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Abstract
PURPOSE The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant transformation of cells and be useful as human cancer preventive agents. CONCLUSIONS (1) Many different types of potential anticarcinogenic substances were evaluated initially for their abilities to prevent or suppress radiation induced malignant transformation in vitro, and certain anticarcinogenic protease inhibitors (APIs) were observed to be the most powerful anticarcinogenic agents at suppressing this surrogate endpoint biomarker of radiation carcinogenesis. (2) Within the category of APIs, those that inhibited the activity of chymotrypsin were effective at far lower molar concentrations than other APIs. The soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) is a particularly powerful chymotrypsin inhibitor that is able to prevent radiation induced transformation in vitro (at concentrations down to nanomolar levels) as well as radiation induced carcinogenesis in vivo without toxicity. (3) There were many other unusual characteristics of APIs that led to the selection of one of these APIs, BBI, as the most appropriate compound for us to develop as a human cancer preventive agent. As one example, the APIs have an irreversible effect on carcinogenesis, while the effects are reversible for most anticarcinogenic agents when they are removed from carcinogenesis assay systems. (4) Numerous studies were performed in attempts to determine the potential mechanisms by which the APIs could prevent or suppress radiation induced carcinogenesis in in vitro and in vivo systems, and the results of these studies are described in this review article. The APIs and the proteases which interact with them appear to play important roles in radiation carcinogenesis. (5) Preparations for human trials using BBI began decades ago. The cost of preparing purified BBI was far too high to consider performing human trials with this agent, so BBI Concentrate (BBIC), a soybean extract enriched in BBI, was developed for the specific purpose of performing human trials with BBI. BBIC achieved Investigational New Drug (IND) Status with the Food and Drug Administration in April,1992, and human BBIC trials began at that time. (6) Several human trials were performed using BBIC and they indicated many potentially beneficial health effects produced by BBIC administration to people in various forms (e.g. tablets). 7) It is hypothesized that BBI takes the place of α-1-antichymotrypsin, an important regulatory compound in the human body, and helps to maintain homeostasis.
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Affiliation(s)
- Ann R Kennedy
- Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Dia VP. Plant sources of bioactive peptides. BIOLOGICALLY ACTIVE PEPTIDES 2021:357-402. [DOI: 10.1016/b978-0-12-821389-6.00003-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Gitlin-Domagalska A, Maciejewska A, Dębowski D. Bowman-Birk Inhibitors: Insights into Family of Multifunctional Proteins and Peptides with Potential Therapeutical Applications. Pharmaceuticals (Basel) 2020; 13:E421. [PMID: 33255583 PMCID: PMC7760496 DOI: 10.3390/ph13120421] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/13/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Bowman-Birk inhibitors (BBIs) are found primarily in seeds of legumes and in cereal grains. These canonical inhibitors share a highly conserved nine-amino acids binding loop motif CTP1SXPPXC (where P1 is the inhibitory active site, while X stands for various amino acids). They are natural controllers of plants' endogenous proteases, but they are also inhibitors of exogenous proteases present in microbials and insects. They are considered as plants' protective agents, as their elevated levels are observed during injury, presence of pathogens, or abiotic stress, i.a. Similar properties are observed for peptides isolated from amphibians' skin containing 11-amino acids disulfide-bridged loop CWTP1SXPPXPC. They are classified as Bowman-Birk like trypsin inhibitors (BBLTIs). These inhibitors are resistant to proteolysis and not toxic, and they are reported to be beneficial in the treatment of various pathological states. In this review, we summarize up-to-date research results regarding BBIs' and BBLTIs' inhibitory activity, immunomodulatory and anti-inflammatory activity, antimicrobial and insecticidal strength, as well as chemopreventive properties.
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Affiliation(s)
| | | | - Dawid Dębowski
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (A.G.-D.); (A.M.)
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Mittal P, Kumar V, Rani A. Effect of genotype, seed development stages, and processing treatments on Bowman-Birk inhibitor in soybean and its level in commercial soy products. ACTA ALIMENTARIA 2020. [DOI: 10.1556/066.2020.49.3.14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Bowman-Birk inhibitor (BBI) is a protease inhibitor that affects protein digestibility; however, it is increasingly being recognised as anutraceutical and cosmeceutical molecule. In the present study, BBI concentration during soybean seed development, its loss during processing treatments, and the level in commercial soy products were determined. Significant differences for BBI concentration were observed across the genotypes and seed development stages. Genotype × seed development stage interaction was also found to be significant (P<0.05) for BBI concentration. Boiling, autoclaving, microwave irradiation, and sprouting resulted in significant (P<0.05) loss of BBI. Minimum loss was observed in sprouting, while autoclaving for 5 min completely deactivated BBI. Microwave irradiation of the soaked seeds resulted in higher BBI loss than of dry seeds. Among the commercial soy products, BBI concentration was high in soy flour brands, minuscule in ready-to-cook miso soup and undetectable in extruded soy products and roasted soy nuts.
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Affiliation(s)
- P. Mittal
- ICAR-Indian Institute of Soybean Research, Khandwa Road, Indore, 452001. India
| | - V. Kumar
- ICAR-Indian Institute of Soybean Research, Khandwa Road, Indore, 452001. India
| | - A. Rani
- ICAR-Indian Institute of Soybean Research, Khandwa Road, Indore, 452001. India
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Reihill JA, Ouyang X, Yang Z, Douglas LEJ, Zhou M, Chen T, Martin SL. A Novel Serine Protease Inhibitor PE-BBI Ameliorates Cockroach Extract-Mediated Airway Epithelial Barrier Dysfunction. Biomolecules 2020; 10:biom10040515. [PMID: 32231120 PMCID: PMC7226075 DOI: 10.3390/biom10040515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 01/17/2023] Open
Abstract
Epithelial barrier dysfunction, characteristic of allergic airway disease may be, at least in part, due to the action of allergen-associated protease activities. Cockroach allergy is a major global health issue, with cockroaches containing considerable serine trypsin-like protease (TLP) activity. The present study sought to evaluate two novel protease inhibitors (PE-BBI and pLR-HL), recently isolated from amphibian skin secretions, for their potential to neutralise cockroach TLP activity and to determine any protective effect on cockroach-induced airway epithelial barrier disruption. Inhibitor potencies against the cockroach-associated activities were determined using a fluorogenic peptide substrate-based activity assay. 16HBE14o- cells (16HBE; a bronchial epithelial cell line) were treated with cockroach extract (CRE) in the presence or absence of the compounds in order to assess cell viability (RealTime Glo luminescent assay) and epithelial barrier disruption (transepithelial resistance and paracellular dextran flux). PE-BBI potently and selectively inhibited CRE TLP activity (pIC50 -8), but not host (16HBE) cell surface activity, which conferred protection of 16HBE cells from CRE-induced cell damage and barrier disruption. Novel protease inhibitor strategies such as PE-BBI may be useful for the treatment of allergic airway disease caused by cockroach proteases.
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Chatterjee C, Gleddie S, Xiao CW. Soybean Bioactive Peptides and Their Functional Properties. Nutrients 2018; 10:E1211. [PMID: 30200502 PMCID: PMC6164536 DOI: 10.3390/nu10091211] [Citation(s) in RCA: 261] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/27/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
Soy consumption has been associated with many potential health benefits in reducing chronic diseases such as obesity, cardiovascular disease, insulin-resistance/type II diabetes, certain type of cancers, and immune disorders. These physiological functions have been attributed to soy proteins either as intact soy protein or more commonly as functional or bioactive peptides derived from soybean processing. These findings have led to the approval of a health claim in the USA regarding the ability of soy proteins in reducing the risk for coronary heart disease and the acceptance of a health claim in Canada that soy protein can help lower cholesterol levels. Using different approaches, many soy bioactive peptides that have a variety of physiological functions such as hypolipidemic, anti-hypertensive, and anti-cancer properties, and anti-inflammatory, antioxidant, and immunomodulatory effects have been identified. Some soy peptides like lunasin and soymorphins possess more than one of these properties and play a role in the prevention of multiple chronic diseases. Overall, progress has been made in understanding the functional and bioactive components of soy. However, more studies are required to further identify their target organs, and elucidate their biological mechanisms of action in order to be potentially used as functional foods or even therapeutics for the prevention or treatment of chronic diseases.
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Affiliation(s)
- Cynthia Chatterjee
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Banting Research Centre, 251 Sir Frederick Banting Drive, Ottawa, ON K1A 0K9, Canada.
- Ottawa Research & Development Centre, Central Experimental Farm, Agriculture and Agri-Food Canada, 960 Carling Avenue Building#21, Ottawa, ON K1A 0C6, Canada.
| | - Stephen Gleddie
- Ottawa Research & Development Centre, Central Experimental Farm, Agriculture and Agri-Food Canada, 960 Carling Avenue Building#21, Ottawa, ON K1A 0C6, Canada.
| | - Chao-Wu Xiao
- Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Banting Research Centre, 251 Sir Frederick Banting Drive, Ottawa, ON K1A 0K9, Canada.
- Food and Nutrition Science Program, Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
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Joanitti GA, Sawant RS, Torchilin VP, Freitas SMD, Azevedo RB. Optimizing liposomes for delivery of Bowman-Birk protease inhibitors - Platforms for multiple biomedical applications. Colloids Surf B Biointerfaces 2018; 167:474-482. [PMID: 29723819 DOI: 10.1016/j.colsurfb.2018.04.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 04/02/2018] [Accepted: 04/16/2018] [Indexed: 11/19/2022]
Abstract
One of the major challenges in the administration of therapeutic proteins involves delivery limitations. Liposomes are well-known drug delivery systems (DDS) that have been used to overcome this drawback; nevertheless, low protein entrapment efficiency (EE) still limits their wide biomedical application on a commercial scale. In the present work, different methods for protein entrapment into liposomes were tested in order to obtain tailored DDS platforms for multiple biomedical applications. The protein used as model was the Black-eyed pea Trypsin and Chymotrypsin Inhibitor (BTCI), a member of the Bowman-Birk protease inhibitor family (BBIs), which has been largely explored for its potential application in many biomedical therapies. We optimized reverse-phase evaporation (REV) and freeze/thaw (F/T) entrapment methods, using a cationic lipid matrix to entrap expressive amounts of BTCI (∼100 μM) in stable liposomes without affecting its protease inhibition activity. The influence of various parameters (e.g. entrapment method, liposome composition, buffer type) on particle size, charge, polydispersity, and EE of liposomes was investigated to provide an insight on how to control such parameters in view of obtaining a high entrapment yield. In addition, BTCI liposome platforms obtained herein showed to be versatile vesicles, allowing surface modification with moieties/polymers of interest (e.g. PEG, transferrin). The aforementioned results are relevant to focusing on the entrapment of other promising BBIs or protein agents sharing similar structural features. These findings encourage future studies to investigate the advantages of using the liposome platforms presented herein to broaden the use of this type of DDS for BBI biomedical applications.
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Affiliation(s)
- Graziella Anselmo Joanitti
- Laboratory of Nanobiotecnology, Institute of Biology, University of Brasília, Brasília, 70910-900, Brazil; Universidade de Brasília (UnB), Campus Ceilândia (FCE) Centro Metropolitano, Conjunto A - Lote 01, Brasília, DF, 72220-900, Brazil.
| | - Rupa S Sawant
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; Vertex Pharmaceuticals, Boston, MA 02210, USA.
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
| | - Sonia Maria de Freitas
- Laboratory of Biophysics, Institute of Biology, University of Brasília, Brasília, 70910-900, Brazil.
| | - Ricardo Bentes Azevedo
- Laboratory of Nanobiotecnology, Institute of Biology, University of Brasília, Brasília, 70910-900, Brazil.
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Orona-Tamayo D, Valverde ME, Paredes-López O. Bioactive peptides from selected latin american food crops – A nutraceutical and molecular approach. Crit Rev Food Sci Nutr 2018; 59:1949-1975. [DOI: 10.1080/10408398.2018.1434480] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Domancar Orona-Tamayo
- Centro de Investigación y de Estudios Avanzados de Instituto Politécnico Nacional. Km. 9.6 Libramiento Norte Carretera Irapuato-León, Irapuato, Guanajuato, México, CP
| | - María Elena Valverde
- Centro de Investigación y de Estudios Avanzados de Instituto Politécnico Nacional. Km. 9.6 Libramiento Norte Carretera Irapuato-León, Irapuato, Guanajuato, México, CP
| | - Octavio Paredes-López
- Centro de Investigación y de Estudios Avanzados de Instituto Politécnico Nacional. Km. 9.6 Libramiento Norte Carretera Irapuato-León, Irapuato, Guanajuato, México, CP
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Cicero AFG, Fogacci F, Colletti A. Potential role of bioactive peptides in prevention and treatment of chronic diseases: a narrative review. Br J Pharmacol 2017; 174:1378-1394. [PMID: 27572703 PMCID: PMC5429326 DOI: 10.1111/bph.13608] [Citation(s) in RCA: 200] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 08/12/2016] [Accepted: 08/18/2016] [Indexed: 12/24/2022] Open
Abstract
In the past few years, increasing interest has been directed to bioactive peptides of animal and plant origin: in particular, researchers have focused their attention on their mechanisms of action and potential role in the prevention and treatment of cancer, cardiovascular and infective diseases. We have developed a search strategy to identify these studies in PubMed (January 1980 to May 2016); particularly those papers presenting comprehensive reviews or meta-analyses, plus in vitro and in vivo studies and clinical trials on those bioactive peptides that affect cardiovascular diseases, immunity or cancer, or have antioxidant, anti-inflammatory and antimicrobial effects. In this review we have mostly focused on evidence-based healthy properties of bioactive peptides from different sources. Bioactive peptides derived from fish, milk, meat and plants have demonstrated significant antihypertensive and lipid-lowering activity in clinical trials. Many bioactive peptides show selective cytotoxic activity against a wide range of cancer cell lines in vitro and in vivo, whereas others have immunomodulatory and antimicrobial effects. Furthermore, some peptides exert anti-inflammatory and antioxidant activity, which could aid in the prevention of chronic diseases. However, clinical evidence is at an early stage, and there is a need for solid pharmacokinetic data and for standardized extraction procedures. Further studies on animals and randomized clinical trials are required to confirm these effects, and enable these peptides to be used as preventive or therapeutic treatments. LINKED ARTICLES This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
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Affiliation(s)
- Arrigo F G Cicero
- Atherosclerosis and Metabolic Diseases Research Center, Medicine and Surgery DeptartmentAlma Mater Studiorum, University of BolognaBolognaItaly
| | - Federica Fogacci
- Atherosclerosis and Metabolic Diseases Research Center, Medicine and Surgery DeptartmentAlma Mater Studiorum, University of BolognaBolognaItaly
| | - Alessandro Colletti
- Atherosclerosis and Metabolic Diseases Research Center, Medicine and Surgery DeptartmentAlma Mater Studiorum, University of BolognaBolognaItaly
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Srikanth S, Chen Z. Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy. Front Pharmacol 2016; 7:470. [PMID: 28008315 PMCID: PMC5143346 DOI: 10.3389/fphar.2016.00470] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 11/18/2016] [Indexed: 12/28/2022] Open
Abstract
Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs) which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI) have been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn, and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and therapeutic effects due to their peculiarity and superabundance.
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Affiliation(s)
| | - Zhong Chen
- Natural Sciences and Science Education, National Institute of Education, Nanyang Technological UniversitySingapore, Singapore
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Mehdad A, Xavier Reis G, Souza AA, Barbosa JARG, Ventura MM, de Freitas SM. A Bowman-Birk inhibitor induces apoptosis in human breast adenocarcinoma through mitochondrial impairment and oxidative damage following proteasome 20S inhibition. Cell Death Discov 2016; 2:15067. [PMID: 27551492 PMCID: PMC4979482 DOI: 10.1038/cddiscovery.2015.67] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/19/2015] [Accepted: 12/03/2015] [Indexed: 12/29/2022] Open
Abstract
Proteasome inhibitors are emerging as a new class of chemopreventive agents and have gained huge importance as potential pharmacological tools in breast cancer treatment. Improved understanding of the role played by proteases and their specific inhibitors in humans offers novel and challenging opportunities for preventive and therapeutic intervention. In this study, we demonstrated that the Bowman-Birk protease inhibitor from Vigna unguiculata seeds, named black-eyed pea trypsin/chymotrypsin Inhibitor (BTCI), potently suppresses human breast adenocarcinoma cell viability by inhibiting the activity of proteasome 20S. BTCI induced a negative growth effect against a panel of breast cancer cells, with a concomitant cytostatic effect at the G2/M phase of the cell cycle and an increase in apoptosis, as observed by an augmented number of cells at the sub-G1 phase and annexin V-fluorescin isothiocyanate (FITC)/propidium iodide (PI) staining. In contrast, BTCI exhibited no cytotoxic effect on normal mammary epithelial cells. Moreover, the increased levels of intracellular reactive oxygen species (ROS) and changes in the mitochondrial membrane potential in cells treated with BTCI indicated mitochondrial damage as a crucial cellular event responsible for the apoptotic process. The higher activity of caspase in tumoral cells treated with BTCI in comparison with untreated cells suggests that BTCI induces apoptosis in a caspase-dependent manner. BTCI affected NF-kB target gene expression in both non invasive and invasive breast cancer cell lines, with the effect highly pronounced in the invasive cells. An increased expression of interleukin-8 (IL-8) in both cell lines was also observed. Taken together, these results suggest that BTCI promotes apoptosis through ROS-induced mitochondrial damage following proteasome inhibition. These findings highlight the pharmacological potential and benefit of BTCI in breast cancer treatment.
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Affiliation(s)
- A Mehdad
- Laboratory of Molecular Biophysics, Institute
of Biological Sciences, University of Brasilia, Brasilia,
Brazil
| | - Giselle Xavier Reis
- Faculty of Medicine, Department of Molecular
Pathology, University of Brasilia, Brasilia, Brazil
| | - AA Souza
- Laboratory of Molecular Biophysics, Institute
of Biological Sciences, University of Brasilia, Brasilia,
Brazil
| | - JARG Barbosa
- Laboratory of Molecular Biophysics, Institute
of Biological Sciences, University of Brasilia, Brasilia,
Brazil
| | - MM Ventura
- Laboratory of Molecular Biophysics, Institute
of Biological Sciences, University of Brasilia, Brasilia,
Brazil
| | - SM de Freitas
- Laboratory of Molecular Biophysics, Institute
of Biological Sciences, University of Brasilia, Brasilia,
Brazil
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Jin T, Yu H, Wang D, Zhang H, Zhang B, Quezada HC, Zhu J, Zhu W. Bowman-Birk inhibitor concentrate suppresses experimental autoimmune neuritis via shifting macrophages from M1 to M2 subtype. Immunol Lett 2016; 171:15-25. [PMID: 26791957 DOI: 10.1016/j.imlet.2016.01.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 01/07/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND In the present study, we investigated the immuno-regulatory and therapeutic effects of Bowman-Birk inhibitor concentrate (BBIC) on experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome (GBS) in human. METHODS EAN in Lewis rats induced by inoculation with peripheral nerve myelin P0 protein peptide 180-199 (P0 peptide) was treated with BBIC at two different therapeutic regimens. RESULTS Our data indicated that the administration of BBIC daily orally effectively inhibited and ameliorated the clinical and pathological signs of EAN. The suppression of EAN was associated with an insufficiency of autoreactive T cells, as reflected by inhibited P0 peptide-specific mononuclear cell proliferation and decreased in CD4 and CD8T cells infiltrating into the peripheral nervous system (PNS). BBIC might mediate its therapeutic effects by shifting macrophages from M1 to M2 subtype as evidenced by increasing Arg-1, CD206 and IL-10 and inhibiting IFN-γ, TNF-α, IL-12, iNOS and CD40 expressions on macrophages as well as enhancing anti-inflammatory cytokines IL-4 and IL-10 and decreasing inflammatory cytokines, IFN-γ, TNF-α and IL-17 in the PNS. CONCLUSION Our results suggest that BBIC may have therapeutic potential in human GBS and other autoimmune diseases in the future.
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Affiliation(s)
- Tao Jin
- Department of Neurology, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China
| | - Hong Yu
- Department of Otorhinolaryngology, Head and Neck Surgery, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden
| | - Dan Wang
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden; Department of Ophthalmology, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China
| | - Hongliang Zhang
- Department of Neurology, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden
| | - Bo Zhang
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden; Department of Neurosurgery, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China
| | - Hernan Concha Quezada
- Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden
| | - Jie Zhu
- Department of Neurology, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden.
| | - Wei Zhu
- Department of Otorhinolaryngology, Head and Neck Surgery, the First Hospital, Jilin University, Xinmin Street 71#, 130021 Changchun, China.
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Hernández-Ledesma B, Hsieh CC. Chemopreventive role of food-derived proteins and peptides: A review. Crit Rev Food Sci Nutr 2015; 57:2358-2376. [DOI: 10.1080/10408398.2015.1057632] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Blanca Hernández-Ledesma
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC-UAM, CEI UAM+CSIC), Madrid, Spain
| | - Chia-Chien Hsieh
- Department of Human Development and Family Studies (Nutritional Science and Education), National Taiwan Normal University, Taipei, Taiwan
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Lin Y, Hang H, Chen T, Zhou M, Wang L, Shaw C. pLR-HL: A Novel Amphibian Bowman-Birk-type Trypsin Inhibitor from the Skin Secretion of the Broad-folded Frog, Hylarana latouchii. Chem Biol Drug Des 2015; 87:91-100. [PMID: 26228512 DOI: 10.1111/cbdd.12626] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 05/01/2015] [Accepted: 07/23/2015] [Indexed: 11/30/2022]
Abstract
In this study, we report a novel heptadecapeptide (LIGGCWTKSIPPKPCLV) of the pLR/ranacyclin family, named pLR-HL, whose structure was deduced from its biosynthetic precursor-encoding cDNA cloned from the skin secretion-derived cDNA library of the broad-folded frog, Hylarana latouchii, by employing a 'shotgun' cloning technique. It contains a disulphide loop between Cys(5) and Cys(15) which is consistent with Bowman-Birk-type protease inhibitors. The primary structure of pLR-HL deduced from the cDNA sequence was confirmed by fractionating the skin secretion using reverse-phase HPLC and subsequent analysis using MALDI-TOF mass spectrometry and LC/MS/MS fragmentation sequencing. On the basis of the establishment of unequivocal amino acid sequence, a synthetic replicate was synthesized by solid-phase Fmoc chemistry, and it displayed a moderately potent trypsin inhibition with a Ki of 143 nm. The substitution of Lys-8 by Phe (Phe(8) -pLR-HL) resulted in abolition of trypsin inhibition but generation of modest inhibition on chymotrypsin with a Ki of 2.141 μm. Additionally, both the disulphide loops of pLR-HL and Phe(8) -pLR-HL were synthesized and tested. Both of the catalytic loops retained similar inhibitory potencies towards trypsin or chymotrypsin in comparison with the original intact molecules. Thus, the replacement of reactive site residues could alter the specificity of these protease inhibitors, while the canonical reactive loop alone can independently constitute biologically active moiety.
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Affiliation(s)
- Yan Lin
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast, Northern Ireland, BT9 7BL, UK.,Key Laboratory for Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Haiying Hang
- Key Laboratory for Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Tianbao Chen
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast, Northern Ireland, BT9 7BL, UK
| | - Mei Zhou
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast, Northern Ireland, BT9 7BL, UK
| | - Lei Wang
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast, Northern Ireland, BT9 7BL, UK
| | - Chris Shaw
- Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast, Northern Ireland, BT9 7BL, UK
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15
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Murugkar DA. Effect of different process parameters on the quality of soymilk and tofu from sprouted soybean. JOURNAL OF FOOD SCIENCE AND TECHNOLOGY 2015; 52:2886-93. [PMID: 25892787 PMCID: PMC4397316 DOI: 10.1007/s13197-014-1320-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 01/06/2014] [Accepted: 03/06/2014] [Indexed: 10/25/2022]
Abstract
The effect of grinding cum blanching (GCB) of sprouted soybean at different temperatures on milk and tofu quality was studied. Three temperatures (121 °C-T1,100 °C-T2 and 80 °C-T3) for GCB were used to produce soymilk and tofu from sprouted soybean which were analysed for the yield, nutritional, anti-nutritional profile, colour attributes, particle size, organoleptic quality and texture profile. Unsprouted Soybeans with GCB at 121 °C served as control (C). There was significant difference (P < 0.5) in trypsin inhibitor content in milk and ranged from 4.1 mg/g in T3 to 1.4 mg/g in T1. Optimal reduction in TI of 75-80 % was achieved in T2. There was significant difference (P < 0.5) in protein extractability and ranged from 84.4 % in C to 93.9 % in T2. Hardness (N) of tofu was around 11.22 in C and reduced to 8.9, 8.6 and 4.4 in T1, T2 and T3 respectively. L values of soymilk ranged from 83.4 in C to 85.8 in T3; in tofu from 83.1(T3) to 87.2 (C) and decreased with the increase in heating temperature and time. Particle size d [3, 2] and volume d [4, 3] between treatments varied significantly (P < 0.0001 and P < 0.0038). Overall acceptability scores on 9 point hedonic scale for all treatments for milk and tofu were above 5. The texture scores of tofu for T3 were very low due to its soft structure. From the above investigations 100 °C was the optimal temperature for GCB of sprouted soybean for the production of good quality soymilk and tofu.
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Affiliation(s)
- Dipika Agrahar Murugkar
- Agro Produce Processing Division, Central Institute of Agricultural Engineering, Nabibagh, Berasia Road, Bhopal, 462 038 India
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16
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Sánchez-Chino X, Jiménez-Martínez C, Dávila-Ortiz G, Álvarez-González I, Madrigal-Bujaidar E. Nutrient and nonnutrient components of legumes, and its chemopreventive activity: a review. Nutr Cancer 2015; 67:401-10. [PMID: 25710272 DOI: 10.1080/01635581.2015.1004729] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Legumes in combination with other products are the staple food for a large part of the world population, especially the low-income fragment, because their seeds provide valuable amounts of carbohydrates, fiber, and proteins, and have an important composition of essential amino acids, the sulphured amino acids being the limiting ones. Furthermore, legumes also have nonnutritional compounds that may decrease the absorption of nutrients or produce toxic effects; however, it has been reported that depending on the dose, these nonnutritional compounds also have different bioactivities as antioxidant, hypolipidemic, hypoglycemic, and anticarcinogenic agents, which have been proven in scientific studies. It has been observed that in countries with a high consumption of legumes, the incidence of colorectal cancer is lower. Some studies have shown that legume seeds are an alternative chemopreventive therapy against various cancers especially colon; this was verified in various animal models of induced by azoxymethane, a colon specific carcinogenic compound, in which a diet was supplemented with different concentrations of beans, lentils, chickpeas, or soybeans, mostly. These studies have proven the anticancer activity of legumes in early stages of carcinogenesis. Therefore, it is important to review the information available to elucidate the chemopreventive mechanisms of action of legume compounds.
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Affiliation(s)
- Xariss Sánchez-Chino
- a Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prolongación de Carpio y Plan de Ayala , Del Miguel Hidalgo, México
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17
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Kumar V, Murugeson S, Vithani N, Prakash B, Gowda LR. A salt-bridge stabilized C-terminal hook is critical for the dimerization of a Bowman Birk inhibitor. Arch Biochem Biophys 2014; 566:15-25. [PMID: 25527163 DOI: 10.1016/j.abb.2014.12.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/05/2014] [Accepted: 12/06/2014] [Indexed: 10/24/2022]
Abstract
Legume Bowman-Birk inhibitors (BBIs) that inhibit mammalian proteases exist as dimers in solution. The structural basis governing dimerization of HGI-III (horsegram seed BBI) was investigated. An intra-monomer salt bridge (D76-K71) stabilizes an atypical hook-like conformation at the C-terminus. We postulate that this hook, positions D75 to enable an inter-monomer salt-bridge D75(a)-K24(b), which results in dimerization. We verify this by K71A and D76A mutations of HGI-III. The mutants were both monomers, likely due to destabilization of the C-terminal hook. Dimerization was sustained in a double mutant K71D/D76K that was anticipated to form a similar hook critical for dimerization. Conversely, K24(b) that interacts with D75(a) of the loop is the specificity determining residue that interacts with trypsin to inhibit its activity. The inter-monomer salt bridge D75(a)-K24(b) must be disrupted for the inhibition of trypsin, requiring HGI-III to transition into a monomer. Size exclusion studies and a model of HGI-III-trypsin complex support this notion. Interestingly, isoforms of the inhibitor present in germinated seeds (HGGIs) are monomers; and most strikingly, the C-termini of these inhibitors are truncated with the loss the C-terminal hook critical for dimerization. The tendency of HGI-III to self-associate seems to relate to its physiological function of a storage protein.
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Affiliation(s)
- Vinod Kumar
- Department of Protein Chemistry and Technology, CSIR-Central Food Technological Research Institute, Mysore 570020, India
| | - Saravanan Murugeson
- Department of Biological Sciences & BioEngineering, Indian Institute of Technology, Kanpur 208016, India
| | - Neha Vithani
- Department of Biological Sciences & BioEngineering, Indian Institute of Technology, Kanpur 208016, India
| | - Balaji Prakash
- Department of Biological Sciences & BioEngineering, Indian Institute of Technology, Kanpur 208016, India; Center of Excellence for Chemical Biology, Indian Institute of Technology, Kanpur 208016, India
| | - Lalitha R Gowda
- Department of Protein Chemistry and Technology, CSIR-Central Food Technological Research Institute, Mysore 570020, India.
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18
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Clemente A, Arques MDC. Bowman-Birk inhibitors from legumes as colorectal chemopreventive agents. World J Gastroenterol 2014; 20:10305-10315. [PMID: 25132747 PMCID: PMC4130838 DOI: 10.3748/wjg.v20.i30.10305] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 02/21/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Aberrant functioning of serine proteases in inflammatory and carcinogenic processes within the gastrointestinal tract (GIT) has prompted scientists to investigate the potential of serine protease inhibitors, both natural and synthetic, as modulators of their proteolytic activities. Protease inhibitors of the Bowman-Birk type, a major protease inhibitor family in legume seeds, which inhibit potently and specifically trypsin- and chymotrypsin-like proteases, are currently being investigated as colorectal chemopreventive agents. Physiologically relevant amounts of Bowman-Birk inhibitors (BBI) can reach the large intestine in active form due to their extraordinary resistance to extreme conditions within the GIT. Studies in animal models have proven that dietary BBI from several legume sources, including soybean, pea, lentil and chickpea, can prevent or suppress carcinogenic and inflammatory processes within the GIT. Although the therapeutic targets and the action mechanism of BBI have not yet been elucidated, the emerging evidence suggests that BBI exert their preventive properties via protease inhibition; in this sense, serine proteases should be considered as primary targets in early stages of carcinogenesis. The validation of candidate serine proteases as therapeutic targets together with the identification, within the wide array of natural BBI variants, of the most potent and specific protease inhibitors, are necessary to better understand the potential of this protein family as colorectal chemopreventive agents.
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19
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Arques MC, Marín-Manzano MC, da Rocha LCB, Hernandez-Ledesma B, Recio I, Clemente A. Quantitative determination of active Bowman-Birk isoinhibitors, IBB1 and IBBD2, in commercial soymilks. Food Chem 2014; 155:24-30. [PMID: 24594149 DOI: 10.1016/j.foodchem.2014.01.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/28/2013] [Accepted: 01/10/2014] [Indexed: 12/27/2022]
Abstract
Naturally-occurring serine protease inhibitors of the Bowman-Birk family exert their potential chemopreventive and/or therapeutic properties via protease inhibition. In this study, we have quantified the amounts of active BBI isoinhibitors, IBB1 and IBBD2, in six commercial soymilks. By using cation exchange chromatography, the BBI isoinhibitors were isolated and their specific trypsin inhibitory activity was used to estimate their amounts in soymilk samples. IBB1 and IBBD2 concentrations ranged from 0.44 to 5.20 and 0.27 to 4.60 mg/100ml of soymilk, respectively; total BBI, considered as the sum of both isoinhibitors, ranged from 0.60 to 9.07 mg/100ml of soymilk. These data show that physiologically relevant amounts of active BBI are present in commercial soymilk and may exert potential health-promoting effects.
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Affiliation(s)
- M Carmen Arques
- Department of Nutrition, Estación Experimental del Zaidín (CSIC), Profesor Albareda 1, 18008 Granada, Spain
| | - M Carmen Marín-Manzano
- Department of Nutrition, Estación Experimental del Zaidín (CSIC), Profesor Albareda 1, 18008 Granada, Spain
| | | | - Blanca Hernandez-Ledesma
- Department of Food Analysis and Bioactivity, Institute of Food Science (CIAL, CSIC-UAM), Nicolás Cabrera 9, 28049 Madrid, Spain
| | - Isidra Recio
- Department of Food Analysis and Bioactivity, Institute of Food Science (CIAL, CSIC-UAM), Nicolás Cabrera 9, 28049 Madrid, Spain
| | - Alfonso Clemente
- Department of Nutrition, Estación Experimental del Zaidín (CSIC), Profesor Albareda 1, 18008 Granada, Spain.
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20
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LIN LILIEL, MICK ROSEMARIE, WARE JEFFREY, METZ JAMES, LUSTIG ROBERT, VAPIWALA NEHA, RENGAN RAMESH, KENNEDY ANNR. Phase I randomized double-blind placebo-controlled single-dose safety studies of Bowman-Birk inhibitor concentrate. Oncol Lett 2014; 7:1151-1158. [PMID: 24944684 PMCID: PMC3961219 DOI: 10.3892/ol.2014.1855] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 11/11/2013] [Indexed: 11/15/2022] Open
Abstract
In previously performed animal studies and Phase I-II human trials, Bowman-Birk inhibitor concentrate (BBIC) appeared to be a promising cancer chemopreventive agent. The present study describes the results of two phase I randomized double-blind placebo-controlled trials performed in male subjects to assess the safety and toxicity of the original and new formulations of BBIC administered in a single dose as a suspension in orange juice. The dose of BBIC varied from 800-2,000 chymotrypsin inhibitor (CI) units. The BBI concentration in the serum samples collected from the subjects was analyzed by a dot-blot analysis procedure using the 5G2 monoclonal antibody, which is specific for reduced BBI. A total of 41 subjects were enrolled, 20 in the initial BBIC study and 21 in the second BBIC study. In these human trials, no clinically relevant changes in hematological or biochemical parameters were observed. Overall, BBIC was found to be well-tolerated. For these BBIC single-dose phase I trials, there was no dose-limiting toxicity for BBIC, even at the highest dose evaluated, and there were no apparent differences between the clinical trial results for the two formulations of BBIC. The bioavailability of BBI in the second clinical trial, which used the new BBIC formulation, was approximately 40 to 43% of the BBI bioavailability reached in the first clinical trial, which used the original BBIC formulation. The observed bioavailability difference was attributed to the different BBIC formulations used in these two clinical trials. These trials demonstrated that BBIC is safe when administered in a single dose of up to 2,000 CI units. Therefore, the results from the two trials indicate that a multi-dose trial of BBIC may be safely performed with doses of up to 2,000 CI units per day.
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Affiliation(s)
- LILIE L. LIN
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - ROSEMARIE MICK
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - JEFFREY WARE
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - JAMES METZ
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - ROBERT LUSTIG
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - NEHA VAPIWALA
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - RAMESH RENGAN
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - ANN R. KENNEDY
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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21
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Production of horsegram (Dolichos biflorus) Bowman-Birk inhibitor by an intein mediated protein purification system. Protein Expr Purif 2013; 89:16-24. [DOI: 10.1016/j.pep.2013.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Revised: 02/04/2013] [Accepted: 02/06/2013] [Indexed: 01/19/2023]
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22
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Amigo-Benavent M, Nitride C, Bravo L, Ferranti P, del Castillo MD. Stability and bioactivity of a Bowman–Birk inhibitor in orange juice during processing and storage. Food Funct 2013; 4:1051-60. [DOI: 10.1039/c3fo30354c] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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23
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Magee PJ, Owusu-Apenten R, McCann MJ, Gill CI, Rowland IR. Chickpea (Cicer arietinum) and Other Plant-Derived Protease Inhibitor Concentrates Inhibit Breast and Prostate Cancer Cell Proliferation In Vitro. Nutr Cancer 2012; 64:741-8. [DOI: 10.1080/01635581.2012.688914] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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24
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The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells. Cancer Metastasis Rev 2010; 29:511-28. [PMID: 20714786 DOI: 10.1007/s10555-010-9241-4] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The process of carcinogenesis is complex and not easy to eliminate. It includes the initial occurrence of genetic alterations which can lead to the inactivation of tumor-suppressor genes and further accumulation of genetic alterations during tumor progression. Looking for food and food components with biological properties, collectively called nutraceuticals, that can hinder such alterations and prevent the inactivation of tumor-suppressor genes is a very promising area for cancer prevention. Proteins and peptides are one group of nutraceuticals that show potential results in preventing the different stages of cancer including initiation, promotion, and progression. In this review, we summarized current knowledge on the use of nutraceutical proteins and peptides in cancer prevention and treatment. We focused on the role of plant protease inhibitors, lactoferrin and lactoferricin, shark cartilage, plant lectins, and lunasin in the apoptosis, angiogenesis, and metastasis of cancer cells. Also included are studies on bioavailability and clinical trials conducted on these promising proteins and peptides.
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25
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Caccialupi P, Ceci LR, Siciliano RA, Pignone D, Clemente A, Sonnante G. Bowman-Birk inhibitors in lentil: Heterologous expression, functional characterisation and anti-proliferative properties in human colon cancer cells. Food Chem 2010. [DOI: 10.1016/j.foodchem.2009.11.051] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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26
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Tang M, Asamoto M, Ogawa K, Naiki-Ito A, Sato S, Takahashi S, Shirai T. Induction of apoptosis in the LNCaP human prostate carcinoma cell line and prostate adenocarcinomas of SV40T antigen transgenic rats by the Bowman-Birk inhibitor. Pathol Int 2010; 59:790-6. [PMID: 19883429 DOI: 10.1111/j.1440-1827.2009.02445.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The soybean-derived serine protease inhibitor, Bowman-Birk inhibitor (BBI), has been reported as a potent chemoprevention agent against several types of tumors. The present study was undertaken to evaluate the effects of BBI on androgen-sensitive/dependent prostate cancers using a human prostate cancer cell (LNCaP) and the transgenic rats developing adenocarcinoma of the prostate (TRAP) model. Treatment of LNCaP prostate cancer cells with 500 microg/mL BBI resulted in inhibition of viability measured on WST-1 assays, with induction of connexin 43 (Cx43) and cleaved caspase-3 protein expression. Feeding of 3% roughly prepared BBI (BBIC) to TRAP from the age 3 weeks to 13 weeks resulted in significant reduction of the relative epithelial areas within the acinus and multiplicity of the adenocarcinomas in the lateral prostate lobes. Cx43- and terminal deoxynucleotidyl transferase mediated dUTP-biotin end labeling of fragmented DNA (TUNEL)-positive apoptotic cancer cells were more frequently observed in the lateral prostates treated with BBIC than in the controls. These in vivo and in vitro results suggest that BBI possesses chemopreventive activity associated with induction of Cx43 expression and apoptosis.
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Affiliation(s)
- MingXi Tang
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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27
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Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109. Breast Cancer Res Treat 2009; 124:27-38. [PMID: 20035377 DOI: 10.1007/s10549-009-0699-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2009] [Accepted: 12/16/2009] [Indexed: 10/20/2022]
Abstract
Serine proteases have been implicated in many stages of cancer development, facilitating tumor cell growth, invasion, and metastasis, and naturally occurring serine protease inhibitors have shown promise as potential anticancer therapeutics. Optimal design of inhibitors as potential therapeutics requires the identification of the specific serine proteases involved in disease progression and the functional targets responsible for the tumor-promoting properties. Here, we use the HMT-3522 breast cancer progression series grown in 3D organotypic culture conditions to find that serine protease inhibitors cause morphological reversion of the malignant T4-2 cells, assessed by inhibition of proliferation and formation of acinar structures with polarization of basal markers, implicating serine protease activity in their malignant growth behavior. We identify PRSS3/mesotrypsin upregulation in T4-2 cells as compared to their nonmalignant progenitors, and show that knockdown of PRSS3 attenuates, and treatment with recombinant purified mesotrypsin enhances, the malignant growth phenotype. Using proteomic methods, we identify CD109 as the functional proteolytic target of mesotrypsin. Our study identifies a new mediator and effector of breast cancer growth and progression.
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28
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Kennedy A. The Status of Human Trials Utilizing Bowman–Birk Inhibitor Concentrate from Soybeans. ACTA ACUST UNITED AC 2009. [DOI: 10.1201/9781420026566.ch12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2023]
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Qi RF, Liu ZX, Xu SQ, Zhang L, Shao XX, Chi CW. Small peptides derived from the Lys active fragment of the mung bean trypsin inhibitor are fully active against trypsin. FEBS J 2009; 277:224-32. [PMID: 19954491 DOI: 10.1111/j.1742-4658.2009.07476.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The Bowman-Birk protease inhibitors have recently attracted attention for their potential as cancer preventive and suppressing agents. They contain two canonical binding loops, both consisting of nine highly conserved residues capable of inhibiting corresponding serine proteases. In this study, we cloned the cDNA of the mung bean trypsin inhibitor, one of the most studied Bowman-Birk protease inhibitors. A modified peptide, Lys33GP, with 33 residues derived from the long chain of the Lys active fragment of mung bean trypsin inhibitor, was successfully expressed in Escherichia coli as a glutathione-S-transferase fusion protein. The recombinant product was obtained with a high yield, and exhibited potent inhibitory activity. Meanwhile, a shorter peptide composed of only 16 residues (the Lys16 peptide), corresponding to the active core of the fragment, was synthesized. Both the recombinant and the synthesized peptides had the same inhibitory activity toward trypsin at a molar ratio of 1 : 1, implying that the Lys16 peptide with two disulfide bonds is possibly the essential structural unit for inhibitory activity. Using site-directed mutagenesis, the P(1) position Lys was replaced by Phe, and the resulting mutant, Lys33K/F, was determined to have potent chymotrypsin inhibitory activity. Both Lys33GP and the Lys33K/F mutant may be potential pharmaceutical agents for the prevention of oncogenesis.
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Affiliation(s)
- Rui-Feng Qi
- Institute of Protein Research, Tongji University, Shanghai, China
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30
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Touil T, Ciric B, Ventura E, Shindler KS, Gran B, Rostami A. Bowman-Birk inhibitor suppresses autoimmune inflammation and neuronal loss in a mouse model of multiple sclerosis. J Neurol Sci 2008; 271:191-202. [PMID: 18544456 DOI: 10.1016/j.jns.2008.04.030] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 04/11/2008] [Accepted: 04/22/2008] [Indexed: 12/25/2022]
Abstract
The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor. BBI concentrate (BBIC) is an extract enriched with BBI, but predominantly contains other ingredients including several protease inhibitors. We previously found that BBIC administration to Lewis rats with experimental autoimmune encephalomyelitis (EAE) significantly suppresses disease. In the present study we determined whether BBI mediates the suppressive effects of BBIC in EAE, evaluated its potential neuroprotective effects, and investigated mechanisms of BBI action. We tested effects of purified BBI on clinical and histopathological parameters of EAE in two models (relapsing/remitting EAE in SJL/J mice and chronic EAE in C57BL/6 mice). Effects of BBI were compared to BBIC in relapsing/remitting EAE, and effects of BBI on neuronal survival were examined during acute optic neuritis. Treatment with BBI in both EAE models significantly improved EAE disease parameters (onset, severity, weight loss, inflammation and demyelination). BBI significantly reduced the incidence of optic neuritis and prevented loss of retinal ganglion cells. In most experiments proliferation of immune cells derived from BBI-treated mice was significantly lower relative to control groups. Using Boyden's chamber assay we found that BBI inhibited invasiveness of activated splenocytes through the matrigel barrier. BBI also induced higher production of EAE-suppressive cytokine IL-10 by immune cells. These results demonstrate that BBI is the active component of BBIC that ameliorates clinical EAE. BBI reduces inflammation and attenuates neuronal loss, making it an excellent candidate for oral therapy in MS. BBI likely ameliorates EAE by inhibiting multiple pathways involved in disease pathogenesis.
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Affiliation(s)
- Tarik Touil
- Department of Neurology, Thomas Jefferson University, Jefferson Hospital for Neuroscience, 900 Walnut Street, Suite 300, Philadelphia, PA 19107, USA
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31
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Abstract
Extracellular plant peptides perform a large variety of functions, including signalling and defence. Intracellular peptides often have physiological functions or may merely be the products of general proteolysis. Plant peptides have been identified and, in part, functionally characterized through biochemical and genetic studies, which are lengthy and in some cases impractical. Peptidomics is a branch of proteomics that has been developed over the last 5 years, and has been used mainly to study neuropeptides in animals and the degradome of proteases. Peptidomics is a fast, efficient methodology that can detect minute and transient amounts of peptides and identify their post-translational modifications. This review describes known plant peptides and introduces the use of peptidomics for the detection of novel plant peptides.
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Affiliation(s)
- Naser Farrokhi
- National Institute of Genetic Engineering and Biotechnology, Pajoohesh Blvd., Tehran-Karaj Highway, 17th Km., Tehran, Iran.
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32
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Abstract
The Bowman-Birk inhibitor (BBI) is a small water-soluble protein present in soybean and almost all monocotyledonous and dicotyledonous seeds. The molecular size of BBI ranges from 1,513 Da to about 20,000 Da. BBI is to seeds what alpha(1)-antitrypsin is to humans. Soy-based food products rich in BBI include soybean grits, soymilk, oilcake, soybean isolate, and soybean protein concentrate. BBI is stable within the pH range encountered in most foods, can withstand boiling water temperature for 10 min, resistant to the pH range and proteolytic enzymes of the gastrointestinal tract, bioavailable, and not allergenic. BBI reduces the proteolytic activities of trypsin, chymotrypsin, elastase, cathepsin G, and chymase, serine protease-dependent matrix metalloproteinases, urokinase protein activator, mitogen activated protein kinase, and PI3 kinase, and upregulates connexin 43 (Cx43) expression. Several studies have demonstrated the efficacy of BBI against tumor cells in vitro, animal models, and human phase IIa clinical trials. FDA considers BBI as a drug. In 1999, FDA allowed a health claim on food labels stating that a daily diet containing 25 grams of soy protein, also low in saturated fat and cholesterol, may reduce the risk of heart disease [corrected] This review highlights the biochemical and functional food properties of the Bowman-Birk inhibitor.
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Affiliation(s)
- Jack N Losso
- Food Protein Biotechnology Laboratory, Department of Food Science, Louisiana State University Agricultural Center, Baton Rouge, LA 70803, USA.
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33
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Lichtenstein GR, Deren JJ, Katz S, Lewis JD, Kennedy AR, Ware JH. Bowman-Birk inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis. Dig Dis Sci 2008; 53:175-80. [PMID: 17551835 DOI: 10.1007/s10620-007-9840-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2006] [Accepted: 04/05/2007] [Indexed: 02/07/2023]
Abstract
Bowman-Birk inhibitor concentrate (BBIC), a soy extract with high protease inhibitor activity, is efficacious in the treatment of colitis in mice and has been used in numerous clinical trials. A randomized, double blind, placebo-controlled trial was performed to investigate the safety and possible benefits of BBIC in patients with active ulcerative colitis. The Sutherland Disease Activity Index (SDAI) was used to assess disease activity, response (Index decrease > or = 3), and remission (Index < or = 1 with no rectal bleeding) in patients receiving 12 weeks of therapy. The Index scores of patients receiving BBIC decreased more than those of the patients receiving placebo (P = 0.067). Beneficial trends were observed in the rates of remission (P = 0.082) and clinical response (P = 0.22). No severe adverse events were observed. This trial suggests a potential benefit over placebo for both achieving clinical response and induction of remission in patients with active ulcerative colitis without apparent toxicity.
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Affiliation(s)
- Gary R Lichtenstein
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA
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Molecular nutraceutics as a mean to investigate the positive effects of legume seed proteins on human health. Trends Food Sci Technol 2007. [DOI: 10.1016/j.tifs.2007.04.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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McCormick DL, Johnson WD, Bosland MC, Lubet RA, Steele VE. Chemoprevention of Rat Prostate Carcinogenesis by Soy Isoflavones and by Bowman-Birk Inhibitor. Nutr Cancer 2007; 57:184-93. [PMID: 17571952 DOI: 10.1080/01635580701277478] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Epidemiology studies suggest that soy consumption confers protection against human prostate cancer. To identify the soy component(s) that may be responsible for this chemopreventive activity, studies were conducted to determine the influence of a soy isoflavone mixture (PTI G-2535; 45% genistein, 22% daidzein, 2% glycitein) and a soy-derived protease inhibitor (Bowman-Birk Inhibitor Concentrate; BBIC) on prostate carcinogenesis in rats. Prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single intravenous injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In separate studies, PTI G-2535 and BBIC were administered continuously at 0 (control), 200, or 2000 mg/kg diet, beginning 1 wk post-MNU. PTI G-2535 and BBIC both conferred modest, but statistically significant and dose-related protection against carcinogenesis in the dorsolateral+anterior prostate. These data demonstrate that both the isoflavone and protein (protease inhibitor) components of soy can inhibit prostate carcinogenesis in the rat. However, the modest individual activities of soy isoflavones and BBIC suggest that while both components may contribute to the chemopreventive activity of soy, combination administration (or exposure to whole soy) may be more effective in prostate cancer prevention than is administration of either component alone.
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Affiliation(s)
- David L McCormick
- Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616, USA.
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Gran B, Tabibzadeh N, Martin A, Ventura ES, Ware JH, Zhang GX, Parr JL, Kennedy AR, Rostami AM. The protease inhibitor, Bowman-Birk Inhibitor, suppresses experimental autoimmune encephalomyelitis: a potential oral therapy for multiple sclerosis. Mult Scler 2007; 12:688-97. [PMID: 17262995 DOI: 10.1177/1352458506070769] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. Proteases generated during inflammation are involved in the induction of tissue damage during inflammatory demyelination in the central nervous system (CNS). The Bowman-Birk Inhibitor (BBI), a soy-derived protease inhibitor with anti-carcinogenic and anti-inflammatory properties, has been shown to be well tolerated in clinical trials for pre-cancerous conditions, such as oral leukoplakia and the inflammatory disease, ulcerative colitis. We hypothesized that BBI may modulate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The BBI concentrate (BBIC), a soybean extract enriched in BBI, was administered to myelin basic protein (MBP)-immunized Lewis rats by gastric gavage in different treatment regimens, during the induction or the effector phase of disease. BBIC significantly delayed disease onset and suppressed disease severity, clinically and pathologically, in all treatment protocols. Both in vitro and ex vivo, BBIC inhibited MBP-specific proliferation of lymph node cells. BBIC reduced the activity of matrix metalloproteinase (MMP)-2 and -9 in spleen cell supernatants and was detected in the CNS of treated rats. BBIC suppresses EAE, it can be administered orally, and it is safe and relatively inexpensive. It may have a therapeutic role in patients with MS.
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MESH Headings
- Administration, Oral
- Animals
- Brain/metabolism
- Cell Division/immunology
- Encephalomyelitis, Autoimmune, Experimental/drug therapy
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Enzyme Inhibitors/pharmacology
- Female
- Gelatinases/antagonists & inhibitors
- Gelatinases/metabolism
- Macrolides/pharmacology
- Multiple Sclerosis/drug therapy
- Myelin Basic Protein/pharmacology
- Rats
- Rats, Inbred Lew
- Spleen/cytology
- T-Lymphocytes/cytology
- T-Lymphocytes/drug effects
- Trypsin Inhibitor, Bowman-Birk Soybean/pharmacokinetics
- Trypsin Inhibitor, Bowman-Birk Soybean/pharmacology
- Trypsin Inhibitors/pharmacokinetics
- Trypsin Inhibitors/pharmacology
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Affiliation(s)
- B Gran
- Division of Clinical Neurology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
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Abstract
Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland caused by increases in number of both epithelial and stromal cells. Clinically, BPH leads to voiding dysfunction, which is most often referred to as lower urinary tract symptoms (LUTS). Historically, the only treatments for LUTS due to BPH were watchful waiting or surgery (transurethral or open prostatectomy). However, over the last 20 years medical therapy has taken a prominent role in the management of BPH. Current medical treatments for BPH include alpha-adrenergic receptor antagonists, inhibitors of the 5-alpha reductase enzyme and various phytotherapies. These agents are generally effective and safe; however, many patients are unable to tolerate the side effects or are refractory to medical management and require surgery. In light of this, many potential new therapies for the treatment of BPH are under development. Some represent a variation of current treatments, whereas others target novel molecular pathways within the prostate. The aim of this review is to examine current pharmacotherapies as well as to highlight emerging drugs that may improve our treatment of patients with LUTS secondary to BPH.
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Affiliation(s)
- Travis L Bullock
- Division of Urology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Leung YK, Gao Y, Lau KM, Zhang X, Ho SM. ICI 182,780-regulated gene expression in DU145 prostate cancer cells is mediated by estrogen receptor-beta/NFkappaB crosstalk. Neoplasia 2006; 8:242-9. [PMID: 16756716 PMCID: PMC1600682 DOI: 10.1593/neo.05853] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Estrogen receptor (ER)-beta is the predominant ER subtype in prostate cancer (PCa). We previously demonstrated that ICI 182,780 (ICI), but not estrogens, exerted dose-dependent growth inhibition on DU145 PCa cells by an ER-beta-mediated pathway. Transcriptional profiling detected a greater than three-fold upregulation of seven genes after a 12-hour exposure to 1 microM ICI. Semiquantitative reverse transcriptase polymerase chain reaction confirmed the upregulation of four genes by ICI: interleukin-12alpha chain, interleukin-8, embryonic growth/differentiation factor, and RYK tyrosine kinase. Treatment with an ER-beta antisense oligonucleotide reduced cellular ER-beta mRNA and induced loss of expression of these genes. Sequence analysis revealed the presence of consensus NFkappaB sites, but not estrogen-responsive elements, in promoters of all four genes. Reporter assay and chromatin immunoprecipitation experiments demonstrated that ICI-induced gene expression could be mediated by crosstalk between ER-beta and the NFkappaB signaling pathway, denoting a novel mechanism of ER-beta-mediated ICI action. Therefore, combined therapies targeting ER-beta and NFkappaB signaling may be synergistic as treatment for PCa.
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Affiliation(s)
- Yuet-Kin Leung
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Ying Gao
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Kin-Mang Lau
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Xiang Zhang
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Shuk-Mei Ho
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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Pospisil P, Iyer LK, Adelstein SJ, Kassis AI. A combined approach to data mining of textual and structured data to identify cancer-related targets. BMC Bioinformatics 2006; 7:354. [PMID: 16857057 PMCID: PMC1555615 DOI: 10.1186/1471-2105-7-354] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Accepted: 07/20/2006] [Indexed: 11/24/2022] Open
Abstract
Background We present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein databases (UniProt, InterPro, NCBI Entrez), and state-of-the-art pathway knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas. Results The data mining method identified previously undetected targets. Our combined strategy applied to each cancer type identified a minimum of 375 proteins expressed within the extracellular space and/or attached to the plasma membrane. The method led to the recognition of human cancer-related hydrolases (on average, ~35 per cancer type), among which were prostatic acid phosphatase, prostate-specific antigen, and sulfatase 1. Conclusion The combined data mining of several databases overcame many of the limitations of querying a single database and enabled the facile identification of gene products. In the case of cancer-related targets, it produced a list of putative extracellular, hydrolytic enzymes that merit additional study as candidates for cancer radioimaging and radiotherapy. The proposed data mining strategy is of a general nature and can be applied to other biological databases for understanding biological functions and diseases.
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Affiliation(s)
- Pavel Pospisil
- Harvard Medical School, Department of Radiology, 200 Longwood Avenue, Boston, Massachusetts, USA
| | - Lakshmanan K Iyer
- Bauer Center for Genomics Research, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts, USA
| | - S James Adelstein
- Harvard Medical School, Department of Radiology, 200 Longwood Avenue, Boston, Massachusetts, USA
| | - Amin I Kassis
- Harvard Medical School, Department of Radiology, 200 Longwood Avenue, Boston, Massachusetts, USA
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Johnson WD, Dooley L, Morrissey RL, Arp L, Kapetanovic I, Crowell JA, McCormick DL. Oncogenicity evaluations of chemopreventive soy components in p53((+/-)) (p53 knockout) mice. Int J Toxicol 2006; 25:219-28. [PMID: 16717037 DOI: 10.1080/10915810600683366] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Epidemiologic data suggest that soy consumption may protect against cancer induction in several tissues in humans. Although the soy components responsible for this activity remain unidentified, isoflavones (e.g., genistein) and protease inhibitors (e.g., Bowman-Birk inhibitor complex [BBIC]) demonstrate chemopreventive activity in several animal cancer models. As part of their preclinical development for cancer prevention, PTI G-2535 (a soy isoflavone mixture containing 45% genistein, 23% daidzein, and 4% glycitein) and BBIC were evaluated for oncogenicity in p53((+/-)) mice. In separate studies, groups of 25 p53((+/-)) mice/sex received daily gavage exposure to PTI G-2535 (0, 250, 1000, or 2500 mg/kg/day) or BBIC (0, 500, 1000, or 2000 mg/kg/day) for 6 months. The high doses of both PTI G-2535 and BBIC were limited by viscosity. p-Cresidine (400 mg/kg/day) served as a positive-control article in both studies. PTI G-2535 induced no gross toxicity in any animal, but did induce a dose-related suppression of body weight gain in male mice. Modest hematologic alterations and increased liver and spleen weights were seen in both sexes exposed to the isoflavone mixture. BBIC had no significant effect on body weight, food consumption, clinical pathology, or organ weights in either sex. Histopathologic evaluations demonstrated no increases in the incidence of either benign or malignant tumors in any group of p53((+/-)) mice exposed to PTI G-2535 or to BBIC. By contrast, the positive-control article, p-cresidine, induced urinary bladder cancers in both studies. Neither PTI G-2535 nor BBIC demonstrates any evidence of oncogenicity in the p53((+/-)) mouse model.
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Affiliation(s)
- William D Johnson
- Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616, USA
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De Mejia EG, Del Carmen Valadez-Vega M, Reynoso-Camacho R, Loarca-Pina G. Tannins, trypsin inhibitors and lectin cytotoxicity in tepary (Phaseolus acutifolius) and common (Phaseolus vulgaris) beans. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2005; 60:137-45. [PMID: 16187017 DOI: 10.1007/s11130-005-6842-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
This study compared the levels of antinutritional components and cytotoxic effect of extracts, from tepary (Phaseolus acutifolius) and common (Phaseolus vulgaris) beans. Antinutritional factors were evaluated by determining their effect on the viability of epithelial cells isolated from rat small intestine. The protein and carbohydrates content were similar in all the genotypes studied (20 and 60%, respectively). Common beans presented higher content of trypsin inhibitors, tannins and lectins than tepary beans. There was not a significant correlation between tannins and cooking time. However, water absorption and cooking time correlated significantly (p < 0.05). Considerable variation was observed in lectin activity (1302-18161 Ul/mg) of extracts from different beans. Tannins, lectins, trypsin inhibitors and fat content differed between bean varieties whereas protein content was similar. The percent cellularity on rat epithelial cells was significantly different among protein extracts from different bean cultivars and ranged between 53.5% and 87.4% (p < 0.05). These results suggest that the incorporation of tepary beans in the diet would not alter the current nutritional contribution of common beans or introduce adverse toxic effects. The agronomic characteristics of tepary beans make them attractive for cultivation. However, the harder to cook phenomenon may be a limiting factor that needs further consideration.
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Affiliation(s)
- Elvira Gonzalez De Mejia
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 61801, USA.
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Qi RF, Song ZW, Chi CW. Structural features and molecular evolution of Bowman-Birk protease inhibitors and their potential application. Acta Biochim Biophys Sin (Shanghai) 2005; 37:283-92. [PMID: 15880256 DOI: 10.1111/j.1745-7270.2005.00048.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The Bowman-Birk inhibitors (BBIs) are well-studied serine protease inhibitors that are abundant in dicotyledonous and monocotyledonous plants. BBIs from dicots usually have a molecular weight of 8k and are double-headed with two reactive sites, whereas those from monocots can be divided into two classes, one approximately 8 kDa in size with one reactive site (another reactive site was lost) and the other approximately 16 kDa in size with two reactive sites. The reactive site is located at unique exposed surfaces formed by a disulfide-linked beta-sheet loop that is highly conserved, rigid and mostly composed of nine residues. The structural features and molecular evolution of inhibitors are described, focusing on the conserved disulfide bridges. The sunflower trypsin inhibitor-1 (SFTI-1), with 14 amino acid residues, is a recently discovered bicyclic inhibitor, and is the most small and potent naturally occurring Bowman-Birk inhibitor. Recently, BBIs have become a hot topic because of their potential applications. BBIs are now used for defense against pathogens and insects in transgenic plants, which has advantages over using toxic and polluting insecticides. BBIs could also be applied in the prevention of cancer, Dengue fever, and inflammatory and allergic disorders, because of their inhibitory activity with respect to the serine proteases that play a pivotal role in the development and pathogenesis of these diseases. The canonical nine-residue loop of BBIs/STFI-1 provides an ideal template for drug design of specific inhibitors to target their respective proteases.
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Affiliation(s)
- Rui-Feng Qi
- College of Life Science, Northwest Normal University, Lanzhou 730070, China.
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Witschi H, Espiritu I. Development of tobacco smoke-induced lung tumors in mice fed Bowman-Birk protease inhibitor concentrate (BBIC). Cancer Lett 2002; 183:141-6. [PMID: 12065088 DOI: 10.1016/s0304-3835(02)00156-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Male strain A/J mice were exposed, 6h a day, 5 days a week for 5 months to a mixture of 89% cigarette sidestream and 11% cigarette mainstream smoke and then allowed to recover for another 4 months in air. The animals were fed Bowman-Birk protease inhibitor concentrate (BBIC) at a concentration of 1% in AIN-93G diet either during smoke exposure, following smoke exposure or during the entire 9 months. At the end of the experiment, the incidence and multiplicity of lung tumors were determined. In a positive control experiment, strain A/J mice were injected with 3-methylcholanthrene (MCA) and fed a diet containing 1% BBIC; these animals were killed 5 months later. It was found that in the animals treated with MCA, BBIC decreased lung tumor multiplicities, whereas in the smoke exposed mice, BBIC did not modulate lung tumor development.
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Affiliation(s)
- Hanspeter Witschi
- Center for Health and the Environment and Department of Molecular Biosciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA.
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Brauer ABE, Kelly G, Matthews SJ, Leatherbarrow RJ. The (1)H-NMR solution structure of the antitryptic core peptide of Bowman-Birk inhibitor proteins: a minimal canonical loop. J Biomol Struct Dyn 2002; 20:59-70. [PMID: 12144352 DOI: 10.1080/07391102.2002.10506822] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Bowman-Birk inhibitor (BBI) proteins contain an inhibitory motif comprising a disulfide-bonded sequence that interacts with serine proteinases. Recently, a small 14-residue peptide from sunflowers (SFTI-1), which has potent anti-trypsin activity, has been found to have the same motif. However, this peptide also has an unusual head-to-tail cyclisation. To address the role of the core inhibitory sequence itself, we have solved the (1)H-NMR solution structure of an antitryptic 11-residue cyclic peptide that corresponds to the core reactive site loops of both SFTI-1 and Bowman-Birk inhibitor proteins. A comparison is made between the secondary chemical shifts found in this family and the canonical regions of several other inhibitors, giving some insight into relative flexibility and hydrogen bonding patterns in these inhibitors. The solution structure of the core peptide in isolation is found to retain essentially the same three-dimensional arrangement of both backbone and side chains as observed in larger antitryptic BBI and SFTI-1 fragments as well as in the complete proteins. The retention of the canonical conformation in the core peptide explains the peptids inhibitory potency. It therefore represents a minimization of both the BBI and SFTI-1 sequences. We conclude that the core peptide is a conformationally defined, canonical scaffold, which can serve as a minimal platform for the engineering of biological activity.
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Affiliation(s)
- Arnd B E Brauer
- Department of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, SW7 2AY, U.K
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Prakash K, Pirozzi G, Elashoff M, Munger W, Waga I, Dhir R, Kakehi Y, Getzenberg RH. Symptomatic and asymptomatic benign prostatic hyperplasia: molecular differentiation by using microarrays. Proc Natl Acad Sci U S A 2002; 99:7598-603. [PMID: 12032329 PMCID: PMC124296 DOI: 10.1073/pnas.112191399] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2001] [Accepted: 04/01/2002] [Indexed: 11/18/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is a disease of unknown etiology that significantly affects the quality of life in aging men. Histologic BPH may present itself either as symptomatic or asymptomatic in nature. To elucidate the molecular differences underlying BPH, gene expression profiles from the prostate transition zone tissue have been analyzed by using microarrays. A set of 511 differentially expressed genes distinguished symptomatic and asymptomatic BPH. This genetic signature separates BPH from normal tissue but does not seem to change with age. These data could provide novel approaches for alleviating symptoms and hyperplasia in BPH.
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Affiliation(s)
- Kulkarni Prakash
- Gene Logic Inc., 708 Quince Orchard Road, Gaithersburg, MD 20878, USA
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