Dimethyl sulfoxide (DMSO) is a small molecule with polar, aprotic and amphiphilic properties. It serves as a solvent for many polar and nonpolar molecules and continues to be one of the most used solvents (vehicle) in medical applications and scientific research. To better understand the cellular effects of DMSO within the concentration range commonly used as a vehicle (0.1–1.5%, v/v) for cellular treatments, we applied Attenuated Total Reflectance (ATR) Fourier Transform Infrared (FT-IR) spectroscopy to DMSO treated and untreated epithelial colon cancer cells. Both unsupervised (Principal Component Analysis-PCA) and supervised (Linear Discriminant Analysis-LDA) pattern recognition/modelling algorithms applied to the IR data revealed total segregation and prominent differences between DMSO treated and untreated cells at whole, lipid and nucleic acid regions. Several of these data were supported by other independent techniques. Further IR data analyses of macromolecular profile indicated comprehensive alterations especially in proteins and nucleic acids. Protein secondary structure analysis showed predominance of β-sheet over α-helix in DMSO treated cells. We also observed for the first time, a reduction in nucleic acid level upon DMSO treatment accompanied by the formation of Z-DNA. Molecular docking and binding free energy studies indicated a stabilization of Z-DNA in the presence of DMSO. This alternate DNA form may be related with the specific actions of DMSO on gene expression, differentiation, and epigenetic alterations. Using analytical tools combined with molecular and cellular biology techniques, our data indicate that even at very low concentrations, DMSO induces a number of changes in all macromolecules, which may affect experimental outcomes where DMSO is used as a solvent.
NLRs are a class of cytoplasmic PRRs with various functions, ranging from pathogen/damage sensing to the modulation of inflammatory signaling and transcriptional control of MHC and related genes. In addition, some NLRs have been implicated in preimplantation and prenatal development. NLRP12 (also known as RNO, PYPAF7, and Monarch-1), a member of the family containing an N-terminal PYD, a NBD, and a C-terminal LRR region, is one of the first described NLR proteins whose role remains controversial. The interest toward NLRP12 has been boosted by its recent involvement in colon cancer, as well as in the protection against some severe infections, such as that induced by Yersinia pestis, the causative agent of plague. As NLRP12 is mainly expressed by the immune cells, and its expression is down-regulated in response to pathogen products and inflammatory cytokines, it has been predicted to play a role as a negative regulator of the inflammatory response. Herein, we present an overview of the NLR family and summarize recent insights on NLRP12 addressing its contribution to inflammatory signaling, host defense, and carcinogenesis.
Despite their similarities, the expression levels and functions of AKR1B1 and AKR1B10 are highly divergent in CRC, and they may have prognostic implications.
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15-LOX-1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has been shown to crosstalk with a number of important signalling pathways. This review looks into the latest developments in understanding the role of 15-LOX-1 in different disease states with emphasis on the emerging role of the enzyme in the tumour microenvironment as well as a newly re-discovered form of cell death called ferroptosis. We also discuss future perspectives on the feasibility of use of this protein as a target for therapeutic interventions.
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