyl and phenoxy units [79,80]. Among marine algae, Ecklonia cava; an edible brown algae is a rich source of phlorotannins than others . In addition to E. cava, other marine algae such as E. stolonifera, Hizikia fusiforme, Eisenia bicyclis, and Eisenia arborea have been reported for various phlorotannins . Phlorotannins have several health beneficial biological activities including, antioxidant , anti-HIV , antiproliferative , anti-inflammatory , radioprotective , antidiabetic , anti-Alzheimer?s disease (acetyl cholinesterase and butyryl cholinesterase inhibitory) , antimicrobial  and antihypertensive or ACE inhibitory activities (Table 3.).
The ACE inhibitory activity of ten Korean seaweeds including, five Phaeophyta (E. cava, E. stolonifera, Pelvetia siliqousa, H. fusiforme, and Undaria pinnatifida), four Rhodophyta (Gigartina tenella, Gelidium amansii, Chondria crassicaulis, and Porphyra tenera), and one Chlorophyta (Capsosiphon fulvescens) have screened by Jung et al. . The ethanol extracts of E. stolonifera, E. cava, P. siliquosa, U. pinnatifida, and G. tenella exhibited significant inhibitory properties against ACE at more than 50% inhibition at a concentration of 163.93 ?g/mL. Moreover, they have found that phlorotannins such as eckol, phlorofucofuroeckol A, and dieckol, which derived from E. stolonifera have shown considerable inhibitory activity against ACE. Among them, phlorofucofuroeckol A is the strongest ACE inhibitor with an IC50 value of 12.74 ?M. Although current knowledge of relationship between the structure and activity of the active phlorotannins is limited, a closed ring dibenzo-1,4-dioxin moiety may be crucial to the above ACE inhibitory effect. In addition, the ACE inhibitory activity may depend on the degree of polymerization of phlorotannin derivatives.
Polyphenolic compounds inhibit ACE activity through sequestration of the enzyme metal factor, Zn2+ ion . Therefore, it has been assumed that phlorotannins might form a complex associated with proteins or glycoproteins to inhibit the ACE activity. Athukorala & Jeon  have reported that flavourzyme enzymatic digest of E. cava, which contains high content of phlorotannins, is a potent ACE inhibitor, exhibited an IC50 of 0.3 ?g/ml and captopril, a commercial antihypertensive exhibited an IC50 of 0.05 ?g/mL. They have hydrolyzed seven marine brown algal species (E. cava, Ishige okamurae, Sargassum fulvellum, Sargassum horneri, Sargassum coreanum, Sargassum thunbergii, and Scytosiphon lomentaria) and analyzed for ACE inhibitory activities. Most of the above algal species showed potent ACE inhibitory activities however, E. cava is the most potent ACE inhibitor among them due to its rich content of phlorotannins.
Furthermore, among twenty-six marine red algae, an aqueous extracts at 20 ?C of Lomentaria catenata and Lithophyllum okamurae have reported for potent ACE inhibitory activity with IC50 values of 12.21 ?g/mL and 13.78 ?g/mL, respectively . From the methanol extracts at 20 ?C, Ahnfeltiopsis flabelliformis possessed the highest ACE inhibitory activity (IC50, 13.8 ?g/mL).
Marine-derived phlorotannins are valuable bioactive compounds and could be introduced for the preparation of novel pharmaceuticals as well as functional foods, and their selection is also a good approach for the treatment or prevention of hypertension.
Recently, much attention has been paid by consumers towards natural bioactive compounds as functional ingredients and hence it can be suggested that, marine-derived ACE inhibitors are alternative tools that can contribute to consumer?s well-being, by being a part of novel nutraceuticals or pharmaceuticals replacing synthetic drugs. Food bioactive compounds are often effective in promoting health and lead to the reduction of disease risk. Especially, bioactive compounds derived from marine organisms have served as a rich source of health-promoting components. Among them, bioactive peptides, chito-oligosaccharides, and phlorotannins are rich sources of natural health enhancers and this fact implies their potential as a functional ingredient in future nutraceutical and pharmaceutical products. According to presented data, it seems that most IC50 values of COS are lower than peptides and phlorotannins, when comparing the ACE inhibitory activity of these marine-derived ACE inhibitors. Until now, most of these ACE inhibitory activities have been observed in vitro or in mouse model systems. Therefore, further research studies are needed in order to investigate their activity in human subjects. In conclusion, it can be suggested that marine-derived ACE inhibitors such as bioactive peptides, chitooligosaccharides, and phlorotannins are potential therapeutic candidates for prevent hypertension and their involvement in the future pharmaceuticals are promising.
This study was supported by a grant from Marine Bioprocess Research Center of the Marine Bio 21 Project funded by the Ministry of Land, Transport and Maritime, Republic of Korea.
References and Notes
|1.||Harris T,Cook EF,Kannel W,Schatzkin A,Goldman L. Blood pressure experience and risk of cardiovascular disease in the elderlyHypertensionYear: 198571181243980054|
|2.||Kannel WB,Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studiesJ HypertensYear: 19908S38|
|3.||Alper AB,Calhoun DA,Oparil S. HypertensionEncyclopedia of Life SciencesNature Publishing GroupLondon, UKYear: 200118|
|4.||Skeggs LT,Kahn JR,Shumway NP. The preparation and function of the hypertension-converting enzymeJ Exp MedYear: 195610329529913295487|
|5.||Li GH,Le GW,Shi YH,Shrestha S. Angiotensin I ? converting enzyme inhibitory peptides derived from food proteins and their physiological and pharmacological effectsNutr ResYear: 200324469486|
|6.||Ondetti MA. Design of specific inhibitors of angiotensin-converting enzyme: New class of orally active antihypertensive agentsScienceYear: 1977196441444191908|
|7.||Atkinson AB,Robertson JIS. Captopril in the treatment of clinical hypertension and cardiac failureLancetYear: 1979283683990928|
|8.||Goretta LA,Ottaviani JI,Keen CL,Fraga CG. Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidinsFEBS LettYear: 200355559760014675780|
|9.||Lee DH,Kim JH,Park JS,Choi YJ,Lee JS. Isolation and characterization of a novel angiotensin-I-converting enzyme inhibitory peptide derived from the edible mushroom Tricholoma giganteumPeptidesYear: 20042562162715165718|
|10.||Maruyama S,Miyoshi S,Tanaka H. Angiotensin-I-converting enzyme inhibitor derived from Ficus caricaAgric Biol ChemYear: 19895327632769|
|11.||Demain AL,Somkuti GA,Hunter-Cevera JC,Rossmoore HW. Novel microbial products for medicine and agricultureElsevier Science PublishersAmsterdam, The NetherlandsYear: 1989|
|12.||Fujita H,Yokoyama K,Yoshikawa M. Classification and antihypertensive activity of angiotensin I-converting enzyme inhibitory peptides derived from food proteinsJ Food SciYear: 200065564569|
|13.||Je JY,Qian ZJ,Lee SH,Byun HG,Kim SK. Purification and antioxidant properties of bigeye tuna (Thunnus obesus) dark muscle peptide on free radical-mediated oxidation systemsJ Med FoodYear: 20081162963719053853|
|14.||Sheih IC,Fang TJ,Wu TK. Isolation and characterization of a novel angiotensin I-converting enzyme (ACE) inhibitory peptide from the algae protein wasteFood ChemYear: 2009115279284|
|15.||Slizyte R,Mozuraityte R,Martinez-Alvarez O,Falch E,Fouchereau-Peron M,Rustad T. Functional, bioactive and antioxidative properties of hydrolysates obtained from cod (Gadus morhua) backbonesProcess BiochemYear: 200944668677|
|16.||Suetsuna K,Chen JR. Identification of antihypertensive peptides from peptic digest of two microalgae, Chlorella vulgaris and Spirulina platensisMar BiotechnolYear: 2001330530914961345|
|17.||Zhao Y,Li B,Liu Z,Dong S,Zhao X,Zeng M. Antihypertensive effect and purification of an ACE inhibitory peptide from sea cucumber gelatin hydrolysateProcess BiochemYear: 20074215861591|
|18.||Je JY,Park JY,Jung WK,Park PJ,Kim SK. Isolation of angiotensin I converting enzyme (ACE) inhibitor from fermented oyster sauce, Crassostrea gigasFood ChemYear: 200590809814|
|19.||Je JY,Park PJ,Byun HK,Jung WK,Kim SK. Angiotensin I converting enzyme (ACE) inhibitory peptide derived from the sauce of fermented blue mussel, Mytilus edulisBioresour TechnolYear: 2005961624162915978996|
|20.||Kim SK,Choi YR,Park PJ,Choi JH,Moon SH. Screening of biofunctional peptides from cod processing wastesJ Korean Soc Agric Chem BiotechnolYear: 200033198204|
|21.||Kim SK,Kim YT,Byun HG,Nam KS,Joo DS,Shahidi F. Isolation and characterization of antioxidative peptides from gelatin hydrolysate of Alaska pollack skinJ Agric Food ChemYear: 2001491984198911308357|
|22.||Jun SY,Park PJ,Jung WK,Kim SK. Purification and characterization of an antioxidative peptide from enzymatic hydrolysates of yellowfin sole (Limanda aspera) frame proteinEur Food Res TechnolYear: 20042192026|
|23.||Ravallec PR,Charlot C,Pires C,Braga V,Batista I,Wormhoudt AV,Gal YL,Fouchereau-Peron M. The presence of bioactive peptides in hydrolysates prepared from processing waste of sardine (Sardina pilchardus)J Sci Food AgricYear: 20018111201125|
|24.||Yokoyama KH,Chiba H,Yoshikawa M. Peptide inhibitors for angiotensin-I-converting enzyme from thermolysin digest of dried bonitoBiosci Biotechnol BiochemYear: 199256154115451369054|
|25.||Kim SY,Je JY,Kim SK. Purification and characterization of antioxidant peptide from hoki (Johnius balengerii) frame protein by gastrointestinal digestionJ Nutr BiochemYear: 200718313816563720|
|26.||Mendis E,Rajapakse N,Kim SK. Antioxidant properties of a radical-scavenging peptide purified from enzymatically prepared fish skin gelatin hydrolysateJ Agric Food ChemYear: 20055358158715686405|
|27.||Jo HY,Jung WK,Kim SK. Purification and characterization of a novel anticoagulant peptide from marine echiuroid worm, Urechis unicinctusProcess BiochemYear: 200843179184|
|28.||Rajapakse N,Jung WK,Mendis E,Moon SH,Kim SK. A novel anticoagulant purified from fish protein hydrolysate inhibits factor XIIa and platelet aggregationLife SciYear: 2005762607261915769484|
|29.||Liu Z,Dong S,Xu J,Zeng M,Song H,Zhao Y. Production of cysteine-rich antimicrobial peptide by digestion of oyster (Crassostrea gigas) with alcalase and bromelinFood ControlYear: 200819231235|
|30.||Stensvag K,Haug T,Sperstad SV,Rekdal O,Indrevoll B,Styrvold OB. Arasin 1, a proline-arginine-rich antimicrobial peptide isolated from the spider crab, Hyas araneusDev Comp ImmunoYear: 200832275285|
|31.||Defelice SL. The nutritional revolution: Its impact on food industry R&DTrends Food Sci TechnolYear: 199565961|
|32.||Erdmann K,Cheung BWY,Schroder H. The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular diseaseJ Nutr BiochemYear: 20081964365418495464|
|33.||Park CH,Kim HJ,Kang KT,Park JW,Kim JS. Fractionation and angiotensin I-converting enzyme (ACE) inhibitory activity of gelatin hydrolysates from by-products of Alaska Pollock surimiFish Aqua SciYear: 2009127985|
|34.||Byun HG,Kim SK. Purification and characterization of angiotensin I converting enzyme (ACE) inhibitory peptides from Alaska Pollack (Theragra chalcogramma) skinProcess BiochemYear: 20013611551162|
|35.||Qian ZJ,Je JY,Kim SK. Antihypertensive effect of angiotensin I converting enzyme-inhibitory peptide from hydrolysates of bigeye tuna dark muscle, Thunnus obesusJ Agric Food ChemYear: 2007558398840317894458|
|36.||Lee SH,Qian ZJ,Kim SK. A novel angiotensin I converting enzyme inhibitory peptide from tuna frame protein hydrolysate and its antihypertensive effect in spontaneously hypertensive ratsFood ChemYear: 201011896102|
|37.||He HL,Chen XL,Sun CY,Zhang YZ,Zhou BC. Analysis of novel angiotensin-I-converting enzyme inhibitory peptides from protease-hydrolyzed marine shrimp Acetes chinensisJ Peptide SciYear: 20061272673316981241|
|38.||Wang YK,He HL,Chen XL,Sun CY,Zhang YZ,Zhou BC. Production of novel angiotensin I-converting enzyme inhibitory peptides by fermentation of marine shrimp Acetes chinensis with Lactobacillus fermentum SM 605Appl Microbiol BiotechnolYear: 20087978579118521593|
|39.||Tsai JS,Chen JL,Pan BS. ACE-inhibitory peptides identified from the muscle protein hydrolysate of hard clam (Meretrix lusoria)Process BiochemYear: 200843743747|
|40.||Zhao Y,Bafang L,Dong S,Liu Z,Zhao X,Wang J,Zeng M. A novel ACE inhibitory peptide isolated from Acaudina molpadioidea hydrolysatePeptidesYear: 2009301028103319463733|
|41.||Lee JK,Hong S,Jeon JK,Kim SK,Byun HG. Purification and characterization of angiotensin I converting enzyme inhibitory peptides from the rotifer, Brachionus rotundiformisBioresour TechnolYear: 20091005255525919540110|
|42.||Suetsuna K,Nakano T. Identification of an antihypertensive peptide from peptic digest of wakame (Undaria pinnatifida)J Nutr BiochemYear: 20001145045411091100|
|43.||Sheih IC,Fang TJ,Wu TK. Isolation and characterization of a novel angiotensin I-converting enzyme (ACE) inhibitory peptide from the algae protein wasteFood ChemYear: 2009115279284|
|44.||Jung WK,Mendis E,Je JY,Park PJ,Son BW,Kim HC,Choi YK,Kim SK. Angiotensin I-converting enzyme inhibitory peptide from yellowfin sole (Limanda aspera) frame protein and its antihypertensive effect in spontaneously hypertensive ratsFood ChemYear: 2006942632|
|45.||Fujita H,Yoshikawa M. LKPNM: A prodrug-type ACE-inhibitory peptide derived from fish proteinImmunopharmacologyYear: 19994412312710604535|
|46.||Matsui T,Matsufuji H,Seki E,Osajima K,Nakashima M,Osajima Y. Inhibition of angiotensin I-converting enzyme by Bacillus licheniformis alkaline protease hydrolysates derived from sardine muscleBiosci Biotech BiochemYear: 199357922925|
|47.||Wang J,Hu J,Cui J,Bai X,Du Y,Miyaguchi Y,Lin B. Purification and identification of a ACE inhibitory peptide from oyster proteins hydrolysate and the antihypertensive effect of hydrolysate in spontaneously hypertensive ratsFood ChemYear: 2008111302308|
|48.||Wu H,He HL,Chen XL,Sun CY,Zhang YZ,Zhou BC. Purification and identification of novel angiotensin-I-converting enzyme inhibitory peptides from shark meat hydrolysateProcess BiochemYear: 200843457461|
|49.||Ichimura T,Hu J,Aita DQ,Maruyama S. Angiotensin I-converting enzyme inhibitory activity and insulin secretion stimulative activity of fermented fish sauceJ Biosci BioengYear: 20039649649916233562|
|50.||Fahmi A,Morimura S,Guo HC,Shigematsu T,Kida K,Uemura Y. Production of angiotensin I converting enzyme inhibitory peptides from sea bream scalesProcess BiochemYear: 20043911951200|
|51.||Cheung HS,Chushman DW. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lungBiochem PharmacolYear: 19712016371648|
|52.||Suetsuna K,Nakano T. Identification of an antihypertensive peptide from peptic digest of wakame (Undaria pinnatifida)J Nutr BiochemYear: 20001145045411091100|
|53.||Rho SJ,Lee JS,Chung YI,Kim YW,Lee HG. Purification and identification of an angiotensin I-converting enzyme inhibitory peptide from fermented soybean extractProcess BiochemYear: 200944490493|
|54.||Qian ZJ,Jung WK,Lee SH,Byun HG,Kim SK. Antihypertensive effect of an angiotensin I-converting enzyme inhibitory peptide from bullfrog (Rana catesbeiana Shaw) muscle protein in spontaneously hypertensive ratsProcess BiochemYear: 20074214431448|
|55.||Shahidi F,Arachchi JKV,Jeon YJ. Food applications of chitin and chitosansTrends Food Sci TechnolYear: 1999103751|
|56.||Kim SK,Nghiep ND,Rajapakse N. Therapeutic prospectives of chitin, chitosan and their derivativesJ Chitin ChitosanYear: 200611110|
|57.||Dou JL,Tan CY,Du YG,Bai XF,Wang KY,Ma XJ. Effects of chitooligosaccharides on rabbit neutrophils in vitroCarbohydr PolymYear: 200769209213|
|58.||Jeon YJ,Kim SK. Continuous production of chitooligosaccharides using a dual reactor systemProcess BiochemYear: 200035623632|
|59.||Jeon YJ,Kim SK. Production of chitooligosaccharides using ultrafiltration membrane reactor and their antibacterial activityCarbohydr PolymYear: 200041133141|
|60.||Kim SK,Rajapakse N. Enzymatic production and biological activities of chitosan oligosaccharides (COS): A reviewCarbohydr PolymYear: 200562357368|
|61.||Hong SP,Kim MH,Oh SW,Han CH,Kim YH. ACE inhibitory and antihypertensive effect of chitosan oligosaccharides in SHRKorean J Food Sci TechnolYear: 19983014761479|
|62.||Park PJ,Je JY,Kim SK. Free radical scavenging activity of chitooligosaccharides by electron spin resonance spectrometryJ Agric Food ChemYear: 2003514624462714705887|
|63.||Park PJ,Lee HK,Kim SK. Preparation of hetero-chitooligosaccharides and their antimicrobial activity on Vibrio parahaemolyticusJ Microbiol BiotechnolYear: 2004144147|
|64.||Shen KT,Chen MH,Chan HY,Jeng JH,Wang YJ. Inhibitory effects of chitooligosaccharides on tumor growth and metastasisFood Chem ToxicolYear: 2009471864187119427889|
|65.||Jeon YJ,Kim SK. Antitumor activity of chitosan oligosaccharides produced in ultrafiltration membrane reactor systemJ Microbiol BiotechnolYear: 200212503507|
|66.||Jeon YJ,Kim SK. Potential immuno-stimulating effect of antitumoral fraction of chitosan oligosaccharidesJ Chitin ChitosanYear: 20016163167|
|67.||Liu B,Liu WS,Han BQ,Sun YY. Antidibetic effects of chito-oligosaccharides on pancreatic islet cells in streptozotocin-induced diabetic ratsWorld J GastroenterolYear: 20071372573117278195|
|68.||Kim KN,Joo ES,Kim KI,Kim SK,Yang HP,Jeon YJ. Effect of chitosan oligosaccharides on cholesterol level and antioxidant enzyme activities in hypercholesterolemic ratJ Korean Soc Food Sci NutrYear: 2005343641|
|69.||Miura T,Usami M,Tsuura Y,Ishida H,Seino Y. Hypoglycemic and hypolipidemic effect of chitosan in normal and neonatal streptozotocin-induced diabetic miceBiol Pharm BullYear: 199518162316258593495|
|70.||Yoon NY,Ngo DN,Kim SK. Acetylcholinesterase inhibitory activity of novel chitooligosaccharide derivativesCarbohydr PolymYear: 200978869872|
|71.||Park PJ,Je JY,Jung WK,Kim SK. Anticoagulant activity of heterochitosans and their oligosaccharide sulfatesEur Food Res TechnolYear: 2004219529533|
|72.||Cho EJ,Rahman A,Kim SW,Baek YM,Hwang HJ,Oh JY,Hwang HS,Lee SK,Yun JW. Chitosan oligosaccharides inhibit adipogenesis in 3T3-L1 adipocytesJ Microbiol BiotechnolYear: 2008181808718239421|
|73.||Park PJ,Je JY,Kim SK. Angiotensin I converting enzyme (ACE) inhibitory activity of hetero-chitooligosaccharides prepared from partially different deacetylated chitosansJ Agric Food ChemYear: 2003514930493412903948|
|74.||Je JY,Park PJ,Kim B,Kim SK. Antihypertensive activity of chitin derivativesBiopolymersYear: 20068325025416763977|
|75.||Ngo DN,Qian ZJ,Je JY,Kim MM,Kim SK. Aminoethyl chitooligosaccharides inhibit the activity of angiotensin converting enzymeProcess BiochemYear: 200843119123|
|76.||Huang R,Mendis E,Kim SK. Improvement of ACE inhibitory activity of chitooligosaccharides (COS) by carboxyl modificationsBioorg Med ChemYear: 2005133649365515862993|
|77.||Park PJ,Ahn LB,Jeon YJ,Je JY. Renin inhibition activity by chitooligosacharidesBioorg Med Chem LettYear: 2008182471247418313296|
|78.||Ragan MA,Glombitza KW. Handbook of physiological methodsCambridge University PressCambridge, UKYear: 1986129241|
|79.||Singh IP,Bharate SB. Phloroglucinol compounds of natural originNat Prod RepYear: 20062355859116874390|
|80.||Glombitza KW,Li SM. Hydroxyphlorethols from the brown alga Carpophyllum maschalocarpumPhytochemistryYear: 19913027412745|
|81.||Heo SJ,Park EU,Lee KW,Jeon YJ. Antioxidant activities of enzymatic extracts from brown seaweedsBioresour TechnolYear: 2005961613162315978995|
|82.||Li Y,Qian ZJ,Ryu BM,Lee SH,Kim MM,Kim SK. Chemical components and its antioxidant properties in vitro: An edible marine brown alga, Ecklonia cavaBioorg Med ChemYear: 2009171963197319201199|
|83.||Artan M,Li Y,Karadeniz F,Lee SH,Kim MM,Kim SK. Anti-HIV-1 activity of phloroglucinol derivative, 6,6?-bieckol, from Ecklonia cavaBioorg Med ChemYear: 2008167921792618693022|
|84.||Kong CS,Kim JA,Yoon NY,Kim SK. Induction of apoptosis by phloroglucinol derivative from Ecklonia cava in MCF-7 human breast cancer cellsFood Chem ToxicolYear: 2009471653165819393283|
|85.||Jung WK,Ahn YW,Lee SH,Choi YH,Kim SK,Yea SS,Choi I,Park SG,Seo SK,Lee SW,Choi IW. Ecklonia cava ethanolic extracts inhibit lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV2 microglia via the MAP kinase and NF-kB pathwaysFood Chem ToxicolYear: 20094741041719111593|
|86.||Zhang R,Kang KA,Piao MJ,Ko DO,Wang ZH,Lee IK,Kim BJ,Jeong YI,Shin T,Park JW,Lee NH,Hyun JW. Eckol protects V79-4 lung fibroblast cells against ?-ray radiation-induced apoptosis via the scavenging of reactive oxygen species and inhibiting of the c-Jun NH2-terminal kinase pathwayEur J PharmacolYear: 200859111412318625217|
|87.||Lee SH,Li Y,Karadeniz F,Kim MM,Kim SK. ??Glycosidase and ??amylase inhibitory activities of phloroglucinal derivatives from edible marine brown alga, Ecklonia cavaJ Sci Food AgricYear: 200910.1002/jsfa.3623|
|88.||Yoon NY,Lee SH,Li Y,Kim SK. Phlorotannins from Ishige okamurae and their acetyl- and butyry-lcholinesterase inhibitory effectsJ Func FoodsYear: 20091331335|
|89.||Nagayama K,Iwamura Y,Shibata T,Hirayama I,Nakamura T. Bactericidal activity of phlorotannins from the brown alga Ecklonia kuromeJ Antimicrob ChemotherYear: 20025088989312461009|
|90.||Jung HA,Hyun SK,Kim HR,Choi JS. Angiotensin-converting enzyme I inhibitory activity of phlorotannins from Ecklonia stoloniferaFisheries SciYear: 20067212921299|
|91.||Liu JC,Hsu FL,Tsai JC,Chan P,Liu JYH,Thomas GN,Tomlinsond B,Loe M-Y,Linf J-Y. Antihypertensive effects of tannins isolated from traditional Chinese herbs as non-specific inhibitors of angiotensin converting enzymeLife SciYear: 2003731543155512865094|
|92.||Athukorala Y,Jeon YJ. Screening for Angiotensin 1-converting enzyme inhibitory activity of Ecklonia cavaJ Food Sci NutrYear: 200510134139|
|93.||Cha SH,Lee KW,Jeon YJ. Screening of extracts from red algae in Jeju for potentials marine angiotensin-I converting enzyme (ACE) inhibitory activityAlgaeYear: 200621343348|
Keywords: angiotensin-I-converting enzyme inhibitors, antihypertensive activity, bioactive peptides, chitooligosaccharides, hypertension, phlorotannins.
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