Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases ...including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.
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-kappaB) that controls over 500 different gene products, has emerged as major mediator of inflammation. Thus agents that can inhibit NF-kappaB 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 6,000 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.
Extensive research within the last two decades has revealed that most chronic illnesses, including cancer, diabetes, and cardiovascular and pulmonary diseases, are mediated through chronic ...inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and even treat various chronic diseases, including cancer. Various nutraceuticals from fruits, vegetables, vitamins, spices, legumes, and traditional Chinese and Ayurvedic medicine have been shown to safely suppress proinflammatory pathways; however, their low bioavailability
in vivo limits their use in preventing and treating cancer. We describe here the potential of nanotechnology to fill this gap. Several nutraceuticals, including curcumin, green tea polyphenols, coenzyme Q, quercetin, thymoquinone and others, have been packaged as nanoparticles and proven to be useful in “nanochemoprevention” and “nano-chemotherapy”.
Observational studies have suggested that lifestyle risk factors such as tobacco, alcohol, high-fat diet, radiation, and infections can cause cancer and that a diet consisting of fruits and ...vegetables can prevent cancer. Evidence from our laboratory and others suggests that agents either causing or preventing cancer are linked through the regulation of inflammatory pathways. Genes regulated by the transcription factor NF-κB have been shown to mediate inflammation, cellular transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Whereas various lifestyle risk factors have been found to activate NF-κB and NF-κB-regulated gene products, flavonoids derived from fruits and vegetables have been found to suppress this pathway. The present review describes various flavones, flavanones, flavonols, isoflavones, anthocyanins, and chalcones derived from fruits, vegetables, legumes, spices, and nuts that can suppress the proinflammatory cell signaling pathways and thus can prevent and even treat the cancer.
The N-terminus of Histone H3 is proteolytically processed in aged chicken liver. A histone H3 N-terminus specific endopeptidase (named H3ase) has been purified from the nuclear extract of aged ...chicken liver. By sequencing and a series of biochemical methods including the demonstration of H3ase activity in bacterially expressed GDH, it was established that the H3ase activity was a moonlighting protease activity of glutamate dehydrogenase (GDH). However, the active site for the H3ase in the GDH remains elusive. Here, using cross-linking studies of the homogenously purified H3ase, we show that the GDH and the H3ase remain in the same native state. Further, the H3ase and GDH activities could be uncoupled by partial denaturation of GDH, suggesting strong evidence for the involvement of different active sites for GDH and H3ase activities. Through densitometry of the H3ase clipped H3 products, the H3ase activity was quantified and it was compared with the GDH activity of the chicken liver nuclear GDH. Furthermore, the H3ase mostly remained distributed in the perinuclear area as demonstrated by MNase digestion and immuno-localization of H3ase in chicken liver nuclei, as well as cultured mouse hepatocyte cells, suggesting that H3ase demonstrated regulated access to the chromatin. The present study thus broadly compares the H3ase and GDH activities of the chicken liver GDH.
Curcumin is the active ingredient of turmeric that has been consumed as a dietary spice for ages. Turmeric is widely used in traditional Indian medicine to cure biliary disorders, anorexia, cough, ...diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Extensive investigation over the last five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits HIV replication, enhances wound healing, protects from liver injury, increases bile secretion, protects from cataract formation, and protects from pulmonary toxicity and fibrosis. Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors. Curcumin has been found to modulate the activity of several key transcription factors and, in turn, the cellular expression profiles. Curcumin has been shown to elicit vital cellular responses such as cell cycle arrest, apoptosis, and differentiation by activating a cascade of molecular events. In this chapter, we briefly review the effects of curcumin on transcription factors NF-KB, AP-1, Egr-1, STATs, PPAR-gamma, beta-catenin, nrf2, EpRE, p53, CBP, and androgen receptor (AR) and AR-related cofactors giving major emphasis to the molecular mechanisms of its action.
The nuclear events of a eukaryotic cell, such as replication, transcription, recombination and repair etc. require the transition of the compactly arranged chromatin into an uncompacted state and ...vice-versa. This is mediated by post-translational modification of the histones, exchange of histone variants and ATP-dependent chromatin remodeling. The SWI
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SNF chromatin remodeling complexes are one of the most well characterized families of chromatin remodelers. In addition to their role in modulating chromatin, they have also been assigned roles in cancer and health-related anomalies such as developmental, neurocognitive, and intellectual disabilities. Owing to their vital cellular and medical connotations, developing an understanding of the structural and functional aspects of the complex becomes imperative. However, due to the intricate nature of higher-order chromatin as well as compositional heterogeneity of the SWI
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SNF complex, intra-species isoforms and inter-species homologs, this often becomes challenging. To this end, the present review attempts to present an amalgamated perspective on the discovery, structure, function, and regulation of the SWI/SNF complex.
Histones are classically known to organize the eukaryotic DNA into chromatin. They are one of the key players in regulating transcriptionally permissive and non-permissive states of the chromatin. ...Nevertheless, their context-dependent appearance within the cytoplasm and systemic circulation has also been observed. The past decade has also witnessed few scientific communications on the existence of vesicle-associated histones. Diverse groups have attempted to determine the significance of these extra-nuclear histones so far, with many of those studies still underway. Of note amongst these are interactions of extra-nuclear or free histones with cellular membranes, mediated by mutual cationic and anionic natures, respectively. It is here aimed to consolidate the mechanism of formation of extra-nuclear histones; implications of histone-induced membrane destabilization and explore the mechanisms of their association/release with extracellular vesicles, along with the functional aspects of these extra-nuclear histones in cell and systemic physiology.
Role of Curcumin in Cancer Therapy Shishodia, Shishir; Chaturvedi, Madan M; Aggarwal, Bharat B
Current problems in cancer,
07/2007, Volume:
31, Issue:
4
Journal Article
The chromatin remodeling activity of mammalian SWI/SNF complex is carried out by either Brahma (BRM) or Brahma-related gene (BRG-1). The BRG-1 regulates genes involved in cell proliferation, whereas ...BRM is associated with cell differentiation, and arrest of cell growth. Global modifications of histones and expression of genes of chromatin-remodeling subunits have not been studied in in vivo model systems. In the present study, we investigate epigenetic modifications of histones and the expression of genes in thioacetamide (TAA)-induced liver injury and regeneration in a mouse model. In the present study, we report that hepatocyte proliferation and H3S10 phosphorylation occur during 60 to 72 h post TAA treatment in mice. Furthermore, there was change in the H3K9 acetylation and H3K9 trimethylation pattern with respect to liver injury and regeneration phase. Looking into the expression pattern of Brg-1 and Brm, it is evident that they contribute substantially to the process of liver regeneration. The SWI/SNF remodeler might contain BRG-1 as its ATPase subunit during injury phase. Whereas, BRM-associated SWI/SNF remodeler might probably be predominant during decline of injury phase and initiation of regeneration phase. Furthermore, during the regeneration phase, BRG-1-containing remodeler again predominates. Considering all these observations, the present study depicts an interplay between chromatin interacting machineries in different phases of thioacetamide-induced liver injury and regeneration.
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