ActiVin®, Dry Creek Nutritions' novel IH636 grape seed proanthocyanidin extract,

is a nutritional ingredient used in a wide variety of dietary supplements and nutraceutical food,

beverage and cosmetic products. It is also the most actively researched grape seed extract on the

market today. Over the past two years, more than 60 research presentations, publications and

abstracts have shown that ActiVin possesses a wide range of antioxidant, chemoprotective and

biological properties, including studies showing that ActiVin:

Following is a comprehensive overview of the independent university research performed

For copies of any of the research reports listed in this overview,

This study reports two cases in which patients suffering from chronic pancreatitis symptoms were ameliorated with grape seed proanthocyanidin extract (ActiVin) after traditional therapy had failed. ActiVin was found to reduce both pain index and incidence of vomiting in these patients.

The protective ability of ActiVin against acute and chronic stress-induced gastric and intestinal mucosal lipid peroxidation, DNA fragmentation and membrane microviscosity were determined in rats, and correlated with increased production of oxygen free radicals. ActiVin provided significant protection against acute and chronic stress-induced gastrointestinal oxidative injury as demonstrated by reduced lipid peroxidation, DNA damage and membrane microviscosity. —Bagchi M, et al., Acute and Chronic Stress-Induced Gastrointestinal Injury in Rats, and Protection by a novel IH636 Grape Seed Proanthocyanidin Extract (GSPE), Free Radical Biology & Medicine, 25: Abstract 235, S83, 1998; Bagchi M, et al., Acute and Chronic Stress-Induced Oxidative Gastrointestinal Injury in Rats, and the Protective Ability of a Novel Grape Seed Proanthocyanidin Extract, Nutrition Research, 19:1189-1199, 1999.

• A potent free radical scavenger and inhibitor of free radical-induced cellular damage, including lipid peroxidation and DNA fragmentation (in vitro & in vivo).
• Bioavailable and a far more powerful antioxidant than vitamins E, C and beta-carotene, as well as a combination of vitamins E and C (in vivo).

• Protects against H₂O₂-induced oxidative injury to macrophage (white blood) and brain cells (in vitro).
• Enhances vitamin C protection against LDL and VLDL oxidation (in vitro).

Grape seed proanthocyanidins are natural antioxidants, which are known to possess a broad spectrum of biological, pharmacological and chemoprotective properties against free radicals and oxidative stress. We have assessed the concentration- or dose-dependant free radical scavenging abilities of ActiVin®, a novel IH636 grape seed proanthocyanidin extract, in both in vitro and in vivo models, and compared these data with vitamins C, E and b -carotene. ActiVin demonstrated excellent concentration/dose-dependent inhibitions in both in vitro and in vivo experiments.

The free radical scavenging abilities (RSA) of ActiVin, vitamin E and vitamin C against biochemically generated superoxide anion and hydroxyl radical were assessed in vitro at varying concentrations via cytochrome c reduction and chemiluminescence response. Chemiluminescence is a general assay for the production of reactive oxygen species, while cytochrome c reduction is a specific assay for superoxide anion. At 50 mg/l, ActiVin demonstrated 84% and 98% greater RSA against superoxide anion and hydroxyl radical, respectively, as compared to natural vitamin E, and at 100 mg/l, ActiVin demonstrated 439% and 575% greater RSA against superoxide anion and hydroxyl radical, respectively, as compared to vitamin C. —Bagchi D, et al., Oxygen Free Radical Scavenging Abilities of Vitamins C and E, and a Grape Seed Proanthocyanidin Extract In Vitro, Research Communications in Molecular Pathology and Pharmacology, 95:170-189, 1997.

The protective abilities of ActiVin, vitamin E, vitamin C, beta-carotene and a combination of vitamins E and C against TPA-induced lipid peroxidation and DNA fragmentation in the brain and liver tissues of mice, as well as against free radical production in the peritoneal macrophages of mice, were assessed in vivo. TPA (12-O-tetradecanoylphorbol-13-acetate) is a well-known inducer of free radicals and tumor promotion in living organisms. Pretreatment of mice with ActiVin (100 mg/kg), vitamin E (100 mg/kg), vitamin C (100 mg/kg), beta-carotene (50 mg/kg) and a combination of vitamins E and C (100 mg/kg each) decreased TPA-induced free radical production in peritoneal macrophage cells by 71%, 43%, 16%, 17% and 51%, respectively, via chemiluminescence response, and 69%, 32%, 15%, 18% and 47%, respectively, via cytochrome c reduction as compared to controls. Pretreatment of mice with the same dosages of ActiVin, vitamin E, vitamin C, beta-carotene and a combination of vitamins E and C decreased TPA-induced DNA fragmentation by 50%, 31%, 14%, 11% and 40%, respectively, in brain tissue, and 47%, 30%, 10%, 11% and 38%, respectively, in liver tissue, while lipid peroxidation was reduced by 61%, 45%, 13%, 8% and 48%, respectively, in brain tissue, 46%, 36%, 12%, 7% and 39%, respectively, in liver mitochondria, and 59%, 47%, 14%, 12% and 53%, respectively, in liver microsomes compared to controls. Pretreatment of mice with ActiVin (25, 50 and 100 mg/kg) resulted in a significant dose-dependent inhibition of TPA-induced free radical production in peritoneal macrophage cells, and lipid peroxidation and DNA fragmentation in brain and liver tissues compared to controls. —Bagchi D, et al., Protective Effects of Grape Seed Proanthocyanidins and Selected Antioxidants Against TPA-Induced Hepatic and Brain Lipid Peroxidation and DNA Fragmentation, and Peritoneal Macrophage Activation in Mice, General Pharmacology, 30:771-776, 1998.

The results of these in vitro and in vivo experiments demonstrate that ActiVin is bioavailable to these vital organs and tissues, and provides significantly greater protection against oxygen free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins E, C and beta-carotene, as well as a combination of vitamins E and C.

Laser Scanning Confocal Microscopy (LSCM) is a novel technique used to assess free radical-induced modulation of intracellular oxidized states as an index of oxidative damage to cultured cells at a single cell level, and to determine the protective effect of a given antioxidant. This LSCM study was designed to assess the protective ability of ActiVin against hydrogen peroxide (H₂O₂)-induced oxidative stress in cultured macrophage J774A.1 and neuroactive PC-12 adrenal pheochromocytoma cells. The overall intracellular oxidized states of these cells were measured following incubation with H₂O₂ and/or ActiVin at an excitation wavelength of 513 nm by LSCM using 2,7-dichlorofluorescein diacetate as the probe. Signals were quantitated by integrating fluorescence over a user defined cell number. Approximately 5.8- and 4.5-fold increases in fluorescence intensity were observed following incubation of macrophage J774A.1 and neuroactive PC-12 cells with 0.5 mM H₂O₂ for 24 hr, respectively. Pretreatment of the macrophage J774A.1 cells with 50 mg/l and 100 mg/l ActiVin decreased H₂O₂–induced fluorescence intensity by 36% and 70%, respectively, while under these same conditions 50% and 70% decreases, respectively, in fluorescence intensities were observed in neuroactive PC-12 cells. These results indicate that ActiVin can significantly protect against hydrogen peroxide-induced oxidative stress in cultured macrophage J774A.1 and neuroactive PC-12 cells. —Bagchi D, et al., Hydrogen Peroxide-Induced Modulation of Intracellular Oxidized States in Cultured Macrophage J774A.1 and Neuroactive PC-12 Cells, and Protection by a Novel Grape Seed Proanthocyanidin Extract, Phytotherapy Research, 12:568-571, 1998.

Naturally occurring proanthocyanidin antioxidants have been reported to possess a broad spectrum of biological, pharmacological and medicinal properties against free radicals and oxidative stress. In our previous studies, IH636 proanthocyanidin extract (GSPE, commercially known as ActiVin) demonstrated excellent concentration- and dose- dependent free radical scavenging abilities both in vitro and in vivo models, and provided significantly better free radical scavenging ability compared to vitamins C, E, and b-carotene. GSPE demonstrated significant cytotoxicity towards human breast, lung and gastric cancer cells, while enhancing the growth and viability of normal cells. Additionally, GSPE protected against tobacco-induced apoptotic cell death in human oral keratinocytes by modulating the expression of p53 genes, and also protected human Chang epithelial cells against chemotherapeutic drugs idarubicin (Ida) or 4-hydroxyperoxycyclophosphamide (4-HC) induced cytotoxicity. Ida or 4-HC-induced apoptotic cell death was significantly reduced in the presence of GSPE. The expression of Bcl-2 gene was significantly increased, while the expressions of p53 and c-myc genes were significantly decreased in GSPE-treated cells. These results suggest that the chemoprotective effects of GSPE are mediated probably by modulation of bcl-2 and/or p53 gene expression. Recently, we demonstrated that GSPE preexposure protects acetaminophen-induced hepatotoxicity and nephrotoxicity in mice. These anti-toxic properties may be due to its inhibitory effects on drug metabolizing enzymes. Along this line, we found that 100 and 250 mg/ml of GSPE inhibited aniline hydroxylation 40% and 60%, respectively, in uninduced microsomes, and 25% and 50%, respectively, in induced microsomes, indicating GSPE’s ability to influence cytochrome P450 2E1 activity. In the present study, the cytoprotective ability of GSPE preexposure was examined on doxorubicin-induced cardiotoxicity, amiodarone-induced pulmonary toxicity, dimethylnitrosamine-induced splenotoxicity, CdCl₂-inducd nephrotoxicity and MOCAP-induced neurotoxicity. In each experiment, half of the test animals (mice) were orally fed GSPE for seven days prior to toxicant exposure, while the other half received no GSPE. Parameters of analysis included changes in serum chemistry (ALT, BUN, and CK), histopathology and integrity of genomic DNA. Results indicate that 7-day GSPE preexposure prior to the drugs/toxicants such as doxorubicin, amiodarone, dimethylnitrosamine and CdCl₂ provided near complete protection in terms of serum chemistry changes (ALT, BUN, and CK), and abolished both forms of cell death, e.g., apoptosis and necrosis. In addition, DNA damage in various tissues triggered by these agents was significantly reduced. Histopathological examination of multiple organs reflected the pattern of serum chemistry and DNA changes. Surprisingly, MOCAP exposure showed symptoms of severe neurotoxicity coupled with serum chemistry changes in the absence of any significant genomic change or brain pathology, where GSPE provided only partial protection. Taken together, these results suggest that GSPE may be beneficial and protect multiple organs from drug and chemical-induced toxic assults. –Bagchi D, et al., Recent Advances in Grape Seed Proanthocyanidin Research: Its Biological Role in Diverse Multicellular Organisms. 1999 SFRR Europe Winter Meeting on Bio-Flavonoids & Polyphenols in Health & Disease, Dinard, France, Abstract OP25, 1999.

Proanthocyanidins are a group of phenolic bioflavonoids found in fruits, vegetables, seeds and bark. We compared oxygen free radical (OFR) scavenging properties of seven widely used proanthocyanidin products: ActiVin, Berkem Grape Seed, Bio Vin Plus, Leucoselect, OptiPure, Polyphenolics and Pycnogenol. OFR scavenging ability was examined by adding the same amount (10 mg/ml) of various proanthocyanidins to the OFR generating systems. Superoxide radicals (O₂-) were generated by the action of xanthine on xanthine oxidase. Irradiating coumarin-3-carboxylic acid (CCA) with 137Cs–ray produced hydroxyl radicals HO) and peroxyl radicals were generated by dissolving 2,2í-azobis (2-amidinopropane) dihydrochloride (AAPH) in PBS buffer. O₂- scavenging activity was studied by determining lag period to completely exhaust the antioxidant ability of the compounds. OH scavenging activity was tested with their abilities to reduce CCA while peroxyl radical scavenging ability was determined by their ability to remove peroxyl radical. The O₂-, OH and peroxyl radical scavenging activities were compared against ascorbate (20 mM), dimethyl sulfoxide (1 mM) and Trolox (100mM), respectively. All the proanthocyanidins tested scavenged O₂-, OH and peroxyl radicals. The potency of O₂- scavenging activity was in the order of ActiVin> Berkem Grape Seed> Leucoselect> OptiPure/ Polyphenolics> Pycnogenol> Bio Vin Plus while those for OH and peroxyl radicals were ActiVin/Pycnogenol> Polyphenolics> OptiPure>Berkem/Bio Vin Plus> Leucoselect, and Polyphenolics/Leucoselect/Berkem Grape Seed/Bio Vin Plus> ActiVin/OptiPure> Pycnogenol, respectively. The results indicate that proanthocyanidins, irrespective of source, are potent scavengers of OFR. –Maulik G, et al., Oxygen Free Radical Scavenging Properties of Proanthocyanidins. Free Radical Biology & Medicine, 27(Suppl. 1): Abstract 90, S39, 1999.

• Inhibits tobacco-induced oxidative damage and cell death significantly greater than vitamins E and C, as well as a combination of vitamins E and C (in vitro).
• Protects against acetaminophen-induced liver and kidney toxicity (in vivo).
• Provides protection against multiple organ toxicities induced by Amiodarone (lung), dimethylnitrosamine (spleen), cadmium chloride (kidney) and MOCAP (brain) (in vivo).
• Enhances detoxification in vivo by inhibiting microsomal cytochrome P450 2E1 isozymes.

The p53 gene is a tumor suppressor and cell cycle regulatory gene. Mutations of the p53 gene occur in high frequency in most forms of cancer. Modulation of p53 gene expression and apoptopic cell death of human oral keratinocytes increases with increasing concentrations of smokeless tobacco extract (STE). In the present study, human oral keratinocytes were treated with STE (0-300 mg/ml) for 24 hr, and changes in the expression of p53 gene were assessed by RT-PCR (reverse transcriptase-polymerase chain reaction) (b-tubulin was used as the housekeeping gene). Approximately a 2.0-fold increase in p53 gene expression was observed following incubation of the cells with 100 mg/ml of STE, beyond which the expression of p53 dramatically decreased with higher concentrations, confirming increased apoptopic cell death with a higher concentrations of STE. Furthermore, the comparative abilities of vitamin C (75 mM), vitamin E (75 mM), a combination of vitamins C plus E (75 mM each) and ActiVin (100 mg/ml) were determined. The results demonstrate that STE significantly modulates p53 gene expression, while these antioxidants reduced STE-induced changes by 22-46%. ActiVin demonstrated significantly better protection as compared to vitamins C and E, individually and in combination. —Bagchi M, et al., Smokeless Tobacco Induced Modulation of p53 Gene and Protective Effect of Antioxidants, 38^th Annual Meeting of the Society of Toxicology, 48(Suppl. 1): Abstract 307, 65, 1999.

The oral use of moist tobacco products chewing tobacco has greatly increased in recent years. The use of smokeless tobacco is associated with the cancers of the mouth, lip, nasal cavities, esophagus and gut. Oral cancer accounts for 3% of all the cancers in the U.S.A. and is the seventh most common cancer. The p53 gene is defined as a tumor suppressor gene. Indeed, mutations in p53 were found to occur in high frequency in most of the common types of human cancer. Stabilization and activation of p53 following variety of genotoxic insults result in the execution of its biological activities. Antioxidants have been shown to demonstrate a broad spectrum of biological, pharmacological, and chemopreventive properties against free radicals and oxidative stress, and may delay an onset of carcinogenesis. Previous studies in our laboratories have demonstrated that ActiVin, a novel grape seed proanthocyanidin extract (GSPE), exhibits excellent free radical scavenging ability both in vitro and in vivo models, and potentiates selective cytotoxicity toward human breast, lung, and gastric cancer cells. Previously, we have reported the oxidative stress and DNA damage in human oral cells following treatment with different concentrations of STE. Apoptotic cell death of human oral keratinocytes was also increased with increasing concentrations of STE, and 51-85% decreases in apoptotic cell death were observed with vitamins C, E, and GSPE, respectively. In the present study, keratinocytes were isolated and cultured from human oral tissues and treated with (0-30mg/ml) of STE for 24 hours and change in the expression of a p53 gene was measured by reverse transcriptase polymerase chain reaction (RT-PCR). Thirty-five cycles were performed for five minutes at 94° C and b-tubulin was used as the housekeeping gene. Approximately a 2.0 fold increase in p53 gene expression was observed following incubation of the oral keratinocytes with 100 mg/ml of STE, beyond which the expression of p53 decreased. Thus, p53 expression dramatically reduced with higher concentration of STE, confirming increased apoptotic cell death with a higher concentration of STE as reported by us earlier. Also, the expression of antiapoptotic Bcl-2 gene also increased with GSPE treatment when measured similarly using RT-PCR. In addition, the expression level of transcription factor c-myc gene responsible for cell cycle growth also altered following treatment with GSPE. Furthermore, the comparative abilities of vitamin C (75mm), vitamin E (75mm), a combination of vitamins C plus E (75mm each), and GSPE (100mg/ml) were determined. Our results demonstrate that STE significantly modulates Bcl-2, p53 and c-myc gene expression, and approximately 22-46% protection was observed with antioxidants. GSPE demonstrated significantly better protection as compared to vitamins C and E, singly and in combination. - Bagchi M, et al., Protective Effects of Vitamins C and E and a Novel Grape Seed Proanthocyanidin Extract on Smokeless Tobacco Induced Oxidative Stress and Modulation of Bcl-2, p53 and c-myc Genes, 1999 SFRR Europe Winter Meeting on Bio-Flavonoids & Polyphenols in Health & Disease, Dinard, France, Abstract P44, 1999.

• Inhibits and even kills human cancer cells, including breast, lung and stomach cancer cells, while enhancing the growth and viability of normal cells (in vitro).
• Protects normal human liver cells from the toxic effects of chemotherapy drugs (in vitro).
• Inhibits the initiation, promotion and progression of DMN-induced liver carcinogenesis (in vivo).

In a recent study, researchers assessed ActiVin-induced cytotoxicity towards selected human cancer cells, including cultured MCF-7 human breast cancer cells, CRL 1739 human gastric adenocarcinoma cells and A-427 human lung cancer cells, by phase contrast microscopy and MTT cytotoxicity assay, and compared these effects with two normal cultured cells, including normal human gastric mucosal cells and J774A.1 murine macrophage cells. The results demonstrated that ActiVin exhibits selective cytotoxicity towards cultured MCF-7 human breast cancer cells, CRL 1739 human gastric adenocarcinoma cells and A-427 human lung cancer cells at 25 mg/l and 50 mg/l concentrations, while ActiVin enhances the growth and viability of the normal cultured cells at these concentrations. —Ye X, et al., Cytotoxic Effects of a Novel IH636 Grape Seed Proanthocyanidin Extract (GSPE) on Cultured Human Cancer Cells, Molecular and Cellular Biochemistry, 196:99-108, 1999.

The molecular mechanisms of action of ActiVin towards chemotherapy drug-induced toxicity towards normal human cells were investigated. Chang liver cells, isolated from normal human liver samples, and human peripheral blood mononuclear cells were treated with the chemotherapeutic agents 4-hydroxy-peroxycyclophosphamide (4-HC) (1 mg/ml) or Idarubicin (1 mM/ml) with or without ActiVin (25 mg/ml) for 48 hr. Apoptosis (programmed cell death) was measured by flow cytometry. Apoptosis was significantly decreased in the presence of ActiVin compared to administration of the drugs alone. Similar effects of ActiVin were also seen with antisense oligonucleotide-induced apoptosis in human liver cells. Subsequently, ActiVin treated liver cells and blood mononuclear cells were analyzed for the expression of key cell cycle/apoptosis regulatory genes such as bcl-2, p53 and c-myc by RT-PCR and Western blot techniques. ActiVin significantly increased expression of bcl-2 antioxidant gene and decreased expression of tumor inducing c-myc gene and apoptosis regulatory p53 gene. The results suggest that the chemopreventive effects of ActiVin are mediated by alterations in bcl-2, p53 and c-myc gene expression, and that ActiVin can be used to ameliorate chemotherapy-induced toxicity to normal cells and tissues. —Joshi SS, et al., Chemopreventive Effects of a Novel Grape Seed Proanthocyanidin Extract Via Alterations in Functions of bcl-2 and p53 genes, The FASEB Journal, 13: Abstract LB139, 1999; Joshi SS, et al., Amelioration of the Cytotoxic Effects of Chemotherapeutic Agents by Grape Seed Proanthocyanidin Extract. Antioxidants & Redox Signaling, 1(4): 563-570, 1999.

The short-term and long-term protective effects of ActiVin were examined on acetaminophen overdose-induced liver toxicity. Mice were administered nontoxic doses of ActiVin (3 or 7 days, 100 mg/kg, orally) followed by hepatotoxic doses of acetaminophen (400 or 500 mg/kg, intraperitoneally). ActiVin dramatically decreased acetaminophen-induced mortality, serum alanine aminotransferase activity, a marker of liver toxicity, and hepatic DNA fragmentation. Histopathological evaluation of liver sections showed remarkable interference of ActiVin against acetaminophen toxicity and substantial inhibition of apoptotic and necrotic liver cell death. Acetaminophen was also shown to phosphorylate (deactivate) the bcl-X_L gene, a death inhibitor gene and a positive regulator of the bcl-2 family of genes. In contrast, ActiVin alone enhanced the expression of bcl-X_L gene and significantly reduced acetaminophen-induced phosphorylation of bcl-X_L gene. Thus, ActiVin can significantly attenuate acetaminophen-induced hepatic DNA damage, apoptotic cell death and positively influence gene expression. —Ray SD, et al., In Vivo Abrogation of Acetaminophen-Induced Hepatic Genomic DNA Fragmentation and Apoptopic Cell Death by a Novel Grape Seed Proanthocyanidin Extract, The FASEB Journal, 12: Abstract 4516, A779, 1998; Ray SD, et al., A Novel Proanthocyanidin IH636 Grape Seed Extract Increases In Vivo Bcl-XL Expression and Prevents Acetaminophen-Induced Programmed and Unprogrammed Cell Death in Mouse Liver, Archives of Biochemistry and Biophysics, 369:42-58, 1999.

• Lowers blood pressure and decreases glycosylated hemoglobin levels in rats.
• Provides cardioprotection by improving left ventricular function, decreasing myocardial infarction and reducing oxidative damage caused by ischemia-reperfusion injury (in vivo).
• Protects against Doxorubicin-induced cardiotoxicity (in vivo).

The pathogenesis of the aging phenomenon and chronic diseases associated with aging is attributed, in part, to glycosylation of proteins and nucleic acids, and augmented free radical formation causing increased tissue damage. In normotensive rats, it was demonstrated that chronic supplementation of ActiVin (250 ppm) in conjunction with ChromeMate® niacin-bound chromium (5 ppm chromium) and OptiZinc® methionine-bound zinc (18 ppm zinc) significantly reduced systolic blood pressure and glycosylated hemoglobin (HbA1C), as well as decreased lipid peroxidation and free radical formation. These results demonstrate potential long-term health benefits of ActiVin used in combination with ChromeMate and OptiZinc. —Preuss HG, et al., Chromium, Zinc, and Grape seed Extract (Flavonoids) Can Overcome Age-Related Increases in SBP of Normotensive Rats, Journal of the American College of Nutrition, 16: Abstract 43, 481, 1997; Tyson DA, et al., Acute Effects of Grape Seed Extract on the Systolic Blood Pressure of Normotensive and Hypertensive Rats, Journal of American College of Nutrition, (submitted).

Free radicals play a crucial role in the pathogenesis of myocardial ischemia-reperfusion injury. The protective ability of ActiVin was assessed during post-ischemic reperfusion injury and ischemic arrest in the heart. Sprague-Dawley rats were divided into two groups: experimental group was fed ActiVin 100 mg/kg body weight for 3 weeks, while the control group was fed water alone. After 3 weeks, rat hearts were made globally ischemic for 30 minutes followed by 2 hours of reperfusion. Left ventricular functions were continuously monitored and release of creatine kinase (a marker for tissue necrosis and inflammation) and malondialdehyde (a presumptive marker for oxidative stress) were estimated. At the end of each experiment, myocardial infarct size was measured by TTC staining method. The results of this study demonstrated that the ActiVin-supplemented group provided elevated cardioprotection as evidenced by improved post-ischemic left ventricular functions (dp, dp/dt_max) and aortic flow, as well as by reduced CK release in the coronary effluent as compared to control groups. This was further supported by reduced myocardial infarct size in the ActiVin-fed group. Formation of malondialdehyde was also reduced by ActiVin supplementation. The results of this study show that ActiVin can provide cardioprotection presumably by virtue of its potent in vivo free radical scavenging ability. —Sato M, et al., Cardioprotective Effects of a Novel IH636 Grape Seed Proanthocyanidin Extract, IX Biennial Meeting of the International Society of Free Radical Research, RFBUBI, 34: Abstract PS 15-60, 207, 1998; Sato M, et al., Cardioprotective Effects of Grape Seed Proanthocyanidin Against Ischemic Reperfusion Injury, Journal of Molecular & Cellular Cardiology, 31:1289-1297, 1999.

The results of these experiments demonstrate that ActiVin:

1. Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX and Stohs SJ, Oxygen Free Radical Scavenging Abilities of Vitamins C and E, and a Grape Seed Proanthocyanidin Extract In Vitro, Research Communications in Molecular Pathology and Pharmacology, 95:179-189, 1997.
1. Bagchi D, Garg A, Krohn RL, Bagchi M, Bagchi DJ, Balmoori J and Stohs SJ, Protective Effects of Grape Seed Proanthocyanidins and Selected Antioxidants Against TPA-Induced Hepatic and Brain Lipid Peroxidation and DNA Fragmentation, and Peritoneal Macrophage Activation in Mice, General Pharmacology, 30:771-776, 1998.
1. Bagchi D, Kuszynski CA, Balmoori J, Bagchi M and Stohs SJ, Hydrogen Peroxide–Induced Modulation of Intracellular Oxidized States in Cultured Macrophage J774A.1 and Neuroactive PC-12 Cells, and Protection by a Novel IH636 Grape Seed Proanthocyanidin Extract, Phytotherapy Research 12:568-571, 1998.
2. Bagchi M, Balmoori J, Bagchi D, Ray SD, Kuszynski CA and Stohs SJ, Smokeless Tobacco, Oxidative Stress, Apoptosis and Antioxidants in Human Oral Keratinocytes, Free Radical Biology & Medicine 26:992-1000, 1999.
3. Ye X, Krohn RL, Liu W, Joshi SS, Kuszynski CA, McGinn TR, Bagchi M, Preuss HG, Stohs SJ and Bagchi D, The Cytotoxic Effects of a Novel IH636 Grape Seed Proanthocyanidin Extract on Cultured Human Cancer Cells, Molecular & Cellular Biochemistry 196:99-108, 1999.
1. Sato M, Maulik G, Ray PS, Bagchi D and Das DK, Cardioprotective Effects of Grape Seed Proanthocyanidin Against Ischemic Reperfusion Injury, Journal of Molecular & Cellular Cardiology 31: 1289-1297, 1999.
2. Bagchi M, Milnes MM, Williams CB, Balmoori J, Ye X, Stohs SJ and Bagchi D, Acute and Chronic Stress-Induced Oxidative Gastrointestinal Injury in Rats, and the Protective Ability of a Novel Grape Seed Proanthocyanidin Extract, Nutrition Research 19: 1189-1199, 1999.
3. Bagchi D, Krohn RL, Balmoori J, Bagchi M, Garg A and Stohs SJ, Comparative In Vitro and In Vivo Free Radical Scavenging Abilities of a Novel Grape Seed Proanthocyanidin Extract and Selected Antioxidants. In: Natural Antioxidants and Anticarcinogens in Nutrition, Health and Disease (Editors: Kumpulainen JT and Salonen JT), The Royal Society of Chemistry, Cambridge, U.K., Publication No. 240, pp. 178-187, 1999.
4. Krohn RL, Ye X, Liu W, Joshi SS, Bagchi M, Preuss HG, Stohs SJ and Bagchi D, Differential Effect of a Novel Grape Seed Proanthocyanidin Extract on Cultured Human Normal and Malignant Cells. In: Natural Antioxidants and Anticarcinogens in Nutrition, Health and Disease (Editors: Kumpulainen JT and Salonen JT), The Royal Society of Chemistry, Cambridge, U.K., Publication No. 240, pp. 443-450, 1999.
5. Ray SD, Kumar MA and Bagchi D, A Novel Proanthocyanidin IH636 Grape Seed Extract Increases In Vivo bcl-XL Expression and Prevents Acetaminophen-Induced Programmed and Unprogrammed Cell Death in Mouse Liver, Archives of Biochemistry and Biophysics 369: 42-58, 1999.
6. Joshi SS, Kuszynski CA, Benner EJ, Bagchi M and Bagchi D, Amelioration of the Cytotoxic Effects of Chemotherapeutic Agents by Grape Seed Proanthocyanidin Extract, Antioxidants & Redox Signaling 1(4): 563-570, 1999.
7. Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS and Preuss HG, Free Radicals and Grape Seed Proanthocyanidin Extract: Importance in Human Health and Disease Prevention, Toxicology (in press).
8. Joshi SS, Kuszynski CA, Bagchi M and Bagchi D, Chemopreventive Effects of Grape Seed Proanthocyanidin Extract on Chang Liver Cells. Toxicology (in press).
9. Tyson DA, Talpur NA, Echard BW, Bagchi D and Preuss HG, Acute Effects of Grape Seed Extract on the Systolic Blood Pressure of Normotensive and Hypertensive Rats. Research Communications in Pharmacology and Toxicology (in press).
10. Sen CK and Bagchi D, Regulation of Inducible Adhesion Molecule Expression in Human Endothelial Cells by Grape Seed Proanthocyanidin Extract. Molecular & Cellular Biochemistry (submitted).
11. Ray SD, Parikh H, Hickey E, Bagchi M and Bagchi D, Differential Effects of IH636 Grape Seed Proanthocyanidin Extract and a DNA Repair Modulator 4-aminobenzamide on Liver Microsomal Cytochrome P450-2E1-Dependent Aniline Hydroxylation. Toxicology Letters (submitted).
12. Banerjee B and Bagchi D, Beneficial Effects of a Novel IH636 Grape Seed Proanthocyanidin Extract in the Treatment of Chronic Pancreatitis. Digestion (submitted).