Biomedical subjects

A R Kennedy

Publications and source records attributed to A R Kennedy.

At least 37 records · Page 2Linked to original sources

PubMed2001

Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei.

Cocaine- and amphetamine-regulated transcript is expressed in hypothalamic regions involved in the central control of food intake. Previous data have implicated cocaine- and amphetamine-regulated transcript as an anorectic peptide. We studied the effect of the active fragment of cocaine- and amphetamine-regulated transcript, cocaine- and amphetamine-regulated transcript-(55-102), on feeding when injected into discrete nuclei of the hypothalamus. Cocaine- and amphetamine-regulated transcript-(55-102) (0.04 nmol) elicited a delayed, but significant, increase in feeding in 24-h fasted rats after injection into the ventromedial nucleus (1-2 h, 261 +/- 60% of control; P < 0.05) and arcuate nucleus (1-2 h, 225 +/- 38% of control; P < 0.05) of the hypothalamus. Administration of a higher dose of cocaine- and amphetamine-regulated transcript-(55-102) (0.2 nmol) elicited a significant increase in feeding after injection into the ventromedial nucleus (1-2 h, 1253 +/- 179% of control; P < 0.001), arcuate nucleus (1-2 h, 265 +/- 43% of control; P < 0.05), paraventricular nucleus (2-4 h food intake, 186 +/- 29% of control; P < 0.05), lateral hypothalamic area (2-4 h, 280 +/- 34% of control; P < 0.001), anterior hypothalamic area (2-4 h, 252 +/- 42% of control; P < 0.01), dorsomedial nucleus (2-4 h, 368 +/- 29% of control;P < 0.001) and supraoptic nucleus (2-4 h, 212 +/- 34% of control; P < 0.05) of the hypothalamus. Administration of cocaine- and amphetamine-regulated transcript-(55-102) into the third ventricle of the hypothalamus resulted in an inhibition in feeding [0-4 h (0.4 nmol), 33 +/- 13% control; P < 0.001], but was associated with marked abnormalities in behavior, which may have interfered with feeding. These behavioral abnormalities were not observed after the administration of cocaine- and amphetamine-regulated transcript-(55-102) directly into the arcuate nucleus. These data suggest that cocaine- and amphetamine-regulated transcript may play an orexigenic role in the hypothalamic feeding circuitry.

Animals↗

PubMed2001

The actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes.

Tuberoinfundibular peptide is a recently discovered agonist for the PTH receptor-2; the latter has a wide distribution including the external zone of the median eminence of the hypothalamus, suggesting a role in neuroendocrine function. We have investigated the effects of tuberoinfundibular peptide on the hypothalamo-pituitary axes in vitro and in vivo. Tuberoinfundibular peptide had effects on the hypothalamo-pituitary-adrenal axis with increased release of ACTH-releasing factor (tuberoinfundibular peptide 100 nM 4.4 +/- 0.6 pmol/explant vs. control 2.9 +/- 0.4 pmol/explant, P < 0.001) and increased release of arginine vasopressin (tuberoinfundibular peptide 100 nM 563.5 +/- 55.5 fmol/explant vs. control 73.4 +/- 9.6 fmol/explant, P < 0.01) from in vitro hypothalamic explants. Intracerebroventricular administration of tuberoinfundibular peptide and PTH((1-34)) resulted in elevated plasma ACTH at 10 min post injection (saline 13.5 +/- 2.1 pg/ml, tuberoinfundibular peptide 3 nmol 32.3 +/- 4.0 pg/ml; P < 0.01 to saline: PTH((1-34)) 10 nmol 28.9 +/- 3.2 pg/ml: P < 0.05 to saline). Tuberoinfundibular peptide also had both in vitro and in vivo effects on the hypothalamo-pituitary-gonadal axis with increased release of LH-releasing hormone (tuberoinfundibular peptide 100 nM 28.5 +/- 5.1 fmol/explant vs. control 19.3 +/- 2.5 fmol/explant, P < 0.05) from in vitro hypothalamic explants. Both intracerebroventricular and peripheral administration of tuberoinfundibular peptide had effects on the hypothalamo-pituitary-gonadal axis. Intracerebroventricular injection of tuberoinfundibular peptide increased plasma LH (tuberoinfundibular peptide 10 nmol 0.70 +/- 0.09 ng/ml vs. saline 0.42 +/- 0.04 ng/ml at 10 min, P < 0.05). Intraperitoneal administration of tuberoinfundibular peptide also increased plasma LH (tuberoinfundibular peptide 30 nmol 0.53 +/- 0.09 ng/ml vs. saline 0.21 +/- 0.04 ng/ml at 10 min, P < 0.05). In addition to these actions on the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes, an increased release of GH-releasing factor (GRF) from hypothalamic explants (tuberoinfundibular peptide 100 nM 770.9 +/- 90.7 pg/explant vs. control 657.8 +/- 77.7 pg/explant, P < 0.01) was observed. Overall, these data show the actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes and suggest that it may play a role in the control of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes.

Animals↗

PubMed2000

Cascades to substituted indoles.

This paper describes the synthesis of dithioindoles from the free-radical cyclizations of arylisonitriles having pendant alkynes. Also described is the synthesis of substituted indoles and spiro-fused indoles from the coupling of dithioindoles with active hydrogen-containing compounds.

Cyclization↗

PubMed2000

3-Acetoxycyclohex-4-ene-1,2-dicarboxylic anhydride.

The title compound, C(10)H(10)O(5), was found to exist as the endo-cis isomer with a pair of enantiomers in the asymmetric unit. The cyclohexene ring is folded about the methylene-to-CH(acetoxy) vector to give a boat conformation.

Journal Article↗

PubMed2000

Norfloxacin dihydrate.

The antibiotic norfloxacin recrystallizes from acetonitrile as a dihydrate with the norfloxacin molecule in a zwitterionic form, i.e. 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazin-4-io)-3-quinolinecarboxylate dihydrate, C(16)H(18)FN(3)O(3).2H(2)O.

Journal Article↗

PubMed2000

The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

Adrenocorticotropic Hormone↗

PubMed2000

Single-dose administration of Bowman-Birk inhibitor concentrate in patients with oral leukoplakia.

The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor and a potential cancer chemopreventive agent for humans. In this Phase I clinical trial, BBI concentrate was administered as a single oral dose to 24 subjects with oral leukoplakia. Pharmacokinetics of BBI was analyzed, and subjects were monitored clinically for toxic effects. Subjects received between 25 and 800 chymotrypsin inhibitor units (CIU) of the compound in a dose escalation trial. BBI was taken up rapidly, and a metabolic product of BBI was excreted in the urine within 24-48 h. No clinical or laboratory evidence of toxicity was observed in the study. Protease activity was also measured in buccal cells to evaluate usefulness as a biomarker. Single-dose BBI concentrate administered up to 800 CIU was well tolerated and appeared to be nontoxic. Further investigation in Phase II clinical trials is being done.

Administration, Oral↗

PubMed2000

Urinary excretion of Bowman-Birk inhibitor in humans after soy consumption as determined by a monoclonal antibody-based immunoassay.

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.

Adult↗

PubMed2000

Clinical modulation of oral leukoplakia and protease activity by Bowman-Birk inhibitor concentrate in a phase IIa chemoprevention trial.

Bowman-Birk inhibitor is a protease inhibitor derived from soybeans that has demonstrated chemopreventive activity in a number of in vitro and animal systems. We conducted a 1-month phase IIa clinical trial of Bowman-Birk inhibitor concentrate (BBIC) in patients with oral leukoplakia. BBIC was administered to 32 subjects with oral leukoplakia for 1 month. We assessed toxicity and clinical and histological response of the lesions, and oral mucosal cell protease activity (PA) and serum micronutrient levels were measured. Clinical response was determined by measurement of pre- and posttreatment individual and total lesion areas and analysis of blinded clinical judgments of photographs. On the basis of prespecified response criteria, 31% of patients achieved a clinical response (two with complete and eight with partial responses). BBIC was nontoxic in doses up to 1066 chymotrypsin inhibitory units. The mean pretreatment total lesion area decreased from 615 to 438 mm2 after BBIC treatment (P < 0.004). A linear fit of the dose-response relationship between dose of BBIC and decrease in total lesion area was suggested (P < 0.08), and analysis of blinded clinical impression from lesion photographs confirmed this relationship (P < 0.01). Overall, at all doses tested, a 24.2% decrease in total lesion area was observed following treatment (sign rank = -142; P < 0.004). High pretreatment PA was associated with greater decreases in PA after BBIC administration (P < 0.02). BBIC demonstrated clinical activity after oral administration to patients with oral leukoplakia. These results indicate that BBIC should be investigated for chemopreventive activity in a randomized clinical trial.

Adult↗

PubMed1999

Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice.

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.

Animals↗

PubMed1999

Bowman-Birk inhibitor concentrate reduces colon inflammation in mice with dextran sulfate sodium-induced ulcerative colitis.

Bowman-Birk inhibitor concentrate (BBIC) is a soybean extract enriched in the Bowman-Birk inhibitor, a protein protease inhibitor. The Bowman-Birk inhibitor can inhibit proteases released from inflammation mediating cells and suppress superoxide anion radical secretion from immunocytes. This study investigates the ability of Bowman-Birk inhibitor concentrate to inhibit colon inflammation in the dextran sulfate sodium model of ulcerative colitis, an inflammatory bowel disease. When compared to mice on a standard diet, mice given food supplemented with 0.5% BBIC during and after dextran sulfate sodium treatment showed suppression of three of four scored histopathological inflammation criteria (P < 0.01), total histopathological score (P < 0.01), a 15% lower mortality rate (P < 0.01), and a delayed onset of mortality. We conclude that dietary Bowman-Birk inhibitor concentrate can beneficially affect dextran sulfate sodium-treated mice and may be useful in the treatment of human inflammatory bowel diseases, particularly ulcerative colitis.

Animals↗

PubMed1999

Effects of the Bowman-Birk inhibitor on clonogenic survival and cisplatin- or radiation-induced cytotoxicity in human breast, cervical, and head and neck cancer cells.

Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor previously shown to potentiate cisplatin-induced cytoxicity in human lung and ovarian cancer cells. To further assess the potential of BBI as a sensitizing agent for cancer radiotherapy and chemotherapy, we evaluated the effects of BBI and a soybean concentrate enriched in BBI known as BBI concentrate (BBIC) on clonogenic survival and radiation- or cisplatin-induced cell killing in MCF7 human breast carcinoma cells, SCC61 and SQ20B human head and neck carcinoma cells, HeLa, HeLa-R1, and HeLa-R3 human cervical carcinoma cells, MCF10 nontumorigenic human epithelial cells, HTori-3 nontumorigenic human thyroid epithelial cells, and C3H10T1/2 mouse fibroblast cells. BBI and BBIC significantly suppressed the clonogenic survival of MCF7 and SCC61 cells. BBIC also suppressed the survival of SQ20B cells and enhanced radiation-induced cell killing in SCC61 and SQ20B cells and cisplatin-induced cell killing in HeLa, HeLa-R1, and HeLa-R3 cells. In contrast, BBI and/or BBIC did not enhance radiation-induced cell killing in MCF10 cells or cisplatin-induced cell killing in C3H10T1/2 cells. BBI did not significantly affect the survival of SQ20B cells or enhance radiation-induced cell killing in SCC61 and SQ20B cells. The clonogenic survivals of MCF10 and C3H10T1/2 cells were not adversely affected by treatment with BBI or BBIC. The clonogenic survival of HTori-3 cells was only moderately suppressed by treatment with BBIC at > or = 80 micrograms/ml. These results suggest that BBIC could be a useful agent for the potentiation of radiation- and cisplatin-mediated cancer treatment without significant adverse effects on surrounding normal tissues.

Adenocarcinoma↗

PubMed1999

Bowman-Birk inhibitor suppresses production of superoxide anion radicals in differentiated HL-60 cells.

The Bowman-Birk protease inhibitor (BBI) is a soybean-derived protease inhibitor with anticarcinogenic and anti-inflammatory properties. BBI has previously been shown to suppress the release of superoxide anion radicals from purified polymorphonuclear leukocytes. In the present study we evaluated the effect of BBI on the production of superoxide anion radicals in differentiated HL-60 cells. HL-60 cells are human lymphocytic cells that acquire neutrophil-like characteristics when treated with dimethyl sulfoxide or tetradecanoyl phorbol acetate. Superoxide anion radical production by differentiated HL-60 cells was measured in the presence of various concentrations of BBI or BBI concentrate, a soybean extract containing high levels of BBI. BBI was observed to suppress superoxide anion radical production by differentiated HL-60 cells in a dose-dependent manner. Extracts of differentiated HL-60 cells were also observed to produce superoxide anion radicals, but this activity was not affected by the presence of BBI. These results suggest that BBI inhibits superoxide anion radical generation in HL-60 cells but does not act as a simple free radical scavenger.

Dose-Response Relationship, Drug↗

PubMed1999

Relationship between protease activity and neu oncogene expression in patients with oral leukoplakia treated with the Bowman Birk Inhibitor.

The protease catalyzing the hydrolysis of the tripeptide fluorescence substrate, butoxycarbonyl-valine-proline-arginine-(7-amino-4-methylcoumarin) (Boc-Val-Pro-Arg-MCA) and the neu oncogenic protein are potentially useful biomarkers for human cancer prevention studies. In the present study, we standardized a specific substrate hydrolysis method for measuring this protease activity in human oral mucosal cells and characterized the relationship between neu oncogene expression and protease activity in patients enrolled in an oral cancer prevention trial using Bowman Birk Inhibitor Concentrate (BBIC) as the cancer preventive agent. The results demonstrate that changes in the protease activity in oral mucosal cells after BBIC treatment correlated with the changes in the neu protein levels in oral mucosal cells (r = 0.726, P < 0.001) and serum (r = 0.675, P < 0.001), suggesting that the Boc-Val-Pro-Arg-MCA hydrolyzing activity can be as useful as neu oncogene expression as a cancer biomarker. In the 25 patients enrolled in the study, the level of neu protein in oral mucosal cells correlated with the serum neu protein concentration in the patients before BBIC treatment (r = 0.645, P < 0.001). However, such a correlation was not observed after the BBIC treatment, suggesting that BBI may inhibit serine protease(s) involved in the cleavage of neu protein on the cell surface, thereby preventing the release of the extracellular domain of neu protein into the circulation. By inhibiting the cleavage of neu protein on the cell surface, BBI could prevent malignant and premalignant cells expressing high levels of neu protein antigen from escaping host immunological surveillance control.

Cell Transformation, Neoplastic↗

PubMed1998

Chemopreventive agents: protease inhibitors.

Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. The anticarcinogenic protease inhibitors are extremely potent agents with the ability to prevent cancer, with some unique characteristics as anticarcinogenic agents. The anticarcinogenic protease inhibitors have the ability to irreversibly suppress the carcinogenic process. They do not have to be continuously present to suppress carcinogenesis. They can be effective when applied in both in vivo and in vitro carcinogenesis assay systems at long time periods after carcinogen exposure, and are effective as anticarcinogenic agents at extremely low molar concentrations. While several different types of protease inhibitors can prevent the carcinogenic process, the most potent of the anticarcinogenic protease inhibitors on a molar basis are those with the ability to inhibit chymotrypsin or chymotrypsin-like proteases. The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is a potent chymotrypsin inhibitor that has been extensively studied for its ability to prevent carcinogenesis in many different model systems. Much of this review is focused on the characteristics of BBI as the anticarcinogenic protease inhibitor, as this is the protease inhibitor that has risen to the human trial stage as a human cancer chemopreventive agent. Part of this review hypothesizes that the Bowman-Birk family of protease inhibitors plays a role in plants similar to that of alpha1-antichymotrypsin in people. Both BBI and alpha1-antichymotrypsin are potent inhibitors of chymotrypsin and chymotrypsin-like enzymes, are highly anti-inflammatory, and are thought to play important roles in the defense of their respective organisms. It is believed that BBI will be shown to play a major role in the prevention and/or treatment of several different diseases, in addition to cancer.

Antineoplastic Agents↗

PubMed1998

Growth inhibition and cytotoxicity induced by Bowman-Birk inhibitor concentrate in cisplatin-resistant human ovarian cancer cells.

Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor that was shown to potentiate the cytotoxicity of cisplatin in our previous studies. To assess the potential of BBI as a sensitizing agent for the chemotherapy of cisplatin-resistant cancers, we evaluated the effects of a soybean concentrate enriched in BBI (known as BBI concentrate or BBIC) on cell growth and clonogenic survival of a human ovarian cancer cell line, A2780, and its cisplatin-resistant sublines, C30, and C200. The presence of BBI and BBIC in the cell culture, medium reduced the clonogenic survival of the A2780, C30, and C200 cells in a dose-dependent manner and enhanced cisplatin-induced growth inhibition and/or cytotoxicity. BBIC alone showed greater inhibitory effects on growth in the cisplatin-resistant cell lines. These results suggest that BBI and BBIC could be useful agents for the treatment of cancers, especially with cisplatin, in tumors resistant to this important anticancer agent.

Cell Death↗

PubMed1998

The Bowman-Birk inhibitor from soybeans as an anticarcinogenic agent.

Certain protease inhibitors are effective at preventing or suppressing carcinogen-induced transformation in vitro and carcinogenesis in animal model systems. One protease inhibitor, the soybean-derived Bowman-Birk inhibitor (BBI) is particularly effective in suppressing carcinogenesis. BBI is a protein of a molecular weight of 8000 with a well-characterized ability to inhibit trypsin and chymotrypsin. BBI has been extensively studied, both as purified BBI and as an extract of soybeans enriched in BBI called BBI concentrate (BBIC). Purified BBI and BBIC have comparable suppressive effects on the carcinogenic process in a variety of in vivo and in vitro systems. BBI appears to be a universal cancer preventive agent. Purified BBI and BBIC suppress carcinogenesis as follows: in 3 different species (mice, rats, and hamsters); in several organ systems and tissue types [eg, colon, liver, lung, esophagus, cheek pouch (oral epithelium), and cells of hematopoietic origin]; and in cells of epithelial and connective tissue origin when given to animals by several different routes of administration, including the diet, leading to different types of cancer (eg, squamous cell carcinomas, adenocarcinomas, and angiosarcomas), and induced by various chemical and physical carcinogens. About half of an oral dose of BBI is taken up into the bloodstream and distributed throughout the body, with excretion via the urine. Pharmacokinetic studies of BBI have been performed in animals with radioactively labeled BBI, whereas antibodies that react with reduced BBI are being used in pharmacokinetic studies in humans. The calculated serum half-life is 10 h in both rats and hamsters. BBIC achieved Investigational New Drug status from the FDA in April 1992 (IND no. 34671; sponsor, Ann R Kennedy), and studies to evaluate BBIC as an anticarcinogenic agent in human populations began. Both BBI and BBIC prevent and suppress malignant transformation in vitro and carcinogenesis in vivo without toxicity.

Animals↗

PubMed1997

Soybean Bowman-Birk protease inhibitor is a highly effective inhibitor of human mast cell chymase.

Soybean Bowman-Birk protease inhibitor (BBI) is an inhibitor of serine proteases with two functional inhibitory domains of different specificities: one is specific for chymotrypsin-like proteases, the other for trypsin-like proteases. Chymase and tryptase are serine proteases which are stored in mast cell granules and released upon degranulation. This work investigated the inhibition of human chymase and tryptase by BBI. Active-site titration of human skin chymase by BBI demonstrated that BBI was a highly effective inhibitor of human chymase. Virtually stoichiometric inhibition of chymase by BBI was observed at 10 nM chymase. Kinetic studies of the inhibition reaction yielded an association rate constant of 4.0 x 10(5) M(-1) s(-1) and a dissociation rate constant of 1.7 x 10(-5) s(-1). From these two constants we estimate a K(i) of 50 pM. Chymase/BBI complexes did not dissociate in SDS-PAGE analyses under nonreducing conditions, consistent with the formation of a very tight complex with little tendency to dissociate. In contrast to chymase, human tryptase was not inhibited by BBI. These studies demonstrate that BBI is a good inhibitor of human chymase, exhibiting reaction properties better than physiological inhibitors described to date.

Binding Sites↗