Targeting CSC-related miRNAs for cancer therapy by natural agents.

The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood.

Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.

Background & Aims: Tumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells.

Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF.

Tumor hypoxia with deregulated expression of hypoxia inducing factor (HIF) and its biological consequence leads to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. Emerging evidence also suggest that hypoxia and HIF signaling pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation, all of which contribute to radiation therapy and chemotherapy resistance. However, the detailed mechanisms by which hypoxia/HIF drive these events are not fully understood.

Training traditional birth attendants to use misoprostol and an absorbent delivery mat in home births.

A 50-fold disparity in maternal mortality exists between high- and low-income countries, and in most contexts, the single most common cause of maternal death is postpartum hemorrhage (PPH). In Bangladesh, as in many other low-income countries, the majority of deliveries are conducted at home by traditional birth attendants (TBAs) or family members. In the absence of skilled birth attendants, training TBAs in the use of misoprostol and an absorbent delivery mat to measure postpartum blood loss may strengthen the ability of TBAs to manage PPH.

Targeting CSCs within the tumor microenvironment for cancer therapy: a potential role of mesenchymal stem cells.

Introduction: Mesenchymal stem cells (MSCs) are one subgroup of adult stem cells and possess a proliferative potential and ability to differentiate into various ceells.

Areas Covered: Emerging evidence suggests that MSCs can reprogram toward cancer stem cells (CSCs), due to alterations of intrinsic and extrinsic microenvironments, leading to tumorigenesis. The CSC concept has fundamental clinical implications because of its involvement in cell migration/invasion, metastasis, and treatment resistance.

Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most frequently diagnosed cancers and the fourth leading cause of cancer-related death in the United States, suggesting that there is an urgent need to design novel strategies for achieving better treatment outcome of patients diagnosed with PDAC. Our previous study has shown that activation of Notch and NF-κB play a critical role in the development of PDAC in the compound K-Ras(G12D) and Ink4a/Arf deficient transgenic mice. However, the exact molecular mechanism by which mutated K-Ras and Ink4a/Arf deficiency contribute to progression of PDAC remains largely elusive.

[Effect of inhibitors serine/threonine protein kinases and protein phosphatases on mitosis progression of synchronized tobacco by-2 cells].

In order to investigate the role of various serine/ threonine protein kinases and protein phosphatases in the regulation of mitosis progression in plant cells the influence of cyclin-dependent (olomoucine) and Ca2+ -calmodulin-dependent (W7) protein kinases inhibitors, as well as protein kinase C inhibitors (H7 and staurosporine) and protein phosphatases inhibitor (okadaic acid) on mitosis progression in synchronized tobacco BY-2 cells has been studied. It was found that BY-2 culture treatment with inhibitors of cyclin dependent protein kinases and protein kinase C causes prophase delay, reduces the mitotic index and displaces of mitotic peak as compare with control cells. Inhibition of Ca2+ -calmodulin dependent protein kinases enhances the cell entry into prophase and delays their exit from mitosis.

The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness.

Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors.

Prebiotic activity of polysaccharides extracted from Gigantochloa levis (Buluh beting) shoots.

Bamboo shoot crude polysaccharides (BSCP) extracted from the shoots of Gigantochloa levis gave about 3.27 ± 0.18% on dry basis and a very minute percentage of protein (0.

A(3) adenosine receptor: a plausible therapeutic target for cardio-protection in diabetes.

Diabetes mellitus categorized as type I and II, is a disease of pancreatic insulin, affecting blood glucose level in the body. Recent evidence suggests that cardiac diseases such as hypertension, coronary artery disease, congestive heart failure, and diabetic cardiomyopathy are associated with diabetes and hyperglycemia. The adenosine receptors (AR) have been reported to play an important role in the regulation of these diseases.

Mislocalization of the exitatory amino-acid transporters (EAATs) in human astrocytoma and non-astrocytoma cancer cells: effect of the cell confluence.

Background: Astrocytomas are cancers of the brain in which high levels of extracellular glutamate plays a critical role in tumor growth and resistance to conventional treatments. This is due for part to a decrease in the activity of the glutamate transporters, i.e.

Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol.

Resveratrol found in fruits, vegetables and beverages such as red wine, has been extensively evaluated for its anticardiovascular disease and cancer preventive effects. Even though studies have demonstrated its anti-tumor effects, there is still no clear explanation for cancer cell selective mechanisms of action of resveratrol. Initial investigations were focused on its anti-oxidant and cytoprotective mechanism of action, yet, a large number of studies have demonstrated that resveratrol can behave either as anti-oxidant or pro-oxidant depending on the selective microenvironment.

Evaluation of the Combined Effects of Stilbenoid from Shorea gibbosa and Vancomycin against Methicillin-Resistant Staphylococcus aureus (MRSA).

The aim of this study is to determine the combined effects of stilbenoids from Shorea gibbosa and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). A total of nine pure compounds, five stilbenoid dimers ε-viniferin, ampelopsin A, balanocarpol, laevifonol and diptoindonesin G and four stilbenoid trimers a-viniferin, johorenol A, ampelopsin E and vaticanol G were evaluated for their antibacterial activities against ATCC 33591 and a HUKM clinical isolate. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for each active compound were determined using the serial microdilution and plate-streak techniques.

The immunological contribution of NF-κB within the tumor microenvironment: a potential protective role of zinc as an anti-tumor agent.

Over decades, cancer treatment has been mainly focused on targeting cancer cells and not much attention to host tumor microenvironment. Recent advances suggest that the tumor microenvironment requires in-depth investigation for understanding the interactions between tumor cell biology and immunobiology in order to optimize therapeutic approaches. Tumor microenvironment consists of cancer cells and tumor associated reactive fibroblasts, infiltrating non-cancer cells, secreted soluble factors or molecules, and non-cellular support materials.

Aberrant epigenetic grooming of miRNAs in pancreatic cancer: a systems biology perspective.

Pancreatic cancer (PC) is a complex disease harboring a myriad of genetic and epigenetic changes. The dismal survival of patients diagnosed with PC is in part due to de novo and acquired resistance to conventional therapeutics, resulting from deregulated signaling including aberrant expression of small nc miRNAs. Emerging research in this area has lead to the identification and characterization of deregulated miRNAs, which have generated a renewed interest and hope in that novel targeting of miRNAs may lead to a better clinical outcome for patients diagnosed with PC.

Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression.

The histone methyltransferase EZH2 is a central epigenetic regulator of cell survival, proliferation, and cancer stem cell (CSC) function. EZH2 expression is increased in various human cancers, including highly aggressive pancreatic cancers, but the mechanisms underlying for its biologic effects are not yet well understood. In this study, we probed EZH2 function in pancreatic cancer using diflourinated-curcumin (CDF), a novel analogue of the turmeric spice component curcumin that has antioxidant properties.

Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, which is, in part, due to intrinsic (de novo) and extrinsic (acquired) resistance to conventional therapeutics, suggesting that innovative treatment strategies are required for overcoming therapeutic resistance to improve overall survival of patients. Oral administration of metformin in patients with diabetes mellitus has been reported to be associated with reduced risk of pancreatic cancer and that metformin has been reported to kill cancer stem cells (CSC); however, the exact molecular mechanism(s) has not been fully elucidated. In the current study, we examined the effect of metformin on cell proliferation, cell migration and invasion, and self-renewal capacity of CSCs and further assessed the expression of CSC marker genes and microRNAs (miRNA) in human pancreatic cancer cells.

Small heat-shock protein HSPB1 mutants stabilize microtubules in Charcot-Marie-Tooth neuropathy.

Mutations in the small heat shock protein HSPB1 (HSP27) are causative for Charcot-Marie-Tooth (CMT) neuropathy. We previously showed that a subset of these mutations displays higher chaperone activity and enhanced affinity to client proteins. We hypothesized that this excessive binding property might cause the HSPB1 mutant proteins to disturb the function of proteins essential for the maintenance or survival of peripheral neurons.

Network modeling of CDF treated pancreatic cancer cells reveals a novel c-myc-p73 dependent apoptotic mechanism.

Systems biology and molecular network modeling are important tools that are finding application in anti-cancer drug discovery. These technologies can be utilized to map and evaluate the entire set of pathways modulated by drugs in cancer cells without loosing key details. Such integrated approaches are especially useful in understanding the mechanism of action of agents that do not have a defined target.

Small molecule inhibitors of bcl-2 family proteins for pancreatic cancer therapy.

Pancreatic cancer (PC) has a complex etiology and displays a wide range of cellular escape pathways that allow it to resist different treatment modalities. Crucial signaling molecules that function downstream of the survival pathways, particularly at points where several of these pathways crosstalk, provide valuable targets for the development of novel anti-cancer drugs. Bcl-2 family member proteins are anti-apoptotic molecules that are known to be overexpressed in most cancers including PC.

Resveratrol-induced apoptosis is enhanced in low pH environments associated with cancer.

Many critical factors such as hypoxia, nutrient deficiency, activation of glycolytic pathway/Warburg effect contribute to the observed low pH in tumors compared to normal tissue. Studies suggest that such tumor specific acidic environment can be exploited for the development of therapeutic strategies against cancer. Independent observations show reduction in pH of mammalian cells undergoing internucleosomal DNA fragmentation and apoptosis.

Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of Notch and NF-κB signaling pathways.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, suggesting that novel strategies for the prevention and treatment of PDAC are urgently needed. K-ras mutations are observed in >90% of pancreatic cancer, suggesting its role in the initiation and early developmental stages of PDAC. In order to gain mechanistic insight as to the role of mutated K-ras, several mouse models have been developed by targeting a conditionally mutated K-ras(G12D) for recapitulating PDAC.