Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-κB and p38 MAPK

Background: Epidemiological and experimental studies have extensively indicated that chronic subclinical systemic inflammation (CSSI) and oxidative stress are risk factors for several chronic diseases, including cancer, arthritis, type 2 diabetes, and cardiovascular and neurodegenerative diseases. This study examined the protective effect of stingless bee honey (SBH) supplementation against lipopolysaccharide (LPS)-induced CSSI, pointing to the possible involvement of NF-κB, p38 MAPK and Nrf2 signaling. Methods: CSSI was induced in male Sprague Dawley rats by intraperitoneal injection of LPS three times per week for 28 days, and SBH (4.6 and 9.3 g/kg/day) was supplemented for 30 days. Results: LPS-induced rats showed significant leukocytosis, and elevated serum levels of CRP, TNF-α, IL-1β, IL-6, IL-8, MCP-1, malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), accompanied with diminished antioxidants. Treatment with SBH significantly ameliorated inflammatory markers, MDA and 8-OHdG, and enhanced antioxidants in LPS-induced rats. In addition, SBH decreased NF-κB p65 and p38 MAPK, and increased Nrf2 expression in the liver, kidney, heart and lung of LPS-induced rats. Furthermore, SBH prevented LPS-induced histological and functional alterations in the liver, kidney, heart and lung of rats. Conclusion: SBH has a substantial protective role against LPS-induced CSSI in rats mediated via amelioration of inflammation, oxidative stress and NF-κB, p38 MAPK and Nrf2 signaling

Tissue-specific cancer-related serpin gene cluster at human chromosome band 3q26

[[abstract]]Approximately one quarter of the identified human serpin genes are cancer-related and clustered mainly at two distinct loci: 6p25 and 18q21. We have studied a novel serpin gene cluster at 3q26 containing at least two recently identified members: the pancreas-specific protease inhibitor, pancpin (PI14), and the brain-associated protease inhibitor, neuroserpin (PI12). In this, unlike a previous study, both PI14 and PI12 at 3q26 were found to consist of 9 exons and 8 introns and to share a perfectly conserved gene organization whose pattern is very different from that of the ov-serpin family. This distinct pattern appears identical in the genomic structures of human plasminogen activator inhibitor-1 (PA11) at 7q21 and protease nexin 1 (PI7) at 2q33-35, confirming that these four genes in three different chromosomes form a discrete subset within the serpin superfamily. As in the other three members whose gene expression is altered during tumorigenesis, PI12 expression was found to be down-regulated in tumor brain tissues and in two brain cancer cell lines: U-87 MG and H4, By screening genomic libraries, we isolated two overlapping clones showing that the marker SGC32223 (centromere) is located within intron F of PI12 and the marker WI-10077 (telomere) is located downstream of the 3'-flanking region of PI14. This finding indicates that the distance between human PI14 and PI12 is similar to 100 kb, and hence we speculate that other tissue-specific cancer-related serpin genes are likely to reside within this 3q26.1 cluster region. (C) 2000 Wiley-Liss, Inc

Human tissue kallikreins as prognostic biomarkers and as potential targets for anticancer therapy

[[abstract]]The tissue kallikrein family represents the largest cluster of contiguous proteinase genes in the entire human genome. Its 15 members are expressed primarily in a tissue-specific manner, but can also be detected in biological fluids such as serum and seminal plasma. The mature active tissue kallikreins play vital roles in numerous physiological and pathological processes, in which they are able to function individually or in cascade pathway(s). Their genetic polymorphisms, alternative splicings and aberrant amounts of transcripts and/or proteins are often correlated with increased cancer risk, thus providing a sensible application for the use of tissue kallikreins as diagnostic, prognostic and predictive tumour markers. in this review, an updated overview of scientific research and patents regarding the functional features and clinical indications of tissue kallikreins in neoplastic diseases is provided

[[alternative]]Characterization of novel α-ketoamide derivatives as potent inhibitors against cathepsin S induced by acidic extracellular pH in pancreatic cancer cells

[[abstract]]Extracellular acidification is known to be a driving force in pancreatic cancer growth and metastasis. Thus, manipulation of acidic peritumoral pH or blockage of key proteins stimulated by acidic extracellular microenvironment may offer considerable potential for pancreatic cancer therapy. Cathepsin S, also known as CTSS or CatS, is a critical proteolytic enzyme found to be up-regulated in malignant cells and secreted into the extracellular milieu to degrade surrounding matrix components. By examining the effect of low pH (6.7) on various pancreatic tumor cell lines, we detected a consistently increased CTSS expression associated with augmented cell migration and invasion. Other features such as CTSS-mediated proteolysis and ECM degradation were also observed under mildly acidic condition. Based on these findings, we designed and synthesized some new small molecules bearing an α-ketoamide warhead to evaluate their ability to inhibit CTSS. Kinetic study revealed these compound inhibitors possess very low Ki values and high specificity against target CTSS enzyme. Further in vitro and in vivo analyses demonstrated these agents not only could protect fibronectin from CTSS-mediated degradation but also induce tumor cell autophagy under extracellular acidification. Together these results indicate the potential of α-ketoamide derivatives as antitumor agents against pancreatic cancer

Generation and characterization of highly selective cathepsin S inhibitors with potentials against pancreatic cancer

[[abstract]]Cathepsin S (CTSS) is a critical cellular protease required for cancer development and metastasis. This proteolytic enzyme is often over-expressed by malignant tumor cells and secreted into the extracellular milieu to degrade surrounding matrix components. Here, we attempted to systematically generate and evaluate potential CTSS inhibitors in hope to identify potent candidates for use as antitumor agents. Detailed kinetic analysis revealed several lead compounds possess very low Ki values and high specificity against target CTSS protease. Results from ECM degradation assays demonstrated that these small molecules could protect fibronectin from CTSS-mediated degradation and consequently hinder tumor cell movement. Treating various pancreatic tumor cell lines with these CTSS inhibitors further resulted in a drastic decrease in cell migration and invasion. The test compounds also reduced the spread of pancreatic tumor cells in orthotopic animal model and thus prolonged mice survival. Finally, these lead molecules exhibited reasonable pharmacokinetic (PK) profiles, suggesting their potential as antitumor agents against pancreatic cancer

Lysosomal cysteine proteinase cathepsin S as a potential target for anti-cancer therapy

[[abstract]]In mammalian cells, cysteine proteinases are localized mainly in the cytoplasm and lysosomal compartments. For lysosomal cysteine proteinases, they are synthesized as inactive zymogens and converted to active forms occurred in the acidic and reducing conditions of late endosomes or lysosomes. Here we review the roles of active lysosomal cysteine proteinases in particular cathepsin S and its importance to many physiological or pathological processes including tumor growth, angiogenesis, and metastasis. Biochemical and clinical studies have shown significant changes in the levels of mRNA expression and enzyme activity of cathepsin S in various cancer tissues and cell lines. Immunologic, molecular and pharmaceutical approaches to alter the expression and proteolytic activity of cathepsin S all provided strong evidence for a causal role of this proteolytic enzyme in tumor progression and invasion. Determination of the X-ray structures of either cathepsin S alone or complexed with inhibitors further offered insights of the active site pocket of cathepsin S, thereby making the rational design of low-molecular weight synthetic inhibitors feasible for anti-cancer drug development and treatment

[[alternative]]活體外癌細胞侵襲實驗技術之回顧與未來發展

[[abstract]]Tumor invasion plays an important first step in complex metastatic process. To understand this physiological event, over the past few decades scientists have tried to untilize different animal species to help study the invasive properties of malignant tumors. Serveral alternative measurements, however, have been developed to replace animal experimentation. These in vitro invasion techniques not only provide a valid model but also offer a rapid, smiple and versatile system for cancer metastasis research. Here we reviewed the overall progress of these invasio assays and, based on the current problems, proposed a better, cheaper and more consistent chamber design for the in vitro tumor invasion assay