Administration Of Grape Seed Proanthocyanidins Research Articles

Hepcidin agonists grape seed proanthocyanidins and berberine hydrochloride improve immunity and prevention against bacterial infection in grass carp (Ctenopharyngodon idella)

Hepcidin is an antimicrobial peptide and iron-regulating factor that has been shown to play a crucial role in combating bacterial diseases, making it a viable alternative to antibiotics. However, its widespread application is limited due to its susceptibility to degradation in vivo and high production costs. Certain extracts from traditional Chinese medicinal plants exhibit significant potential in treating iron overload conditions. This study aims to identify an effective and practical herbal agent as a hepcidin agonist. The results indicated that grape seed proanthocyanidins (GSP) and berberine hydrochloride (BBR) significantly upregulate the expression levels of hepcidin and ferritin genes in L8824 cells. Additionally, both compounds exhibited excellent in vitro antibacterial activity. Interestingly, the combined application of these two substances yields unexpectedly favorable results. Oral administration of GSP + BBR effectively promoted growth in grass carp, enhanced survival rates, and significantly increased serum innate immunity indicators. Furthermore, it reduced bacterial loads in the head kidney, spleen, hepatopancreas, and intestinal of grass carp following infection. Additionally, it elevated the expression levels of immune genes IL-1β, IL-6, and TNF-α in the head kidney after infection, and markedly alleviated pathological damage in intestinal tissues. These results demonstrated that GSP and BBR act as hepcidin agonists to enhance the expression of endogenous hepcidin, providing a novel approach for the prevention of bacterial infections in aquaculture.

Grape seed proanthocyanidins improves depression-like behavior by alleviating oxidative stress and NLRP3 activation in the hippocampus of prenatally-stressed female offspring rats

ABSTRACT Over several decades, there is a growing evidence, which has shown that prenatal stress (PS) contributes to depression in offspring. Grape seed proanthocyanidins (GSPs), which contain dimers, trimers, oligomers of catechin and epicatechin, are known to possess antidepressant effects. The present study aimed to investigate the mechanism of antidepressant effects of GSPs on female juvenile prenatally stressed offspring rats. The results showed that the female juvenile offspring rats exposed to PS exhibited depression-like behavior manifested as longer immobility time and lesser consumption of sucrose solution. Prenatal stress reduced the number of hippocampal neurons and increased the level of the reactive oxygen species (ROS) in the hippocampus of the female juvenile offspring rats. Furthermore, the expression of PYD domains-containing protein 3 (NLRP3) and its downstream cytokines, Caspase-1, and interleukin-1β (IL-1β), were increased in the hippocampus of the female juvenile offspring rats exposed to PS. Administration of GSPs not only improved depression-like behavior and enhanced the number of hippocampal neurons, but also abated excessive ROS generation and inhibited the activation of the NLRP3-Caspase-1 signaling pathway. Taken together, GSPs counteract PS-induced hippocampal neuron loss and depression-like behavior by alleviating oxidative stress and NLRP3 activation. The present study provides a new insight for GSPs as an effective therapeutic agent for adolescent depression.

Abstract 5442: Down-regulation of miRNA-214 expression by bioactive molecules mitigates invasive potential of melanoma cells through ALCAM/TFAP2 signaling

Abstract Melanoma is responsible for 80% of skin cancer related deaths in the United States and represents fifth most common neoplasia in humans. Over the past decades, the incidence of melanoma has increased by 3% to 8% per year in western countries. Therefore, it is essential to understand the molecular regulatory pathways that contribute to melanoma aggressiveness and metastatic dissemination. MicroRNAs (miRNAs) are small noncoding regulatory RNAs that contribute to tumor formation and progression, for their ability to regulate gene expression post-transcriptionally by either inhibiting protein translation or degrading target mRNAs. miR-214 is overexpressed in various types of cancers and is associated with the regulation of numerous carcinogenic processes including cell differentiation, senescence, angiogenesis and cell migration/invasion, etc. In the present study, we demonstrated that miR-214 shows distinct over expression in melanoma cell lines (A375, Hs294t, SK-Mel119, and SK-Mel28) as compared to its expression in normal human epidermal melanocytes (NHEM), and this overexpression of miR-214 in melanoma cells was associated with the invasive potential than NHEM. Treatment of melanoma cells with an inhibitor of miR-214 (50 nM) resulted in inhibition of cell invasion ability. We also determined the effects of bioactive phytochemical grape seed proanthocyanidins (GSPs) on the expression levels of miRNA-214 in melanoma cell lines (A375 and Hs294t) and its underlying molecular targets. Treatment of A375 and Hs294t cells with GSPs resulted in suppression of the levels of miRNA-214, which leads to decrease in migration potential of melanoma cell lines. By using 3D melanoma progression model, we also verified this suppressive effect of GPSs on melanoma invasion. The transition from the non-invasive to the invasive and metastatic stage is accompanied by the loss of AP-2 transcription factors (TFAP-2) and expression of activated leukocyte cell adhesion molecule (ALCAM) and those are associated with miRNA-214 overexpression. Here, we observed that the treatment of GSPs decreases ALCAM expression and restore TFAP-2 levels in melanoma cell lines. Further, dietary administration of GSPs significantly reduce the metastasis potential of A375 cells in different vital organs such as lung, liver, kidney, and spleen, and this suppressive effect of GSPs on invasive potential of A375 cells was associated with the reduction in the levels of miRNA-214 and ALCAM. Our results indicate that modulation of miR-214 influences in vitro cell movement and extravasation from blood vessels in vivo. Together, these studies suggest that an identification of metastasis related miRNAs may provide potential diagnostic biomarkers and better understanding of the complex functions of miRNAs, as well as therapeutic targets for clinical application. Note: This abstract was not presented at the meeting. Citation Format: Ram Prasad, Santosh K. Katiyar. Down-regulation of miRNA-214 expression by bioactive molecules mitigates invasive potential of melanoma cells through ALCAM/TFAP2 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5442. doi:10.1158/1538-7445.AM2017-5442

Protective Role of Grape Seed Proanthocyanidins Against Ccl4 Induced Acute Liver Injury in Mice.

BackgroundWe investigated the effect of grape seed proanthocyanidins (GSPs) on carbon tetrachloride (CCl4)-induced acute liver injury.Material/MethodsSixty SPF KM mice were randomly divided into 6 groups: the control group, CCl4-model group, bifendate group (DDB group), and low-, moderate-, and high-dose GSP groups. The following parameters were measured: serum levels of alanine aminotransferase (ALT); aspartate aminotransferase (AST); tumor necrosis factor (TNF)-α; interleukin-6 (IL-6); high-mobility group box (HMGB)-1; body weight; liver, spleen, and thymus indexes; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity; HMGB1 mRNA; malondialdehyde (MDA) content; hepatocyte proliferation; and changes in liver histology.ResultsCompared to the CCl4-model group, decreases in liver index and increases in thymus index significantly increased SOD and GSH-Px activities and reduced MDA content, and higher hepatocyte proliferative activity was found in all GSP dose groups and the DDB group (all P<0.001). Compared with the CCl4-model group, serum TNF-α and IL-6 levels and HMGB 1 mRNA and protein expressions decreased significantly in the high GSP dose group (all P<0.05).ConclusionsOur results provide strong evidence that administration of GSPs might confer significant protection against CCl4-induced acute liver injury in mice.

Abstract 1916: Proanthocyanidins from grape seeds inhibit growth of head and neck squamous cell carcinoma by decreasing dna methylation and reactivation of silenced tumor suppressors

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in diagnostic and therapeutic methods, survival of HNSCC patients remains unchanged over the last 30 years. Epigenetic alterations are commonly associated with several types of cancers including HNSCC. Studies have shown that DNA hypermethylation plays important roles in the risk of cancers by inactivating the tumor suppressor genes/proteins. Thus, epigenetic changes are considered as promising therapeutic targets for cancer treatment. Dietary phytochemicals offer promising options for the development of effective strategies for the prevention of cancer, and thus can be utilized as complementary and alternative medicine. In the present study, we investigated the effect of grape seed proanthocyanidins (GSPs) on DNA methylation and growth of HNSCC cells in vitro and in vivo models. Our analytical data revealed that the levels of global DNA methylation and DNA methyltransferase (DNMT) activity were higher in HNSCC cells compared with normal human bronchial epithelial cells (NHBEC). Treatment of HNSCC cells (FaDu and SCC-1) with GSPs for 6 days results in significant decrease in global DNA methylation (70-80%, P&amp;lt;0.001) level, DNMT activity (60-80%) as well as in levels of DNMT proteins (DNMT 3A and DNMT 3B) compared to non-GSPs-treated control cells. The observation on DNA methylation levels was verified by analyzing the levels of 5-methylcytosine (5-mC) using dot-blot analysis. Additionally, GSPs treatment also reactivated tumor suppressor proteins, such as Cip1/WAF1/p21 and p27 in HNSCC cells. Treatment of HNSCC cells with 5-Aza-dc, an inhibitor of DNA methylation, also resulted in suppression of DNA methylation as well as DNMT protein expression and DNMT activity in these cells. Tumor xenograft studies were performed to further determine the effect of GSPs on the growth of HNSCC cells using athymic nude mouse model. Our in vivo study demonstrated that administration of GSPs (0.5%, w/w) in supplementation with AIN76A control diet resulted in inhibition of xenograft growth of FaDu cells in nude mice (80%; P&amp;lt;0.01) compared to the tumor xenograft growth in mice fed with non-GSPs-supplemented control diet. The growth inhibitory effect of dietary GSPs on the HNSCC tumor xenografts was associated with the inhibition of DNA methylation, DNMT activity and reactivation of silenced tumor suppressor proteins in tumor tissues. Together, this preclinical study provides evidence that GSPs act as a DNA demethylating agent and able to reactivate an epigenetically silenced tumor suppressors to inhibit growth of HNSCC cells. Citation Format: Santosh K. Katiyar, Ram Prasad. Proanthocyanidins from grape seeds inhibit growth of head and neck squamous cell carcinoma by decreasing dna methylation and reactivation of silenced tumor suppressors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1916. doi:10.1158/1538-7445.AM2015-1916

Proanthocyanidins from grape seeds inhibit UV-radiation-induced immune suppression in mice: detection and analysis of molecular and cellular targets.

Ultraviolet (UV)-radiation-induced immunosuppression has been linked with the risk of skin carcinogenesis. Approximately, 2 million new cases of skin cancers, including melanoma and nonmelanoma, diagnosed each year in the USA and therefore have a tremendous bad impact on public health. Dietary phytochemicals are promising options for the development of effective strategy for the prevention of photodamaging effects of UV radiation including the risk of skin cancer. Grape seed proanthocyanidins (GSPs) are such phytochemicals. Dietary administration of GSPs with AIN76A control diet significantly inhibits UV-induced skin tumor development as well as suppression of immune system. UV-induced suppression of immune system is commonly determined using contact hypersensitivity (CHS) model which is a prototype of T-cell-mediated immune response. We present evidence that inhibition of UV-induced suppression of immune system by GSPs is mediated through: (i) the alterations in immunoregulatory cytokines, interleukin (IL)-10 and IL-12, (ii) DNA repair, (iii) stimulation of effector T cells and (iv) DNA repair-dependent functional activation of dendritic cells in mouse model. These information have important implications for the use of GSPs as a dietary supplement in chemoprevention of UV-induced immunosuppression as well as photocarcinogenesis.

Grape seed proanthocyanidins (GSPs) inhibit the growth of cervical cancer by inducing apoptosis mediated by the mitochondrial pathway.

Grape seed proanthocyanidins (GSPs), a biologically active component of grape seeds, have been reported to possess a wide array of pharmacological and biochemical properties. Recently, the inhibitory effects of GSPs on various cancers have been reported, but their effects on cervical cancer remain unclear. Here, we explored the effect of GSPs on cervical cancer using in vitro and in vivo models. In vitro, the treatment of HeLa and SiHa cells with GSPs resulted in a significant inhibition of cell viability. Further investigation indicated that GSPs led to the dose-dependent induction of apoptosis in cancer cells. The underlying mechanism was associated with increased expression of the pro-apoptotic protein Bak-1, decreased expression of the anti-apoptotic protein Bcl-2, the loss of mitochondrial membrane potential, and the activation of caspase-3, suggesting that GSPs induced cervical cancer cell apoptosis through the mitochondrial pathway. In addition, the administration of GSPs (0.1%, 0.2%, and 0.4%, w/v) as a supplement in drinking water significantly inhibited the tumor growth of HeLa and SiHa cells in athymic nude mice, and the number of apoptotic cells in those tumors was also increased significantly. Taken together, our studies demonstrated that GSPs could inhibit the growth of cervical cancer by inducing apoptosis through the mitochondrial pathway, which provides evidence indicating that GSPs may be a potential chemopreventive and/or chemotherapeutic agent for cervical cancer.

Bioactive Phytochemical Proanthocyanidins Inhibit Growth of Head and Neck Squamous Cell Carcinoma Cells by Targeting Multiple Signaling Molecules

Despite advances in surgical and medical therapies, approximate 50% survival rate of head and neck squamous cell carcinoma (HNSCC) has had marginal improvement in the last 30 years. Therefore, alternative strategies are required for the management of HNSCC. Here, we report the chemotherapeutic effect of proanthocyanidins on HNSCC cells using in vitro and in vivo models. Treatment of human HNSCC cell lines from different sub-sites, such as oral cavity (SCC1), larynx (SCC5), tongue (OSC19) and pharynx (FaDu), with grape seed proanthocyanidins (GSPs) reduced their cell viability and induced cell death in a dose- and time-dependent manner. GSPs induced inhibition of cell viability was associated with: (i) G1-phase arrest, (ii) inhibition of expressions of cyclins (cyclin D1 and Cyclin D2) and cyclin-dependent kinases (Cdk), (iii) increased expression of the Cdk inhibitory proteins (Cip1/p21, Kip1/p27), enhanced binding of Cdk inhibitors to Cdks, and downregulation of E2F transcription factor. GSPs significantly (P<0.05−0.001) increased apoptosis of SCC1 and OSC19 cells with induction of Bax, reduced expression of Bcl-2, and activation of caspase-3. GSPs also reduced the expression of epidermal growth factor receptor (EGFR), and treatment of SCC1 cells with erlotinib, an EGFR-targeting small molecule tyrosine kinase inhibitor, significantly (P<0.05−0.001) reduced cell viability and increased cell death. Dietary administration of GSPs (0.5%, w/w) in supplementation with AIN76A control diet inhibited the growth of SCC1 tumor xenografts in athymic nude mice, which was associated with: (i) inhibition of cell proliferation, (ii) induction of apoptosis of tumor xenograft cells, (iii) decreased expression of cyclins and Cdks, (iv) decreased expression of EGFR, and (v) increased expression of Cip1/p21 and Kip1/p27 proteins and their increased binding to Cdks in tumor xenograft samples. Together, these results suggest that GSPs may be a promising candidate for head and neck squamous cell carcinoma therapy.

Effects of Oligomeric Grape Seed Proanthocyanidins on Heart, Aorta, Kidney in DOCA‐Salt Mice: Role of Oxidative Stress

Growing experimental and clinical data highlights the important roles of increased reactive oxygen species production in cardiovascular remodeling (CR). Oligomeric grape seed proanthocyanidins (GSPs) have been shown to be potent antioxidants and free radical scavengers. Mice were treated with DOCA-salt to induce CR and were given distilled water or oligomeric GSPs for 4 weeks. The heart weight (HW) index and kidney weight (KW) index were expressed as heart weight/body weight (HW/BW) and kidney weight/body weight (KW/BW); the histological changes were investigated by hematoxylin and eosin and Van Gieson staining.The endothelial-dependent vasodilation function induced by acetylcholine was investigated in isolated thoracic aorta ring. Colorimetric analysis was used to assay superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and nitric oxide (NO) content in serum and hydroxyproline content in cardiac tissue. Administration of GSPs markedly alleviated the elevation of HW/BW ratio, KW/BW ratio and cross-sectional area of cardiomyocytes, decreased collagen deposition in heart and attenuated histopathology injury, and improves endothelial-dependent aorta ring relaxation in vitro accompany by increasing of NO content in serum. Meanwhile, treatment with GSPs significantly ameliorated oxidative stress via increasing SOD activities and decreasing MDA formation. These findings suggest that administration of GSPs has the potential to attenuate DOCA-salt induced CR and KH and preserve NO activity and endothelial function, which mechanism may contribute to its antioxidant characteristic, at least in part.

Abstract 1614: Grape seed proanthocyanidins inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and inhibition of PI3K/Akt pathway

Abstract The American Cancer Society reported that 35,420 Americans died in 2009 because of pancreatic cancer. It is an aggressive malignancy that is frequently diagnosed at an advanced stage with poor prognosis. Phosphoinositide 3-kinase (PI3K)/Akt is a potent survival pathway that may mediate resistance to chemotherapeutic drugs and conventional therapies in pancreatic cancer patients. Thus, PI3K/Akt is considered as a promising therapeutic target for this cancer. Dietary phytochemicals offer promising options for the development of effective strategies for the prevention of cancer, and thus can be utilized as complementary and alternative medicine. Therefore, to develop newer and more effective chemotherapeutic agent for pancreatic cancer, we have examined the effect of grape seed proanthocyanidins (GSPs) on the growth of pancreatic cancer cell lines and the molecular mechanisms underlying this effect using PANC-1, AsPC-1 and Miapaca-2 cell lines as a model. The effect of GSPs on pancreatic cancer cell lines was studied on cell proliferation, cell cycle regulation, apoptosis and PI3K/Akt pathway using MTT assay, western blotting and FACS analysis. In vitro treatment of pancreatic cancer cells (Miapaca-2, PANC-1, and AsPC-1) with GSPs resulted in: (i) growth inhibition, which was associated with G2/M-phase arrest, and includes the inhibition of the expressions of cyclin B1, Cdc25B and Cdc25c proteins. (ii) Induction of apoptosis of pancreatic cancer cells by GSPs was associated with the enhanced expression of Bax, and caspase-3 activation while reduced levels of anti-apoptotic proteins (Bcl2, Bcl-xl). (iii) Blocking of PI3K/Akt pathway. Exposure of Miapaca-2 and PANC-1 cancer cells to PI3K inhibitor (wortmannin) also resulted in a dose-dependent induction of apoptosis in these cells. The in vitro data were further verified using in vivo tumor xenograft model. Administration of GSPs (0.2% and 0.5%, w/w) as a supplement of an AIN76A control diet resulted in a dose-dependent inhibition of the growth of Miapaca-2 tumor xenografts in athymic nude mice (35-65%; P&amp;lt;0.05-0.01) compared to non-GSPs-treated controls. The growth inhibitory effect of dietary GSPs on the pancreatic xenograft tumors was associated with the induction of apoptotic cell death of tumor cells, and induction of Bax expression and activation of caspase-3 while decreased the expression of anti-apoptotic proteins. Further, the levels of phospho-Akt and the proteins of PI3K family (PI3K 110 and PI3K 85) were markedly decreased in the xenograft tumors treated with GSPs compared with controls. Together, this preclinical study provides evidence that the chemotherapeutic effect of GSPs on the growth of pancreatic cancer cells in vitro and in vivo is mediated, at least in part, through the induction of apoptosis, G2/M phase arrest and blocking of PI3K/Akt cell survival pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1614. doi:1538-7445.AM2012-1614

Abstract 2368: Reversal of epithelial to mesenchymal transition in non-small cell lung cancer cells by grape seed proanthocyanidins leads to decreased cancer cell migration

Abstract Epithelial to mesenchymal transition (EMT) in cancer endows tumor cells with enhanced migratory and invasive property. EMT is considered as a major event during distant tumor metastasis and is mostly regulated by chronic and sustained inflammation. Cyclooxygenase-2 (COX-2) overexpression has been shown in &amp;gt;70% of lung adenocarcinomas and has reciprocal relationship with E-cadherin expression, an epithelial marker. Since, lung cancer is a highly malignant cancer with a potent capacity to metastasize distantly, an approach that decreases its invasive potential or the ability of cell migration may facilitate the development of an effective strategy for its treatment and/or prevention. Dietary phytochemicals offer promising new options for the development of more effective strategies for the prevention of cancer cell invasion and metastasis, and thus can be utilized as complementary and alternative medicine. We hypothesize that reduction of basal level of COX-2, a biomarker of inflammation, in non-small cell lung cancer (NSCLC) cells by grape seed proanthocyanidins (GSPs) should lead to reversal of EMT and that will result in reduced capacity of cell migration. Here we report that treatment of NSCLC A549 cells with various concentrations of GSPs (0, 10, 20, 40 µg/ml) for 24 h resulted in a dose-dependent reduction of COX-2 expression. Using an in vitro cell migration assay, we found that treatment of cells with GSPs (0, 10, 20, 40 µg/ml) inhibited tumor cell migration from 25±5%-55±5% compared to non-treated control cells. Western blot analysis revealed that treatment of A549 cells with GSPs also resulted in upregulation of epithelial markers (E-cadherin, Keratin-8 and Keratin-18) concomitant with decrease in the levels of mesenchymal markers (Fibroncetin, N-cadherin and Vimentin). Further, treatment of cells with phorbol-12-myristate 13-acetate, an inducer of COX-2, resulted in increased cell migration (118±5%-140±8%) compared to control cells and simultaneously reduced the levels of E-cadherin. Treatment of cells with celecoxib, an inhibitor of COX-2, rescued E-cadherin expression and inhibited cell migration (21±5%-63±5%). Dietary administration of GSPs (0.2% w/w) with control AIN76A-diet to athymic nude mice resulted in reduced xenograft growth and reduced expression of COX-2 in A549 tumor xenografts, and that resulted in upregulation of epithelial markers (E-cadherin, Kertain-8 and Keratin-18) while downregulation of mesenchymal biomarkers (N-cadherin and Fibronectin) in xenograft tissues. Together these data suggest that reversal of epithelial to mesenchymal transition in human NSCLC cells by GSPs is associated with the down regulation of COX-2, and that leads to inhibition of cancer cell migration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2368. doi:10.1158/1538-7445.AM2011-2368

Oligomerized grape seed proanthocyanidins ameliorates isoproterenol‐induced cardiac remodeling in rats: role of oxidative stress

The effects of oligomerized grape seed proanthocyanidins (GSP) on haemodynamics, cardiac hypertrophy and fibrosis as well as apoptosis signal-regulating kinase 1 (ASK1) and nuclear factor-κB (NF-κB) cascades in isoproterenol (Iso)-induced cardiac remodelling (CR) rat model were investigated, in addition, the serum SOD activities and MDA content were assayed. Rats were treated with Iso to induce CR and were given distilled water or GSP for 1 week. Control rats received vehicle instead of Iso. Administration of GSP markedly alleviated the elevation of the left ventricle weight (LVW)/body weight (BW), heart weight (HW)/body weight (BW) ratio and cross-sectional area of cardiomyocytes, decreased collagen deposition in the heart, and improved the haemodynamic index. Meanwhile, treatment with GSP significantly ameliorated oxidative stress by improving SOD activities and decreasing MDA formation. Moreover, GSP apparently inhibited the expression ASK1, NF-κB and its targeted gene - COX-2. These findings suggest that administration of GSP has the potential to attenuate Iso-induced CR by repressing oxidative stress and inhibiting the activation of the cellular signaling cascades involving the ASK1 and NF-κB pathways, at least in part, providing a molecular mechanism for the cardioprotective effect of GSP.

Grape Seed Proanthocyanidins Inhibit the Growth of Human Non-Small Cell Lung Cancer Xenografts by Targeting Insulin-Like Growth Factor Binding Protein-3, Tumor Cell Proliferation, and Angiogenic Factors

Lung cancer is a leading cause of cancer-related deaths worldwide. Here, we assessed the chemotherapeutic effect of grape seed proanthocyanidins (GSPs) on human non-small cell lung cancer (NSCLC) cells in vitro and in vivo using a tumor xenograft model. The effects of GSPs on human NSCLC cell lines in terms of cellular proliferation were determined. The chemotherapeutic effects of a GSP- supplemented AIN76A control diet fed to nude mice bearing tumor xenografts (A549 and H1299) were evaluated in terms of biomarkers of cell proliferation and angiogenesis and on insulin-like growth factor binding protein-3 using immunohistochemical detection, ELISA, and Western blotting. In vitro treatment of NSCLC cells with GSPs resulted in inhibition of cellular proliferation. Administration of GSPs (0.1%, 0.2%, and 0.5%, w/w) as a supplement of an AIN76A control diet resulted in a dose-dependent inhibition of the growth of NSCLC (A549 and H1299) tumor xenografts in athymic nude mice (25-76%; P < 0.05-0.001). The growth-inhibitory effect of GSPs on the NSCLC xenograft tumors was associated with the enhancement of the levels of insulin-like growth factor binding protein-3 in the tumor microenvironment and plasma and antiproliferative, antiangiogenic, and proapoptotic effects. This preclinical study reveals for the first time that dietary GSPs have the ability to inhibit the growth of human NSCLC tumor xenografts grown in vivo in athymic nude mice. More studies are needed to develop GSPs as a pharmacologically safe agent for the prevention of lung cancer in humans.

Grape seed proanthocyanidins ameliorates isoproterenol-induced myocardial injury in rats by stabilizing mitochondrial and lysosomal enzymes: An in vivo study

This study was designed to examine the effects of grape seed proanthocyanidins (GSP) against myocardial injury (MI) induced by isoproterenol (ISO), in a rat model. Induction of rats with ISO (85 mg/kg body weight, subcutaneously) for 2 days resulted in a significant decrease in the activities of heart mitochondrial enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and α-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase). The activities of lysosomal enzymes (α- d-glucuronidase, α- d- N-acetylglucosaminidase, cathepsin-D, acid phosphatases and α- d-galactosidase) were increased significantly in the heart and serum of ISO-induced rats. The prior administration of GSP for 6 days a week for 5 weeks significantly increased the activities of mitochondrial and respiratory chain enzymes and significantly decreased the activities of lysosomal enzymes in the heart tissues of ISO-induced rats, which proves the stress stabilizing action of GSP. Oral administration of grape seed proanthocyanidins alone (50, 100 and 150 mg/kg) to normal rats did not show any significant effect in all the parameters studied. These biochemical functional alterations were supported by the macroscopic enzyme mapping assay of ischemic myocardium. Thus, this study shows that 100 and 150 mg/kg of GSP gives protection against ISO-induced MI and demonstrates that GSP has a significant effect in the protection of heart.

Efficacy of grape seed proanthocyanidins on serum and heart tissue lipids in rats subjected to isoproterenol-induced myocardial injury

The present study was aimed to evaluate the preventive role of grape seed proanthocyanidins (GSPs) on serum and tissue lipid enzymes in isoproterenol (ISO)-induced myocardial injury in male Wistar albino rats. GSP was administered orally to rats (150–180 g) in three different doses, by gastric gavage (50, 100 and 150 mg/kg GSP), 6 days a week for 5 weeks. At the end of this period, all the rats, except the normal untreated rats that served as the control group, were administered ISO, 85 mg/kg subcutaneously, for 2 consecutive days to induce myocardial injury. After 48 h, rats ( n = 6 per group) were anesthetized with anesthetic ether, sacrificed and the levels of biochemical observations of the serum and heart tissues were performed. Biochemical assessment of myocardial injury was done by measuring the activities of serum thiobarbituric acid reactive substances and plasma lactate, which were significantly elevated in the rats administered with ISO. Further, our results suggest that prior administration of GSPs significantly maintained the cholesterol, phospholipids, triglycerides, and free fatty acids levels in serum and heart tissue of the ISO-induced myocardial injury in rats. The experiments conclude that GSPs possess cardioprotective and hypolipidemic effect on the treatment of ISO-induced myocardial injury.

Cardioprotective effect of grape seed proanthocyanidins on isoproterenol-induced myocardial injury in rats

Purpose To investigate whether grape seed proanthocyanidins (GSP) might protect the heart against myocardial injury (MI) induced by isoproterenol (ISO), in a rat model. Methods GSP was administered orally to Wistar albino rats (150–180 g) in three different doses, by gastric gavage (50, 100 and 150 mg kg − 1 GSP), 6 days a week for 5 weeks. At the end of this period, all the rats, except the normal untreated rats that served as the control group, were administered ISO, 85 mg kg − 1 subcutaneously, for 2 consecutive days to induce myocardial injury. After 48 h, rats ( n = 6 per group) were anaesthetized with anesthetic ether, sacrificed and the levels of biochemical and histological observations of the heart tissues were performed. Result Our results suggest that prior administration of GSP maintained the levels of the marker enzymes (AST, ALT, LDH and CK) in all the treatment groups (GSP-50-ISO, GSP-100-ISO and GSP-150-ISO) when compared to ISO-injected rats. The entire baseline groups also showed no significant alterations in serum marker enzyme levels in comparison to that of control group. Interestingly, in this study, there was no significant change in the basal levels of myocardial TBARS, GST, SOD and CAT on administration of GSP in all the three dosages (GSP-50-BL, GSP-100-BL and GSP-150-BL). However, a significant decrease occurred in the levels of GSH and GPx in group GSP-50-BL, which in the absence of any cellular injury (as evidenced by histological studies), is considered to be non-lethal. In the ISO-injected group there was a significant rise in TBARS and a significant decrease in GSH, GPx, GST, SOD and CAT when compared to group control. The administration of GSP maintained the activities of these enzymes close to normal levels when compared to group ISO, which proves the stress stabilizing action of GSP. The biochemical and histological evidence from this study shows that 100 and 150 mg kg − 1 of GSP protected against ISO-induced myocardial injury. Conclusion This study demonstrates that GSP has a significant effect in the protection of heart against MI induced by ISO. We believe that pretreatment with GSP may contribute to developing novel strategies in the prevention and treatment of cardiotoxic effects of elevated levels of catecholamine.