Nadia Saadat

Potential Role of Garcinol as an Anticancer Agent

Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential.

Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance.

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cells enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

Differences in metabolomic profiles of male db/db and s/s, leptin receptor mutant mice

Leptin, a protein hormone secreted by adipose tissue, plays an important role in regulating energy metabolism and the immune response. Despite similar extremes of adiposity, mutant mouse models, db/db, carrying spontaneous deletion of the active form of the leptin receptor (LEPR-B) intracellular signaling domain, and the s/s, carrying a specific point mutation leading to a dysfunctional LEPR-B-STAT3 signaling pathway, have been shown to have robust differences in glucose homeostasis. This suggests specific effects of leptin, mediated by non-STAT3 LEPR-B pathways. Differences in the LEPR-B signaling pathways in these two LEPR-B mutant mice models are expected to lead to differences in metabolism. In the current study, the hypothesized differences in metabolism were investigated using the metabolomics approach. Proton nuclear magnetic resonance spectroscopy ((1)HNMR) was conducted on 24 h urine samples in deuterium oxide using a 500 MHz instrument at 25°C. Principle Component Analysis showed clear separation of urine NMR spectra between the groups (P < 0.05). The CHENOMX metabolite database was used to identify several metabolites that differed between the two mouse models. Significant differences (P < 0.05) in metabolites associated with the glycine, serine, and homocysteine metabolism were observed. The results demonstrate that the metabolomic profile of db/db and s/s mice are fundamentally different and provide insight into the unique metabolic effects of leptin exerted through non-STAT3 LEPR-B pathways.

Dietary Garcinol Arrests Pancreatic Cancer in p53 and K-ras Conditional Mutant Mouse Model

Abstract Pancreatic cancer (PC) patients have poor prognosis and survival rate. Gemcitabine, the drug of choice has a dismal 15% response rate. Earlier, we reported that Garcinol alone and in combination with gemcitabine showed a dose-dependent favorable response on PC cell lines. This study probes the in vivo effects of dietary Garcinol on PC progression in transgenic PC mice (KPC; K-ras and p53 conditional mutant). KPC male mice were divided into: KC- Control diet; KGr-0.05% Garcinol diet; KGm-Gemcitabine injected; KGG – Garcinol diet + Gemcitabine injected groups. Changes in tumor progression, toxicity, or cell morphology were monitored by magnetic resonance imaging, Fore-stomach, and blood smear, respectively. Pancreatic Intraepithelial Neoplasia (mPanIN) grading with hematoxylin and eosin (H&E) staining was conducted on pancreas and validated by immunohistochemistry. The KGr group showed improved survival, no observable toxicity with marked reduction in papilloma formation in the fore-stomach, and a higher ratio of NK and NKT cells compared to Non-NK lymphocytes. Additionally, the KGr, KGm, and KGG groups showed reduction in tumor volumes and reduced number of advanced mouse PanIN3. Dietary Garcinol alone and in combination with gemcitabine retarded the progression of PC in transgenic PC mice, arresting the cancer in the earlier stages, improving prognosis and survival.

ProAlgaZyme and its subfractions increase plasma HDL cholesterol via upregulation of ApoA1, ABCA1, and SRB1, and inhibition of CETP in hypercholesterolemic hamsters

Background: Plasma HDL cholesterol levels are inversely related to cardiovascular disease, which is the leading cause of death worldwide. This study investigated the effect of an algae infusion, ProAlgaZyme (PAZ), and its subfractions (P1, P2, P3, P4) on plasma HDL in a hamster model. Methods: Sixty male golden Syrian hamsters (8 weeks old) were randomized into controls (W) or PAZ (P), P1, P2, P3, and P4 (n = 10 per group). An infusion of either 5% (P1, P2, P3) or 20% (P, P4) concentration (v/v) was administered via the drinking water for 4 weeks, while the hamsters were being fed a high-fat diet (30% of calories from fat). Serum lipids were assayed and liver samples subjected to reverse transcription polymerase chain reaction to determine the relative transcription levels of genes involved in HDL/reverse cholesterol transport metabolism, ie, ApoA1, ABCA1, CETP, and SRB1. Results: Non-HDL cholesterol was significantly reduced in the P ( P , 0.05), P3 and P4 (P , 0.001) groups as compared with the W group, while HDL cholesterol showed a significant increase in the P, P3, and P4 groups (P , 0.001). Moreover, the total cholesterol/HDL ratio was significantly improved in the P, P1, and P2 ( P , 0.05), and P3 and P4 (P , 0.001) groups. The shift in cholesterol towards the higher density fractions was validated by density gradient ultracentrifugation. Real-time quantitative polymerase chain reaction showed a significant increase in hepatic ApoA1 (P, P4) and ABCA1 (P3, P4) expression, consistent with an increase in HDL production, biogenesis, and maturation. A two-fold increase in SRB1 expression indicates that P4 further augments the reverse cholesterol transport mechanism. Reduction of CETP expression (P4) is consistent with a decrease in the transfer of cholesteryl ester to LDL, further increasing the amount of cholesterol held as HDL particles. Conclusion: ProAlgaZyme and its subfractions significantly improved the plasma cholesterol profile by lowering non-HDL and increasing HDL, possibly via the reverse cholesterol transport