Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction

Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin’s pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.

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Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials

Advances in copper complexes as anticancer agents.

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-CELL suppressive activity

Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.

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Arsenic: toxicity, oxidative stress and human disease.

Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms.

Breast cancer remains the leading cause of cancer death among females worldwide. It signifies a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Current treatment modalities, including surgery, radiotherapy, and adjuvant chemotherapy or hormone therapy, have not been successful enough to impart significant improvement in the morbidity or mortality of breast cancer. This cancer is highly resistant to chemotherapy as no effective treatment exists for advanced disease conditions. Moreover, there is a dearth of ideal protein biomarkers of breast cancer in plasma or serum that can be used with desired sensitivity and specificity. Along with the existing therapeutic modalities of breast cancer the focus of researchers and clinicians have shifted towards the exploration of the preventive and therapeutic uses of natural products, including dietary phytoconstituents. Curcumin, the principal active component of Indian curry spice turmeric, has been found to exert preventive and therapeutic effects in various cancers. This is, in part, due to its ability to influence a diverse range of molecular targets and signaling pathways. The ability of curcumin to enhance the efficacy of existing chemotherapeutic agents is an added advantage. The current review critically analyzes various aspects of curcumin-related research conducted for molecular understanding of its efficacy in in vitro and in vivo models of breast cancer. The article also highlights recent developments with synthetic analogs of curcumin and nanocurcumin which are in the horizon of next generation targeted therapy with curcumin in breast cancer.

Chemopreventive and chemotherapeutic potential of curcumin in breast cancer

Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy.

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Recurrent Glioblastoma: Where we stand.

Groundwater arsenic contamination has been a health hazard for West Bengal, India. Oxidative stress to DNA is recognized as an underlying mechanism of arsenic carcinogenicity. A phytochemical, curcumin, from turmeric appears to be potent antioxidant and antimutagenic agent. DNA damage prevention with curcumin could be an effective strategy to combat arsenic toxicity. This field trial in Chakdah block of West Bengal evaluated the role of curcumin against the genotoxic effects of arsenic. DNA damage in human lymphocytes was assessed by comet assay and fluorescence-activated DNA unwinding assay. Curcumin was analyzed in blood by high performance liquid chromatography (HPLC). Arsenic induced oxidative stress and elucidation of the antagonistic role of curcumin was done by observation on reactive oxygen species (ROS) generation, lipid peroxidation and protein carbonyl. Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, glutathioneS-transferase, glutathione peroxidase and non-enzymatic glutathione were also analyzed. The blood samples of the endemic regions showed severe DNA damage with increased levels of ROS and lipid peroxidation. The antioxidants were found with depleted activity. Three months curcumin intervention reduced the DNA damage, retarded ROS generation and lipid peroxidation and raised the level of antioxidant activity. Thus curcumin may have some protective role against the DNA damage caused by arsenic.

http://www.cancerfoundationofindia.org/activities/research/pdf/PDF-6.pdf

Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal:

Arsenic is a ubiquitous toxic metalloid whose natural leaching from geogenic resources of earths crust into groundwater has become a dreadful health hazard to millions of people across the globe. Arsenic has been documented as a top most potent human carcinogen by Agency of Toxic Substances and Disease Registry. There have been a number of schools of opinions regarding the underlying mechanism of arsenic-induced carcinogenicity, but the theory of oxidative stress generated by arsenic has gained much importance. Imbalance in the cellular redox state and its associated complications have been closely associated with nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic-leucine zipper transcription factor that activates the antioxidant responsive element and electrophilic responsive element, thereby upregulating the expression of a variety of downstream genes. This review has been framed on the lines of differential molecular responses of Nrf2 on arsenic exposure as well as the chemopreventive strategy which may be improvised to regulate Nrf2 in order to combat arsenic-induced oxidative stress and its long-term carcinogenic effect.

Jaydip Biswas

Papers

Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms.

Chemopreventive and chemotherapeutic potential of curcumin in breast cancer

Recurrent Glioblastoma: Where we stand.

Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal:

Nrf2-mediated redox signaling in arsenic carcinogenesis: a review.