Low-Dose Cadmium Exposure Reduces Human Prostate Cell Transformation in Culture and Up-Regulates Metallothionein and MT-1G mRNA.
Journal - Nonlinearity in biology, toxicology, medicine (United States )
Chronic low-level exposure to environmental toxins, including cadmium (Cd), is a growing problem in the industrialized world. One promising strategy for protection from these toxins is the use of low-dose exposure of environmental chemicals to induce cell tolerance and recovery, a phenomenon known as "protective hormesis". Hormetic [low-dose stimulatory] effects occur in a variety of systems and with a number of chemicals. Cd is a potent carcinogen in rodents and has also been linked to human lung and prostate cancers. In the present study, we have evaluated the protective effects of low and ultra-low dose, long-term Cd exposure in the normal human prostate cells, RWPE-1. Cells were exposed to low and ultra-low doses (0, 0 (S(-36)), 10(-6), 10(-7), 10(-18), 10(-21), 10(-32), or 10(-36)M) of Cd for 20 weeks followed by treatment with 10(-5)M Cd for another 8 weeks. Continuous exposure of RWPE-1 cells to 10(-5)M Cd results in malignant transformation. However, cells pretreated with low and ultra-low doses of Cd had delayed transformation compared with controls. In addition, the number of transformed cell mounds was lower in pretreated cells indicating that low and ultra-low dose exposure had protective effects against high-dose Cd induced carcinogenesis. The expression of metallothionein (MT), the primary Cd detoxification protein, was induced by low-dose exposure to Cd and maintained during the 20 weeks. In addition, MT-1G mRNA was up-regulated 2- to 3-fold by low-dose and ultralow-dose Cd exposures and may be the mechanism of protective hormesis in this model. MT-1G mRNA might also serve as a biological indicator of very low-dose environmental Cd exposure.
Protective effect of a polyherbal preparation, Brahma rasayana against tumor growth and lung metastasis in rat prostate model system.
Journal - Journal of experimental therapeutics & oncology (United States )
Rasayanas are a group of herbal formulations and are used to improve health of the body. Recent studies have demonstrated the immunostimulatory and antioxidant activities of some of these rasayanas and their usefulness in tumor regression. The objective of the study is to evaluate Brahma rasayana for the inhibition of tumor development and prevention of metastasis in vivo using Copenhagen rats and MAT-LyLu cell model system. Copenhagen rats injected with MAT-LyLu cells were treated with Brahma rasayana once daily. This treatment was followed from the second day of cell inoculation until the end of the experiment. The study comprises a comparison of survival time, body weight, tumor incidence, tumor size, tumor weight, histopathological examination of the lung metastasis and serum testosterone levels between rasayana treated and control animals. Brahma rasayana treatment resulted in a 25-37% decrease in palpable tumor incidence, a delay of 1-2 weeks in the tumor occurrence, lower mean tumor volumes, by as much as 14-35% and significant reduction in tumor weight and lung metastasis in comparison to untreated controls. The Ayurvedic poly herbal preparation, Brahma rasayana may play a beneficial role in preventing tumor incidence, tumor growth and metastatic spread. These are inexpensive preparations that have little or no adverse side effects with a potential as lead chemopreventive compounds and which might prove useful for the treatment of disorders such as human prostate cancer.
|ISSN : ||1359-4117|
|Mesh Heading : ||Animals Body Weight Chemoprevention Disease Models, Animal Disease Progression Injections, Intravenous Lung Neoplasms Male Neoplasm Metastasis Plant Extracts Prostatic Neoplasms Rats Testosterone veterinary blood|
|Mesh Heading Relevant : ||prevention & control secondary prevention & control pharmacology drug therapy pathology|
Differential regulation of cytokines and transcription factors in liver by curcumin following hemorrhage/resuscitation.
Journal - Shock (Augusta, Ga.) (United States )
Inflammatory cytokines interleukin 1 (IL-1), IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) have been recognized as important mediators of pathophysiological and immunological events associated with shock. These inflammatory events after hemorrhage and resuscitation are characterized by the activation of transcription regulators such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Curcumin, an anti-inflammatory remedy used in Indian medicine, is known to suppress NF-kappaB and AP-1 activation and also to reduce ischemia-reperfusion injuries in animal models. Therefore, the aim of this study was to determine whether administration of curcumin before hemorrhagic shock has any salutary effects on cytokines and the redox-sensitive transcription factors NF-kappaB and AP-1. mRNA levels of IL-1alpha, IL-1beta, IL-2, IL-6, IL-10, and TNF-alpha were determined by reverse transcriptase-polymerase chain reaction in rat livers collected at 2 and 24 h after hemorrhage/resuscitation. The effect of curcumin on the activation of NF-kappaB and AP-1 was determined by electrophoretic mobility shift assays. Significant increases in the levels of liver cytokines IL-1alpha, IL-1beta, IL-2, IL-6, and IL-10 were observed in the 2-h posthemorrhage/resuscitation group compared with sham animals. In contrast, oral administration of curcumin for 7 days followed by hemorrhage/resuscitation regimen resulted in significant restoration of these cytokines to depleted levels, and, in fact, IL-1beta levels were lower than sham levels. Also, the 24-h postresuscitation group showed similar patterns with some exceptions. NF-kappaB and AP-1 were differentially activated at 2 and 24 h posthemorrhage and were inhibited by curcumin pretreatment. Serum aspartate transaminase estimates indicate decreased liver injury in curcumin-pretreated hemorrhage animals. These results suggest that protection against hemorrhage/resuscitation injury by curcumin pretreatment may result from the inactivation of transcription factors involved and regulation of cytokines to beneficial levels.
|ISSN : ||1073-2322|
|Mesh Heading : ||Animals Aspartate Aminotransferases Blotting, Western Cell Nucleus Curcumin Cytokines Enzyme Inhibitors Hemorrhage Inflammation Interleukin-1 Interleukin-10 Interleukin-2 Interleukin-6 Liver Male Proto-Oncogene Proteins c-fos Proto-Oncogene Proteins c-jun RNA, Messenger Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Time Factors Transcription Factor AP-1 Transcription Factors Tumor Necrosis Factor-alpha blood metabolism metabolism biosynthesis biosynthesis biosynthesis biosynthesis metabolism metabolism metabolism metabolism biosynthesis|
|Mesh Heading Relevant : ||Resuscitation pharmacology biosynthesis pharmacology metabolism metabolism biosynthesis|
Picroliv modulates the expression of insulin-like growth factor (IGF)-I, IGF-II and IGF-I receptor during hypoxia in rats.
Journal - Cellular and molecular life sciences : CMLS (Switzerland )
The insulin-like growth factors (IGFs), IGF-I and IGF-II, play important roles in normal growth and differentiation. In recent studies, IGFs have been implicated in tissue repair and regeneration after hypoxicischemic injury. The growth effects of these genes are exerted primarily through IGF-I receptor (IGF-IR). We have earlier shown that picroliv, obtained from the roots of Picrorhiza kurrooa, reduces cellular damage caused by hypoxia in vitro. We have now studied the modulation of IGF-I, IGF-II and IGF-IR in hypoxia and the ability of picroliv to modify their expression in vivo. Male Sprague-Dawley rats, placed in 10% oxygen for 4 days, were sacrificed, and the expression of IGF-I, IGF-II and IGF-IR was determined by immunohistochemistry, in situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR) in brain, liver and lung. One group of animals was pretreated with picroliv and the other served as control. IGF-I and IGF-IR were expressed in distinct regions of the brain but not in liver or lung. IGF-I was mainly expressed in the hippocampus and cerebellum, whereas IGF-IR expression was also observed in the cortex. A significant reduction in the messenger RNA (mRNA) level of these genes was observed in response to hypoxia. Pretreatment with picroliv not only prevented such downregulation but more importantly resulted in increased levels of IGF-I and IGF-IR. These observations correlated with reduced neuronal cell death observed in these animals. The mRNA of IGF-II was constitutively expressed and was not altered by hypoxia. Modulation of IGF-I and IGF-II expression by picroliv, a novel pharmacological agent, could benefit in similar clinical settings such as myocardial ischemia and certain cerebral injuries.
|ISSN : ||1420-682X|
|Mesh Heading : ||Animals Anoxia Brain Cinnamates Gene Expression Regulation Glycosides Immunohistochemistry In Situ Hybridization Insulin-Like Growth Factor I Insulin-Like Growth Factor II Liver Lung Male RNA, Messenger Rats Rats, Sprague-Dawley Receptor, IGF Type 1 Reverse Transcriptase Polymerase Chain Reaction Vanillic Acid drug effects metabolism drug effects genetics metabolism genetics metabolism drug effects metabolism drug effects metabolism drug effects genetics metabolism genetics metabolism|
|Mesh Heading Relevant : ||physiopathology pharmacology pharmacology drug effects drug effects drug effects pharmacology|
Inhibition of growth and regulation of IGFs and VEGF in human prostate cancer cell lines by shikonin analogue 93/637 (SA).
Journal - Anticancer research (GREECE )
BACKGROUND: Insulin-like growth factors (IGFs) are important mitogens and are involved in normal and malignant cellular proliferation. IGFs and IGF binding proteins (IGFBPs) regulate the prostatic cell growth and reduction/blocking of IGFs has been suggested to be of therapeutic value in prostate cancer. beta,beta-dimethyl acryl shikonin, an extract from the roots of plant Arnebia nobilis has been shown to have anticancer properties but was found to be toxic. Subsequently, several analogoues of beta,beta-dimethyl acryloyl shikonin were synthesized and one of them shikonin analogue 93/637 (SA) was significantly less toxic compared to beta,beta-dimethyl acryloyl shikonin. MATERIALS AND METHODS: We have investigated the effect of SA on prostate cancer cell (DU 145, LNCaP and PC-3) growth and expression of IGFs (IGF-I, IGF-II and IGF-I receptor (IGF-IR)), IGFBP-3 and vascular endothelial growth factor (VEGF). RESULTS: SA had growth inhibitory effect on PC-3 cells in a dose dependent manner. It also showed slight inhibitory effect on the growth of DU 145 and LNCaP cells at low doses ranging from 250 nM to 1 microM and has moderate inhibitory effect at concentrations 2.5 microM and above. Lactate dehydrogenase (LDH) activity assays indicated cellular damage, only at higher concentrations of SA that are greater than 1 microM. Gene expression studies by RT-PCR have demonstrated a decrease in mRNAs of IGF-II in DU 145, IGF-I, and IGF-IR in LNCaP, and IGF-II and VEGF in PC-3 cells and an increase in IGFBP-3 in both DU 145 and PC-3 cells by treatment with SA. CONCLUSIONS: The results demonstrate the inhibitory effect of SA on cellular growth and IGFs specifically in PC-3 cells and suggest a potential therapeutic use in treatment of prostate cancer.
|ISSN : ||0250-7005|
|Mesh Heading : ||Antineoplastic Agents, Phytogenic Cell Survival Endothelial Growth Factors Humans Insulin-Like Growth Factor Binding Protein 3 L-Lactate Dehydrogenase Lymphokines Male Naphthoquinones Prostatic Neoplasms RNA, Messenger Receptors, Somatomedin Somatomedins Tumor Cells, Cultured Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors drug effects metabolism metabolism pathology analysis|
|Mesh Heading Relevant : ||pharmacology genetics genetics genetics pharmacology drug therapy genetics genetics|
Picroliv -- a natural product protects cells and regulates the gene expression during hypoxia/reoxygenation.
Journal - Molecular and cellular biochemistry (NETHERLANDS )
Cellular adaptation to hypoxia involves regulation of specific genes such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and hypoxia inducible factor (HIF)-1 . In this study, we have evaluated the protective effect of picroliv (a purified iridoid glycoside fraction from roots of Picrorhiza kurrooa with hepatoprotective, anti-inflammatory and antioxidant properties) against hypoxic injury by examining lactate dehydrogenase (LDH) release in Hep 3B and Glioma cells. The expression of hypoxia regulated genes, VEGF and HIF-1 was studied in human umbilical vein endothelial cells (HUVEC), Hep 3B and Glioma cells. Picroliv reduced the cellular damage caused by hypoxia as revealed by a significant reduction in LDH release compared to untreated control. The expression of VEGF and HIF-1 subunits (HIF-1alpha and HIF-1beta) was enhanced by treatment with picroliv during normoxia and hypoxia in HUVEC and Hep 3B cells and on reoxygenation the expression of these genes was significantly reduced as revealed by mRNA analysis using RT-PCR. Simultaneous treatment with picroliv during hypoxia inhibited VEGF and HIF-1 expression in Glioma cells whereas the expression was not reduced by picroliv treatment during reoxygenation as evidenced by both RT-PCR and Northern hybridization. VEGF expression as revealed by immunofluorescence studies correlates well with the regulations observed in the mRNA expression. We have also examined the kinase activity of tyrosine phosphorylated proteins and protein kinase C (PKC) in Glioma cells treated with picroliv during hypoxia/reoxygenation. A selective inhibition of protein tyrosine kinase activity leading to tyrosine dephosphorylation of several proteins including 80 kd protein, and a reduction in PKC was seen in cells treated with picroliv and hypoxia. These findings suggest that picroliv may act as a protective agent against hypoxia/reoxygenation induced injuries, and the underlying mechanism may involve a novel signal transduction pathway.
|ISSN : ||0300-8177|
|Mesh Heading : ||Base Sequence Blotting, Northern Cell Survival Cinnamates DNA Primers Endothelial Growth Factors Gene Expression Regulation Glycosides Humans L-Lactate Dehydrogenase Lymphokines Oxygen Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Vanillic Acid Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors genetics metabolism metabolism genetics metabolism|
|Mesh Heading Relevant : ||Cell Hypoxia drug effects pharmacology drug effects pharmacology metabolism pharmacology|
Mutations of the p16 gene product are rare in prostate cancer.
Journal - The Prostate (UNITED STATES )
BACKGROUND: The p16 gene product is a negative regulator of cell cycle and has been shown to be deleted or mutated in a number of tumor cell lines and primary tumors. The role of p16 in prostate cancer is not defined. Prostate cancer tissues and cell lines were evaluated for p16 gene alterations. METHODS: Five metastatic prostate cancer cell lines were analyzed for p16 gene structure and its expression by Southern and Northern blot analyses. Forty-one DNA specimens from 18 microdissected primary tumor specimens, adjacent normal tissues, and cell lines were amplified by polymerase chain reaction for p16 protein coding and splice junction sequences. Mutations were analyzed by single strand conformation polymorphism and DNA sequencing. RESULTS: DU 145 cell line exhibited a missense mutation in codon 84 (GAC to TAC). With the exception of previously reported polymorphism, no mutation was detected in p16 coding or splice junction sequences in primary prostate cancer specimens. CONCLUSIONS: Inactivation of p16 gene by mutations in the protein coding sequence does not play a major role in the genesis of primary prostate cancer.
|ISSN : ||0270-4137|
|Mesh Heading : ||Blotting, Northern Blotting, Southern Carrier Proteins Cyclin-Dependent Kinase Inhibitor p16 DNA Probes DNA, Neoplasm Genes, Tumor Suppressor Humans Male Microsatellite Repeats Polymerase Chain Reaction Polymorphism, Single-Stranded Conformational Prostatic Neoplasms Tumor Cells, Cultured genetics pathology|
|Mesh Heading Relevant : ||Mutation genetics genetics genetics|
Thymosin 1 Stimulates Endothelial Cell Migration, Angiogenesis, and Wound Healing1
Journal - The Journal of Immunology
In wound healing, lymphoid cells release soluble factors that
attractfibroblasts and macrophages, initiating repair, endothelial
cellmigration, angiogenesis, and matrix production. We analyzedthe
effect of thymosin 1 (T1) on
endothelial cell migration,angiogenesis, and wound healing.
T1, a 28 amino acid peptideinitially isolated from the
thymus, enhanced the morphologicdifferentiation of endothelial cells
and was a potent chemoattractantfor endothelial cells and monocytes in
vitro. In vivo, T1 stimulatedangiogenesis in a
subcutaneous model. When given either topicallyor i.p., it accelerated
wound healing in a punch model, demonstratingthat T1
promotes angiogenesis and wound healing.