Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Dampening inflammation by modulating tlr signalling

Fabrication of gold nanoparticles for targeted therapy in pancreatic cancer

The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium-derived nitric oxide (EDNO), synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular diseases, including hypertension, diabetes, and atherosclerosis. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in defining the pathologic mechanisms involved. Considerable evidence supports a causal role for the enhanced production of reactive oxygen species (ROS) by vascular cells. ROS directly inactivate EDNO, act as cell-signaling molecules, and promote protein dysfunction, events that contribute to the initiation and progression of endothelial dysfunction. Increasing data indicate that strategies designed to limit vascular ROS production can restore endothelial function in humans with vascular complications. The purpose of this review is to outline the various ways in which ROS can influence endothelial function and dysfunction, describe the redox mechanisms involved, and discuss approaches for preventing endothelial dysfunction that may highlight future therapeutic opportunities in the treatment of cardiovascular disease.

Redox control of endothelial function and dysfunction: Molecular mechanisms and therapeutic opportunities

Real-time RT-PCR is a relatively new technology that uses an online fluorescence detection system to determine gene expression levels. It has the potential to significantly improve detection of breast cancer metastasis by virtue of its exquisite sensitivity, high throughput capacity and quantitative readout system. To assess the utility of this technology in breast cancer staging, we determined the relative expression levels of 12 cancer-associated genes (mam, PIP, mamB, CEA, CK19, VEGF, erbB2, muc1, c-myc, p97, vim and Ki67) in 51 negative-control normal lymph nodes and in 17 histopathology-positive ALNs. We then performed a receiver operating characteristic (ROC) curve analysis to determine the sensitivity and specificity levels of each gene. Areas under the ROC curve indicated that the most accurate diagnostic markers were mam (99.6%), PIP (93.3%), CK19 (91.0%), mamB (87.9%), muc1 (81.5%) and CEA (79.4.0%). mam was overexpressed in 16 of 17 lymph nodes known to contain metastatic breast cancer at levels ranging from 22- to 2.8 x 10(5)-fold above normal mean expression, whereas PIP was overexpressed from 30- to 2.2 x 10(6)-fold above normal in 13 lymph nodes. Real-time RT-PCR analysis of pathology-negative LN from breast cancer patients revealed evidence of overexpression of PIP (6 nodes), mam (3 nodes) and CEA (1 node) in 8 of 21 nodes (38%). Our results provide evidence that mam, PIP, CK19, mamB, muc1 and CEA can be applied as a panel for detection of metastatic and occult micrometastatic disease.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.1312

Quantitative real-time RT-PCR detection of breast cancer micrometastasis using a multigene marker panel.

Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer: correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection.

Oxidative damage markers as possible discriminatory biomarkers in breast carcinoma.

Serial serum Carcinoembryonic antigen (CEA) levels were measured in 150 individuals (50 patients with breast cancer, 50 benign breast diseases and 50 other controls). These levels were correlated with clinicopathological parameters and follow-up information. Serum CEA levels were independent of the primary tumor status, their histology, lymphoreticular response and the patients' characteristics as well as the age, sex and the menstrual status. However, the nodal status, number of involved nodes and the grade of the tumors had significant influence on the level of serum CEA. Breast cancer patients especially those with metastasis had significantly higher serum CEA levels as compared to the controls and those with localised disease, irrespective of the site of metastasis. These levels were lowered appreciably by the disease regression and were raised or stable during the disease progression. Receiver operating characteristic (ROC) curve showed metastasis to be more frequent in patients with pretreatment serum CEA levels above 25 ng/ml and persistent post treatment CEA levels above 15 ng/ml. Serum CEA level was found to be a valuable prognostic indicator for advanced breast cancer and serial serum CEA levels provided an average lead time of about 3.9 months before the clinical appearance of metastasis.

Carcinoembryonic antigen: an invaluable marker for advanced breast cancer.

OBJECTIVES To understand the association between biomarkers of oxidative stress, antioxidants, trace elements, and cell proliferation index in relation to the disease progression in the pathophysiology of breast diseases. DESIGN AND METHODS Concentrations of markers of oxidative stress, antioxidants, trace elements, and cell proliferation index were evaluated in the patients with benign breast diseases, malignant breast diseases, and healthy volunteers as controls. Multinomial logistic regression analysis was used to identify the contribution of the selected indexes using odds ratio and associated confidence interval. RESULTS The level of markers of oxidative stress (malondialdehyde [MDA]) and cell proliferation index were found to be significantly higher with significantly depleted levels of antioxidants and trace elements in breast cancer patients compared with control subjects as well as benign breast disease patients. A similar pattern of changes were observed between benign and control subjects. CONCLUSION An inadequate amount of antioxidant enzymes and trace elements may be an important contributing factor associated with oxidative stress leading to elevated levels of MDA and cell proliferation index in relation to disease progression and clinical stage in the pathophysiology of breast diseases.

Association between biomarkers of oxidative stress, trace elements, and cell proliferation index in patients with benign and malignant breast diseases.

NF-κB is recognized as a redox-sensitive transcription factor and has been implicated in cellular response to oxidative stress. The study was designed to correlate the changes in antioxidant status with the levels of nuclear factor-κB (NF-κB) p65 subunit DNA-binding activity in relation to lymph node involvement, tumor size, and staging in breast carcinoma patients. Case control study comprised of 40 breast carcinoma patients along with 40 age- and sex-matched healthy subjects as controls. Levels of enzymatic/nonenzymatic antioxidants along with the trace elements were measured to study the antioxidant status in the study subjects. Levels of NF-κB p65 subunit DNA-binding activity was estimated by ELISA assay. The levels of enzymatic, nonenzymatic antioxidants, and trace elements were found to be significantly depleted in breast carcinoma patients in comparison to healthy controls suggesting significantly decreased levels of antioxidant activity in the breast carcinoma patients. Also, these results indicate that antioxidant levels decrease progressively with the advancement of stage and subsequent progression of disease. DNA-binding activity of NF-κB p65 subunit was higher in breast cancer patients in comparison to normal healthy controls, and the activity was found to increase with the advancement of disease. Significant correlation was observed between the DNA-binding activity of NF-κB p65 subunit and antioxidant status in the patients. The logistic regression analysis revealed decreased levels of antioxidants and increased level of DNA-binding activity of NF-κB p65 subunit were significantly associated with incidence of breast carcinoma. Depleted antioxidant status and increased level of DNA-binding activity of NF-κB p65 subunit thus point clearly of an association in relation to disease progression, clinical stage, and cytological grade in the pathophysiology of breast carcinoma.

NF-κB p65 subunit DNA-binding activity: association with depleted antioxidant levels in breast carcinoma patients.

lymph nodes, spleen, liver, bone marrow, and other sites. Non-Hodgkin's lymphoma is cancer of the lymphoid tissue, which includes the lymph nodes, spleen, and other organs of the immune system. Although the specific etiological factors of multiple myeloma and lymphoma are not yet known, considerable evidence indicate that both genetic and environment may play a role in their evolution.Oxidative stress, mediated by reactive oxygen species, may result in direct DNA damage as well as in lipid peroxidation, protein modification, membrane disruption, and mitochondrial damage. Some human studies have provided evidence of the potential role of oxidative stress in cancer etiology (Halliwell and Gutteridge, 1999, Marnett, 2000). ROS initiate autocatalytic lipid peroxidation, which generates a large variety of potential genotoxic breakdown products, including alkoxyl radicals (LO.), peroxyl radicals (LOO.), and aldehydes, such as malondialdehyde (MDA). MDA is an important lipid oxidative damage product because it has both mutagenic and carcinogenic activity. It can cause cross linking in lipids, proteins and nucleic acids (Freeman, 1982, Flohe et al., 1985). Oxidative stress also damage DNA resulting in the formation of bulky adducts. 8-hydroxy-2-deoxy Guanosine is one of the major product of oxidative damage that is abundant, mutagenic and can be detected reliably (Kasai et al., 1984, Kasai and Nishimura, 1984). This stable pre-mutagenic oxidative modification has also been recognized as a potential marker connoting target organ damage from reactive oxygen species (ROS) and its level is well correlated with the incidence of cancer (Poulsen et al., 1998). An attempt has been made to investigate the level of oxidative damage by quantification of levels of Malondialdehyde and 8-hydroxy

/pdf/oxidative-stress-induced-lipid-peroxidation-and-dna-adduct-2319nhuj4w.pdf

H. D. Khanna

Papers

Oxidative damage markers as possible discriminatory biomarkers in breast carcinoma.

Carcinoembryonic antigen: an invaluable marker for advanced breast cancer.

Association between biomarkers of oxidative stress, trace elements, and cell proliferation index in patients with benign and malignant breast diseases.

NF-κB p65 subunit DNA-binding activity: association with depleted antioxidant levels in breast carcinoma patients.

Oxidative stress Induced lipid peroxidation and DNA Adduct formation in the pathogenesis of multiple myeloma and lymphoma