Effects of quercetin on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) secretion and induction of apoptosis in human prostate cancer cells

BACKGROUND: Quercetin, the predominant flavonoid, has been reported to lower the risk of several cancers. This flavonoid found in onion, grapes, green vegetables, etc. has been shown to possess potent antiproliferative effects against various malignant cells. This study was designed to investigate its effects on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) proteins secretion and also apoptosis induction in the human prostate cancer cell line, PC-3. METHODS: We evaluated the secretion of IGF-I, -II and IGFBP-3 in quercetin treated cells by immunoradiometric (IRMA) method. Apoptosis was studied in quercetin treated cells by TUNEL and DNA fragmentation. Protein expressions of Bcl-2, Bcl-x(L), Bax and caspase-3 were studied by western blot. RESULTS: At a dose of 100 μM concentration, we observed increased IGFBP-3 accumulation in PC-3 cells conditioned medium with a dose dependent increase with 2 fold over a base line, and significantly reduced the both IGF-I and IGF-II levels. Apoptosis induction was also confirmed by TUNEL assay. Bcl-2 and Bcl-x(L )protein expressions were significantly decreased and Bax and caspase-3 were increased. CONCLUSION: These results suggest that the decreased level of IGFs could be due to the increased levels of IGFBP-3, because of the high binding affinity towards IGFs, thereby decreasing the cell proliferation. The increased level of IGFBP-3 was associated with increased pro-apoptotic proteins and apoptosis in response to quercetin, suggesting it may be a p53-independent effector of apoptosis in prostate cancer cells

Pregnancy related lumbo-pelvic pain: a prevalence study in a tertiary institute in Pondicherry, India

Background: Pregnancy related low lumbo- pelvic pain (PLPP) is a common complaint that occurs in 60-70% of pregnancies. It can begin at any point during pregnancy. Although most cases are mild, approximately one third of women experience severe pain. The aim of the study was to determine the prevalence of PLPP among antenatal mothers in a tertiary care institute in Pondicherry, India and assess the disability caused therein.Methods: 202 consecutive pregnant women screened for PLPP in the antenatal clinic in Aarupadi Veedu Medical College Hospital Pondicherry, India by questionnaire and assessment of lumbar spine by Mckenzie protocol 2003 and pelvis by specific physical examination for evaluation of low back ache. 31 women had low back ache out of 202 who took part in screening procedure in the antenatal clinic at tertiary care institute to study the point prevalence in the given population disability was assessed by Oswestry disability index scoring questionnaire.Results: Prevalence of PLPP was as low as 15.35% compared to an average of 45% in European studies. PLBP was the dominant clinical pattern 54.84%, PLPP plus PPGP combined was 41.94% and PPGP was a very rare pattern 3.23% Oswestry disability index (ODI) in this study suggests scores upto 30 (mild to moderately disability).Conclusions: PLPP is a disabling palpable clinical problem less recognised in India and most often dismissed as part of pregnancy. Sensitization of obstetrician and the orthopaedician to interact in a multidisciplinary approach would address the problem effectively

Role of urine sediment cytology in the diagnosis of renal disorders in comparison with biochemical and histopathological findings

Background:The functional reserve of the kidney being large, serum biochemical parameters do not show abnormality until late. The need to recognize minimal damage in the kidneys is hence valuable. Urine sediment examination is cost effective, time saving and is called “liquid renal biopsy”. The present study was aimed to evaluate the role of urine sediment examination in predicting the severity of renal damage and compare the results with serum biochemical parameters, 24 hour urine protein values and renal biopsy findings.  Methods:A total of 149 patients presenting with symptoms pertaining to renal disease were included in the study. Clinical information and serum biochemical parameters were obtained. Urine examination was done and renal biopsy performed in all the cases. 2 scoring systems were adopted to grade the urine sediment findings and renal biopsy grading devised by A. Z. Gyory et al. was used to grade the renal injury. 24 hour urine protein was estimated by Esbach’s method. Urine sediment scores, serum biochemical parameters, 24 hour urine protein values were compared with the grades of renal injury on renal biopsies and statistical significance calculated.Results:32.8% of patients with renal disease were in the age group of 31-40 years. Nephrotic syndrome was the most common clinical presentation (33.5%) followed by nephritic syndrome (21.4%). The most common histopathological diagnosis was post infectious glomerulonephritis (n = 26) followed by acute interstitial nephritis (n = 17). 14 cases of lupus nephritis were diagnosed all of which were confirmed by “full house” pattern of immunofluorescence. Both the urine sediment scores had high specificity and positive predictive values in predicting the severity of renal injury. 24 hour urine protein had high positive predictive value in predicting the severity of renal injury. Serum biochemical parameters were insignificant in predicting the severity of renal injury.Conclusion: Urine sediment examination can be used as an effective diagnostic test for predicting the severity of renal injury. The decision of further investigations and follow-up can be certainly decided by taking urine microscopy findings and 24 hour urine protein values into consideration.

Quercetin Suppresses Cyclooxygenase-2 Expression and Angiogenesis through Inactivation of P300 Signaling

Quercetin, a polyphenolic bioflavonoid, possesses multiple pharmacological actions including anti-inflammatory and antitumor properties. However, the precise action mechanisms of quercetin remain unclear. Here, we reported the regulatory actions of quercetin on cyclooxygenase-2 (COX-2), an important mediator in inflammation and tumor promotion, and revealed the underlying mechanisms. Quercetin significantly suppressed COX-2 mRNA and protein expression and prostaglandin (PG) E(2) production, as well as COX-2 promoter activation in breast cancer cells. Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner. The in vitro streptavidin-agarose pulldown assay and in vivo chromatin immunoprecipitation assay showed that quercetin considerably inhibited the binding of the transactivators CREB2, C-Jun, C/EBPβ and NF-κB and blocked the recruitment of the coactivator p300 to COX-2 promoter. Moreover, quercetin effectively inhibited p300 histone acetyltransferase (HAT) activity, thereby attenuating the p300-mediated acetylation of NF-κB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activity. Addition of quercetin to roscovitine-treated cells did not change the roscovitine-induced inhibition of p300 HAT activity. Conversely, gene delivery of constitutively active p300 significantly reversed the quercetin-mediated inhibition of endogenous HAT activity. These results indicate that quercetin suppresses COX-2 expression by inhibiting the p300 signaling and blocking the binding of multiple transactivators to COX-2 promoter. Our findings therefore reveal a novel mechanism of action of quercetin and suggest a potential use for quercetin in the treatment of COX-2-mediated diseases such as breast cancers

Post-Translational Loss of Renal TRPV5 Calcium Channel Expression, Ca2+ Wasting, and Bone Loss in Experimental Colitis

Dysregulated Ca2+ homeostasis likely contributes to the etiology of IBD-associated loss of bone mineral density (BMD). Experimental colitis leads to decreased expression of Klotho, a protein which supports renal Ca2+ reabsorption by stabilizing TRPV5 channel on the apical membrane of distal tubule epithelial cells

Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib

Dietary flavonolds have many health-promoting actions, including anticancer activity via proteasome inhibition. Bortezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but Is not effective In chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive In vitro to bortezomlb-induced apoptosis when cultured in medium, the killing activity was blocked when cultured In 50% fresh autologous plasma. Dietary flavonoids, quercetin and myrocetin, which are abundant In plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH) 2 , in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution Is required when giving dietary advice to patients. © 2008 by The American Society of Hematology

Quercetin abrogates chemoresistance in melanoma cells by modulating ΔNp73

<p>Abstract</p> <p>Background</p> <p>The alkylating agent Dacarbazine (DTIC) has been used in the treatment of melanoma for decades, but when used as a monotherapy for cancer only moderate response rates are achieved. Recently, the clinical use of Temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents because of its greater bioavailability and ability to cross the blood brain barrier. The response rates achieved by TMZ are also unsatisfactory, so there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promoted a p53-mediated response and sensitized melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ and propose a mechanism that involves the modulation of a truncated p53 family member, ΔNp73.</p> <p>Methods</p> <p>DB-1 melanoma (p53 wildtype), and SK Mel 28 (p53 mutant) cell lines were treated with TMZ (400 μM) for 48 hrs followed by Qct (75 μM) for 24 hrs. Cell death was determined by Annexin V-FITC staining and immunocytochemical analysis was carried out to determine protein translocation.</p> <p>Results</p> <p>After treatment with TMZ, DB-1 cells demonstrated increased phosphorylation of Ataxia telangiectasia mutated (ATM) and p53. However, the cells were resistant to TMZ-induced apoptosis and the resistance was associated with an increase in nuclear localization of ΔNp73. Qct treatment in combination with TMZ abolished drug insensitivity and caused a more than additive induction of apoptosis compared to either treatment alone. Treatment with Qct, caused redistribution of ΔNp73 into the cytoplasm and nucleus, which has been associated with increased p53 transcriptional activity. Knockdown of ΔNp73 restored PARP cleavage in the TMZ treated cells, confirming its anti-apoptotic role. The response to treatment was predominantly p53 mediated as the p53 mutant SK Mel 28 cells showed no significant enhancement of apoptosis.</p> <p>Conclusion</p> <p>This study demonstrates that Qct can sensitize cells to TMZ and that the mechanisms of sensitization involve modulation of p53 family members.</p

Anticancer potential of Thevetia peruviana fruit methanolic extract

Abstract Background: Thevetia peruviana (Pers.) K. Schum or Cascabela peruviana (L.) Lippold (commonly known as ayoyote, codo de fraile, lucky nut, or yellow oleander), native to Mexico and Central America, is a medicinal plant used traditionally to cure diseases like ulcers, scabies, hemorrhoids and dissolve tumors. The purpose of this study was to evaluate the cytotoxic, antiproliferative and apoptotic activity of methanolic extract of T. peruviana fruits on human cancer cell lines. Methods: The cytotoxic activity of T. peruviana methanolic extract was carried out on human breast, colorectal, prostate and lung cancer cell lines and non-tumorigenic control cells (fibroblast and Vero), using the MTT assay. For proliferation and motility, clonogenic and wound-healing assays were performed. Morphological alterations were monitored by trypan blue exclusion, as well as DNA fragmentation and AO/EB double staining was performed to evaluate apoptosis. The extract was separated using flash chromatography, and the resulting fractions were evaluated on colorectal cancer cells for their cytotoxic activity. The active fractions were further analyzed through mass spectrometry. Results: The T. peruviana methanolic extract exhibited cytotoxic activity on four human cancer cell lines: prostate, breast, colorectal and lung, with values of IC50 1.91 ± 0.76, 5.78 ± 2.12, 6.30 ± 4.45 and 12.04 ± 3.43 μg/mL, respectively. The extract caused a significant reduction of cell motility and colony formation on all evaluated cancer cell lines. In addition, morphological examination displayed cell size reduction, membrane blebbing and detachment of cells, compared to non-treated cancer cell lines. The T. peruviana extract induced apoptotic cell death, which was confirmed by DNA fragmentation and AO/EB double staining. Fractions 4 and 5 showed the most effective cytotoxic activity and their MS analysis revealed the presence of the secondary metabolites: thevetiaflavone and cardiac glycosides. Conclusion: T. peruviana extract has potential as natural anti-cancer product with critical effects in the proliferation, motility, and adhesion of human breast and colorectal cancer cells, and apoptosis induction in human prostate and lung cancer cell lines, with minimal effects on non-tumorigenic cell lines. Keywords: Cytotoxic activity, Anti-proliferative activity, Motility, Apoptosis, Human cancer cells, Flavonoid, Cardiac glycoside

Scientific Evidence and Rationale for the Development of Curcumin and Resveratrol as Nutraceutricals for Joint Health

Interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) are key cytokines that drive the production of inflammatory mediators and matrix-degrading enzymes in osteoarthritis (OA). These proinflammatory cytokines bind to their respective cell surface receptors and activate inflammatory signaling pathways culminating with the activation of nuclear factor κB (NF-κB), a transcription factor that can be triggered by a host of stress-related stimuli including, excessive mechanical stress and ECM degradation products. Once activated, NF-κB regulates the expression of many cytokines, chemokines, adhesion molecules, inflammatory mediators, and several matrix-degrading enzymes. Therefore, proinflammatory cytokines, their cell surface receptors, NF-κB and downstream signaling pathways are therapeutic targets in OA. This paper critically reviews the recent literature and outlines the potential prophylactic properties of plant-derived phytochemicals such as curcumin and resveratrol for targeting NF-κB signaling and inflammation in OA to determine whether these phytochemicals can be used as functional foods