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Ann R Kennedy - One of the best experts on this subject based on the ideXlab platform.
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phase i randomized double blind placebo controlled single dose safety studies of Bowman Birk Inhibitor concentrate
Oncology Letters, 2014Co-Authors: Lilie L Lin, Rosemarie Mick, Jeffrey B Ware, James M Metz, Robert H Lustig, Neha Vapiwala, Ramesh Rengan, Ann R KennedyAbstract: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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Bowman Birk Inhibitor Concentrate and Oral Leukoplakia: A Randomized Phase IIb Trial
Cancer prevention research (Philadelphia Pa.), 2013Co-Authors: William B Armstrong, Ann R Kennedy, Thomas H Taylor, Raymond J. Melrose, Diana V. Messadi, Marjorie Perloff, Francisco Civantos, William GoodwinAbstract:Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.
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The Health Benefits of the Bowman-Birk Inhibitor
Antitumor Potential and other Emerging Medicinal Properties of Natural Compounds, 2013Co-Authors: Ann R KennedyAbstract:There have been numerous reviews on the beneficial effects and health benefits of the soybean protease Inhibitor known as the Bowman-Birk Inhibitor (BBI) [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. The early in vitro studies were so promising that in vivo studies were performed at a very early stage of BBI development. The results of animal carcinogenicity studies were sufficiently promising that permission to perform BBI human trials was sought. It was planned that human trials using BBI would be performed with BBI Concentrate (BBIC), a soybean extract enriched in BBI. BBIC achieved Investigational New Drug (IND) Status with the FDA in 1992, and human trials began at that time. There have been six INDs involving BBI human trial work for the following endpoints: cancer prevention (regression of a pre-malignant lesion known as oral leukoplakia), treatment of benign prostatic hyperplasia, prostate cancer detection and treatment (with measurements of prostate specific antigen levels and prostate volume, etc.), treatment of ulcerative colitis, gingivitis, or esophagitis (and/or alleviation of adverse side effects of lung cancer treatment), as described elsewhere [15]. There are numerous publications on the results from these trial areas [16, 17, 18, 19, 20, 21]. In this “expert opinion”, the current status of BBI experimentation and human trials will be discussed.
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development of the Bowman Birk Inhibitor for oral cancer chemoprevention and analysis of neu immunohistochemical staining intensity with Bowman Birk Inhibitor concentrate treatment
Laryngoscope, 2010Co-Authors: William B Armstrong, Steven X Wan, Ann R Kennedy, Thomas H Taylor, Frank L MeyskensAbstract:Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial. Part I is a selected literature review. Part II is a retrospective analysis of pathological specimens prospectively obtained from the Phase IIa clinical trial of Bowman-Birk Inhibitor concentrate. Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin Inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment. Mean Neu staining score was significantly higher in lesions compared with uninvolved mucosa (P <.001). Pretreatment staining scores for biopsy specimens of lesions and control biopsy specimens of normal-appearing tissues were correlated (Spearman correlation coefficient [r] = 0.375, P =.045), but no correlation between lesion and control biopsy specimen scores was evident after treatment. The change in Neu staining score with Bowman-Birk Inhibitor concentrate treatment in control site biopsy specimens demonstrated an inverse relationship of change in lesion area with Bowman-Birk Inhibitor concentrate treatment (Spearman r = -0.493, P <.007). Bowman-Birk Inhibitor concentrate shows promise to become an effective nontoxic chemopreventive agent based on results of extensive preclinical studies, and Phase I and Phase IIa clinical trials. Bowman-Birk Inhibitor concentrate has dose-related clinical activity against oral leukoplakia and modulates levels of Neu and protease activity. The current investigation identified increased Neu staining intensity in hyperplastic lesions compared with simultaneously obtained biopsy specimens of normal-appearing mucosa both before and after Bowman-Birk Inhibitor concentrate treatment. This finding supports prior observations that increased Neu expression is present in a subset of oral premalignant lesions and head and neck cancers. The trend of increased Neu staining score in control biopsy tissues of subjects exhibiting decreased lesion area following Bowman-Birk Inhibitor concentrate treatment raises questions about the mechanisms of Bowman-Birk Inhibitor concentrate action. One possible explanation is that Bowman-Birk Inhibitor stabilizes the extracellular domain of Neu, thereby preventing receptor truncation and internalization. Further study of modulation of Neu and protease activity by Bowman-Birk Inhibitor concentrate treatment may provide insights into the role of proteases and protease Inhibitors in oral premalignant lesions and the mechanisms underlying Bowman-Birk Inhibitor concentrate effects. A Phase IIb randomized, placebo-controlled clinical trial to determine the clinical effectiveness of Bowman-Birk Inhibitor concentrate and further evaluate these candidate biomarkers is under way.
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Development of the Bowman-Birk Inhibitor for oral cancer chemoprevention and analysis of Neu immunohistochemical staining intensity with Bowman-Birk Inhibitor concentrate treatment.
The Laryngoscope, 2010Co-Authors: William B Armstrong, Ann R Kennedy, Thomas H Taylor, X. Steven Wan, Frank L MeyskensAbstract:Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial. Part I is a selected literature review. Part II is a retrospective analysis of pathological specimens prospectively obtained from the Phase IIa clinical trial of Bowman-Birk Inhibitor concentrate. Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin Inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment. Mean Neu staining score was significantly higher in lesions compared with uninvolved mucosa (P
David E. Wemmer - One of the best experts on this subject based on the ideXlab platform.
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three dimensional structure of soybean trypsin chymotrypsin Bowman Birk Inhibitor in solution
Biochemistry, 1993Co-Authors: Milton H Werner, David E. WemmerAbstract:The three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution has been determined by two-dimensional 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing using the program XPLOR. The structure was defined by 907 NOEs involving intra- and interresidue contacts which served as distance constraints for a protocol of dynamical simulated annealing. In addition, 48 phi angle constraints involving non-proline amino acids, 29 chi angle constraints, six omega angle constraints for the X-Pro peptide bond, and 35 stereoassignments for prochiral centers were incorporated during the course of the calculation. The protein is characterized by two distinct binding domains for serine protease. Each domain is comprised of a beta-hairpin (antiparallel beta-sheet and a cis-proline-containing type VIb reverse turn) with a short segment making a third strand of antiparallel beta-sheet. The structure determination and refinement are described, and the structure is compared to other structures of Bowman-Birk Inhibitors as well as other families of serine protease Inhibitors.
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Three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution.
Biochemistry, 1992Co-Authors: Milton H Werner, David E. WemmerAbstract:The three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution has been determined by two-dimensional 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing using the program XPLOR. The structure was defined by 907 NOEs involving intra- and interresidue contacts which served as distance constraints for a protocol of dynamical simulated annealing. In addition, 48 phi angle constraints involving non-proline amino acids, 29 chi angle constraints, six omega angle constraints for the X-Pro peptide bond, and 35 stereoassignments for prochiral centers were incorporated during the course of the calculation. The protein is characterized by two distinct binding domains for serine protease. Each domain is comprised of a beta-hairpin (antiparallel beta-sheet and a cis-proline-containing type VIb reverse turn) with a short segment making a third strand of antiparallel beta-sheet. The structure determination and refinement are described, and the structure is compared to other structures of Bowman-Birk Inhibitors as well as other families of serine protease Inhibitors.
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1h assignments and secondary structure determination of the soybean trypsin chymotrypsin Bowman Birk Inhibitor
Biochemistry, 1991Co-Authors: Milton H Werner, David E. WemmerAbstract:The {sup 1}H resonance assignments and secondary structure of the trypsin/chymotrypsin Bowman-Birk Inhibitor from soybeans were determined by nuclear magnetic resonance spectroscopy (NMR) at 600 MHz in an 18% acetonitrile-d{sub 3}/aqueous cosolvent. Resonances from 69 to 71 amino acids were assigned sequence specifically. Residues Q11-T15 form an antiparallel {beta}-sheet with residues Q21-S25 in the tryptic Inhibitory domain and an analogous region of antiparallel sheet forms between residues S38-A42 and Q48-V52 in the chymotryptic Inhibitory domain. The Inhibitory sites of each fragment (K16-S17 for trypsin, L43-S44 for chymotrypsin) are each part of a type VI like turn at one end of their respective region of the antiparallel {beta}-sheet. These structural elements are compared to those found in other Bowman-Birk Inhibitors.
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1H assignments and secondary structure determination of the soybean trypsin/chymotrypsin Bowman-Birk Inhibitor.
Biochemistry, 1991Co-Authors: Milton H Werner, David E. WemmerAbstract:The {sup 1}H resonance assignments and secondary structure of the trypsin/chymotrypsin Bowman-Birk Inhibitor from soybeans were determined by nuclear magnetic resonance spectroscopy (NMR) at 600 MHz in an 18% acetonitrile-d{sub 3}/aqueous cosolvent. Resonances from 69 to 71 amino acids were assigned sequence specifically. Residues Q11-T15 form an antiparallel {beta}-sheet with residues Q21-S25 in the tryptic Inhibitory domain and an analogous region of antiparallel sheet forms between residues S38-A42 and Q48-V52 in the chymotryptic Inhibitory domain. The Inhibitory sites of each fragment (K16-S17 for trypsin, L43-S44 for chymotrypsin) are each part of a type VI like turn at one end of their respective region of the antiparallel {beta}-sheet. These structural elements are compared to those found in other Bowman-Birk Inhibitors.
Milton H Werner - One of the best experts on this subject based on the ideXlab platform.
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three dimensional structure of soybean trypsin chymotrypsin Bowman Birk Inhibitor in solution
Biochemistry, 1993Co-Authors: Milton H Werner, David E. WemmerAbstract:The three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution has been determined by two-dimensional 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing using the program XPLOR. The structure was defined by 907 NOEs involving intra- and interresidue contacts which served as distance constraints for a protocol of dynamical simulated annealing. In addition, 48 phi angle constraints involving non-proline amino acids, 29 chi angle constraints, six omega angle constraints for the X-Pro peptide bond, and 35 stereoassignments for prochiral centers were incorporated during the course of the calculation. The protein is characterized by two distinct binding domains for serine protease. Each domain is comprised of a beta-hairpin (antiparallel beta-sheet and a cis-proline-containing type VIb reverse turn) with a short segment making a third strand of antiparallel beta-sheet. The structure determination and refinement are described, and the structure is compared to other structures of Bowman-Birk Inhibitors as well as other families of serine protease Inhibitors.
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Three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution.
Biochemistry, 1992Co-Authors: Milton H Werner, David E. WemmerAbstract:The three-dimensional structure of soybean trypsin/chymotrypsin Bowman-Birk Inhibitor in solution has been determined by two-dimensional 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing using the program XPLOR. The structure was defined by 907 NOEs involving intra- and interresidue contacts which served as distance constraints for a protocol of dynamical simulated annealing. In addition, 48 phi angle constraints involving non-proline amino acids, 29 chi angle constraints, six omega angle constraints for the X-Pro peptide bond, and 35 stereoassignments for prochiral centers were incorporated during the course of the calculation. The protein is characterized by two distinct binding domains for serine protease. Each domain is comprised of a beta-hairpin (antiparallel beta-sheet and a cis-proline-containing type VIb reverse turn) with a short segment making a third strand of antiparallel beta-sheet. The structure determination and refinement are described, and the structure is compared to other structures of Bowman-Birk Inhibitors as well as other families of serine protease Inhibitors.
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1h assignments and secondary structure determination of the soybean trypsin chymotrypsin Bowman Birk Inhibitor
Biochemistry, 1991Co-Authors: Milton H Werner, David E. WemmerAbstract:The {sup 1}H resonance assignments and secondary structure of the trypsin/chymotrypsin Bowman-Birk Inhibitor from soybeans were determined by nuclear magnetic resonance spectroscopy (NMR) at 600 MHz in an 18% acetonitrile-d{sub 3}/aqueous cosolvent. Resonances from 69 to 71 amino acids were assigned sequence specifically. Residues Q11-T15 form an antiparallel {beta}-sheet with residues Q21-S25 in the tryptic Inhibitory domain and an analogous region of antiparallel sheet forms between residues S38-A42 and Q48-V52 in the chymotryptic Inhibitory domain. The Inhibitory sites of each fragment (K16-S17 for trypsin, L43-S44 for chymotrypsin) are each part of a type VI like turn at one end of their respective region of the antiparallel {beta}-sheet. These structural elements are compared to those found in other Bowman-Birk Inhibitors.
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1H assignments and secondary structure determination of the soybean trypsin/chymotrypsin Bowman-Birk Inhibitor.
Biochemistry, 1991Co-Authors: Milton H Werner, David E. WemmerAbstract:The {sup 1}H resonance assignments and secondary structure of the trypsin/chymotrypsin Bowman-Birk Inhibitor from soybeans were determined by nuclear magnetic resonance spectroscopy (NMR) at 600 MHz in an 18% acetonitrile-d{sub 3}/aqueous cosolvent. Resonances from 69 to 71 amino acids were assigned sequence specifically. Residues Q11-T15 form an antiparallel {beta}-sheet with residues Q21-S25 in the tryptic Inhibitory domain and an analogous region of antiparallel sheet forms between residues S38-A42 and Q48-V52 in the chymotryptic Inhibitory domain. The Inhibitory sites of each fragment (K16-S17 for trypsin, L43-S44 for chymotrypsin) are each part of a type VI like turn at one end of their respective region of the antiparallel {beta}-sheet. These structural elements are compared to those found in other Bowman-Birk Inhibitors.
Robin J. Leatherbarrow - One of the best experts on this subject based on the ideXlab platform.
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inhibition of human β tryptase by Bowman Birk Inhibitor derived peptides creation of a new tri functional Inhibitor
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Dina Scarpi, Jeffrey D. Mcbride, Robin J. LeatherbarrowAbstract:Bowman-Birk Inhibitor proteins (BBIs), which are potent Inhibitors of chymotrypsin-like proteases, do not inhibit human beta-tryptase despite this protein having a chymotrypsin-like fold. We have reported previously that, in contrast, BBI-derived peptides (whose sequences incorporate the solvent exposed reactive site loop motif) are able to inhibit human beta-tryptase. This is due to their small size, which allows them to access the restricted active site(s) of tryptase, which has an unusual tetrameric arrangement with four active sites flanking a central pore. In this paper, we have examined the possibility of creating additional interactions within this pore by adding extensions to the BBI-peptide motif. We have taken the core disulfide-bridged sequence SCTKSIPPQCY and examined a series of extensions, at both the C- and N-termini, that bear a second positively charged Lys residue at their end. The aim was to construct Inhibitors that could make additional interactions in tryptase by spanning the gap between adjacent active sites in the enzyme, producing a double-headed Inhibitor; a positively charged group was used as the dominant specificity of this enzyme is for a positively charged P1 residue. Both N- and C-terminal extensions are found to produce Inhibitors of much increased potency, with a strong dependence of potency on chain length. Moreover, it was found that the C- and N-terminal extensions were able to synergise, with their combination on the same peptide producing an even better Inhibitor with a potency 10(4)-fold greater than the original sequence. We suggest that the C- and N-terminal extensions are picking up interactions with separate additional sites on the tryptase, making the doubly extended BBI peptide a tri-functional tryptase Inhibitor.
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synthesis and bio assay of rcm derived Bowman Birk Inhibitor analogues
Organic and Biomolecular Chemistry, 2004Co-Authors: Steven M. Miles, Robin J. Leatherbarrow, Stephen P. Marsden, William J. CoatesAbstract:Bowman–Birk Inhibitor analogues containing 2, 3 and 4-carbon analogues of the natural disulfide were synthesised via solid phase microwave-assisted RCM and found to have Ki values against chymotrypsin in the low to sub-micromolar range, the best replacement for the disulfide arising from the linkage by RCM of two L-homoallylglycine residues.
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Synthesis and bio-assay of RCM-derived Bowman–Birk Inhibitor analogues
Organic & biomolecular chemistry, 2003Co-Authors: Steven M. Miles, Robin J. Leatherbarrow, Stephen P. Marsden, William J. CoatesAbstract:Bowman–Birk Inhibitor analogues containing 2, 3 and 4-carbon analogues of the natural disulfide were synthesised via solid phase microwave-assisted RCM and found to have Ki values against chymotrypsin in the low to sub-micromolar range, the best replacement for the disulfide arising from the linkage by RCM of two L-homoallylglycine residues.
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A conserved cis peptide bond is necessary for the activity of Bowman-Birk Inhibitor protein.
Biochemistry, 2002Co-Authors: Arnd B.e. Brauer, Stephen Matthews, Gonzalo J. Domingo, Robert M. Cooke, Robin J. LeatherbarrowAbstract:The Bowman-Birk Inhibitor (BBI) family of protease Inhibitors has an Inhibitory region comprising a disulfide-linked nine-residue loop that adopts the characteristic canonical motif found in many serine protease Inhibitors. A unique feature of the BBI loop is the presence of a cis peptide bond at the edge of the Inhibitory loop. BBI-related protein fragments that encapsulate this loop retain the structure and Inhibitory activity of the parent protein. The most common BBI loop sequence has a proline-proline element with a cis-trans geometry at P3'-P4'. We have examined this element by analysis of the Inhibitory activity and structure for a series of synthetic fragments where each of these proline residues has been systematically replaced with alanine. The results show that only when a proline is present at P3' are potent inhibition and a cis peptide bond at that position in the solution structure observed, suggesting that this conformation is required for biological activity. Though a P4' proline is not essential for activity, it effectively stabilizes the cis conformation at P3' by suppressing alternative conformations. This is most evident from the Pro-Ala variant, which comprises a 1:1 mixture of slowly exchanging and structurally different cis and trans isomers. Monitoring the action of trypsin on this mixture by NMR shows that this protease interacts selectively with the cis P3' structure, providing direct evidence for the link between activity and the nativelike structure of the cis isomer. This is, to the best of our knowledge, the first example where cis isomer selectivity can be demonstrated for a proteinase.
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inhibition of human β tryptase by Bowman Birk Inhibitor derived peptides
Journal of Peptide Research, 2002Co-Authors: Dina Scarpi, J D Mcbride, Robin J. LeatherbarrowAbstract:Four 11-residue peptides based on the Bowman-Birk Inhibitor (BBI) structure were synthesized. These were tested for their ability to inhibit human beta-tryptase. Peptides with a basic residue at P1 inhibited tryptase even though the intact BBI protein is inactive. This result is interpreted in terms of the unique structural arrangement of active sites in tryptase which prevent access by large protein Inhibitors.
Jeffrey H. Ware - One of the best experts on this subject based on the ideXlab platform.
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Bowman-Birk Inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis.
Digestive diseases and sciences, 2007Co-Authors: Gary R. Lichtenstein, Ann R Kennedy, Julius J. Deren, Seymour Katz, James D. Lewis, Jeffrey H. WareAbstract: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 ≥ 3), and remission (Index ≤ 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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Protection against Adverse Biological Effects Induced by Space Radiation by the Bowman-Birk Inhibitor and Antioxidants
Radiation research, 2006Co-Authors: Ann R Kennedy, Zhaozong Zhou, Jeremiah J. Donahue, Jeffrey H. WareAbstract:This study was undertaken to evaluate the protective effects of the soybean-derived Bowman-Birk Inhibitor (BBI), BBI concentrate (BBIC) and/or antioxidants against the adverse biological effects induced by space radiation in cultured human epithelial cells. The effects of BBI, BBIC and a combination of ascorbic acid, co-enzyme Q10, L-selenomethionine (SeM) and vitamin E succinate on proton and HZE-particle [high-energy (high E) nuclei of heavier (high atomic number, Z) elements] radiation-induced cytotoxicity in MCF10 human breast epithelial cells and a phenotypic change associated with transformation in HTori-3 human thyroid epithelial cells were assessed with a clonogenic survival assay and a soft agar colony formation assay. The results demonstrate that BBIC and antioxidants are effective in protecting against space radiation-induced cytotoxicity in MCF10 cells and BBI, BBIC and antioxidants are effective in protecting against a space radiation-induced phenotypic change associated with transformation of HTori-3 cells.
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Detection of Bowman-Birk Inhibitor and anti-Bowman-Birk Inhibitor antibodies in sera of humans and animals treated with Bowman-Birk Inhibitor concentrate.
Nutrition and cancer, 2002Co-Authors: X. Steven Wan, Jeffrey H. Ware, David G Serota, James A. Crowell, Ann R KennedyAbstract:The Bowman-Birk Inhibitor (BBI) is a soybean-derived serine protease Inhibitor with anticarcinogenic activities. BBI, in the form of BBI concentrate (BBIC), is currently being evaluated in clinical trials as a human cancer-preventive agent. In the present study, an enzyme-linked immunosorbent assay was used to measure BBI concentrations in serum samples collected from human subjects and animals treated with BBIC. The results demonstrate that the serum BBI concentration was higher than the baseline level for the patients after treatment with BBIC at 100-800 chymotrypsin-Inhibitor units/day for 0.5, 1, 2, 4, and 6 mo. The increase in serum BBI concentration was also observed in dogs treated with BBIC at 100-1,000 mg/kg/day for 52 wk, and the increase was dose dependent. The results also indicate that anti-BBI antibodies were present in animals and the serum levels of anti-BBI antibodies increased significantly in mice treated with BBIC at 100-1,000 mg/kg/day for 15 and 26 wk. The increase in the serum level of anti-BBI antibodies in dogs treated with BBIC was not statistically significant, and no increase in the serum level of anti-BBI antibodies was observed in human subjects after BBIC treatment. These results suggest that orally ingested BBI is absorbed by human subjects and animals and that some animals develop antibodies to BBI in response to treatment with BBIC.
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Urinary excretion of Bowman-Birk Inhibitor in humans after soy consumption as determined by a monoclonal antibody-based immunoassay.
Cancer epidemiology biomarkers & prevention : a publication of the American Association for Cancer Research cosponsored by the American Society of Pre, 2000Co-Authors: X. Steven Wan, Jeffrey H. Ware, Karl E. Anderson, Ann R KennedyAbstract:The Bowman-Birk Inhibitor (BBI) found in soybeans is a serine protease Inhibitor with anticarcinogenic activity. In the present study, an ELISA for BBI was developed with the use of a monoclonal antibody against a reduced form of BBI. This newly developed ELISA method was used to measure the urinary levels of BBI metabolites in nine human subjects after consumption of 36-oz or 60-oz soymilk (containing 105 or 175 mg of BBI) at two time points 36 h apart. The results demonstrate that urinary BBI excretion rates peaked within 6 h and decreased to baseline levels within 12-24 h after soymilk ingestion. The changes in BBI:creatinine ratios in urine closely paralleled the changes in urinary BBI excretion rates after soymilk consumption. These data suggest that BBI ingested p.o. is absorbed and could be bioavailable for cancer chemoprevention in other organs in addition to those in the gastrointestinal tract.
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treatment with soybean derived Bowman Birk Inhibitor increases serum prostate specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice
The Prostate, 1999Co-Authors: Steven X Wan, Jeffrey H. Ware, Paul M. Newberne, Lili Zhang, Sydney M Evans, Larry C Clark, Ann R KennedyAbstract:Background Bowman Birk Inhibitor (BBI) is an anticarcinogenic serine protease Inhibitor that may inhibit the protease activity of prostate-specific antigen (PSA) and the growth of human prostate cancer xenografts in nude mice. Methods Human prostate cancer xenografts were established by implanting LNCaP cells into the prostate glands of NCRNU-M athymic nude mice. The animals with established tumors were maintained on a control diet or diets supplemented with 1% BBI or 1%, 2%, or 3% BBI concentrate (BBIC) for 6 weeks. The serum PSA concentrations were determined before and after the BBI or BBIC treatment period. The final tumor loads were determined at autopsy. Results Treatment with BBI or BBIC decreased the final tumor load and increased the tumor doubling time and PSA density in the nude mice bearing human prostate cancer xenografts. Conclusions BBI and/or BBIC could be useful for prostate cancer treatment.