Activation of nuclear factor (NF)-κB, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of ‘NF-κB addiction’ in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, β-catenin, AR, GR and ER). As NF-κB is ‘preactive’ in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus ‘one size does not fit all’ cancers.
Initially discovered in 1938 as a "fertility factor," vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-κB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation.
We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity.
Because tumors develop resistance to chemotherapeutic agents, the cancer research community continues to search for effective chemosensitizers. One promising possibility is to use dietary agents that sensitize tumors to the chemotherapeutics. In this review, we discuss that the use of resveratrol can sensitize tumor cells to chemotherapeutic agents. The tumors shown to be sensitized by resveratrol include lung carcinoma, acute myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer. The chemotherapeutic agents include vincristine, adriamycin, paclitaxel, doxorubicin, cisplatin, gefitinib, 5-fluorouracil, velcade, and gemcitabine. The chemosensitization of tumor cells by resveratrol appears to be mediated through its ability to modulate multiple cell-signaling molecules, including drug transporters, cell survival proteins, cell proliferative proteins, and members of the NF-κB and STAT3 signaling pathways. Interestingly, this nutraceutical has also been reported to suppress apoptosis induced by paclitaxel, vincristine, and daunorubicin in some tumor cells. The potential mechanisms underlying this dual effect are discussed. Overall, studies suggest that resveratrol can be used to sensitize tumors to standard cancer chemotherapeutics.
Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”.
Inflammation, although first characterized by Cornelius Celsus, a physician in first Century Rome, it was Rudolf Virchow, a German physician in nineteenth century who suggested a link between inflammation and cancer, cardiovascular diseases, diabetes, pulmonary diseases, neurological diseases and other chronic diseases. Extensive research within last three decades has confirmed these observations and identified the molecular basis for most chronic diseases and for the associated inflammation. The transcription factor, Nuclear Factor-kappaB (NF-κB) that controls over 500 different gene products, has emerged as major mediator of inflammation. Thus agents that can inhibit NF-κB and diminish chronic inflammation have potential to prevent or delay the onset of the chronic diseases and further even treat them. In an attempt to identify novel anti-inflammatory agents which are safe and effective, in contrast to high throughput screen, we have turned to “reverse pharmacology” or “bed to benchside” approach. We found that Ayurveda, a science of long life, almost 6000 years old, can serve as a “goldmine” for novel anti-inflammatory agents used for centuries to treat chronic diseases. The current review is an attempt to provide description of various Ayurvedic plants currently used for treatment, their active chemical components, and the inflammatory pathways that they inhibit.
Background Little is known concerning the function of inositol 1,4,5-triphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca2+ release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated following Gαq-protein-coupled receptors (GPCR) stimulation affecting Ca2+ cycling, enhancing myocyte performance and, potentially, favoring an increase in the incidence of arrhythmias. Methods and Results IP3R function was determined in human left ventricular (LV) myocytes and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electrical and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human LV myocytes. Following GPCR activation, Ca2+ mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action-potential, and occurrence of early after-depolarizations. Ca2+ transient amplitude and cell shortening are enhanced, and extra-systolic and dysregulated Ca2+ elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that GPCR activation provide inotropic reserve, which is hampered by electrical instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca2+ load by IP3Rs promote Ca2+ extrusion by forward mode Na+/Ca2+ exchange, an important mechanism of arrhythmic events. Conclusions Thus, the GPCR/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.
The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na+ current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca2+ cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca2+ transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
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