Proteases and their Receptors as Mediators of Inflammation-Associated Colon Cancer

Trusevych, Elizabeth; MacNaughton, Wallace K.

doi:10.2174/1381612821666150514104800

Cited by 16 publications

(11 citation statements)

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“…In addition to elevated levels of cytokines, chemokines, and ROS production, inflammasomes are strongly linked to increased rates of epithelial proliferation and angiogenesis, and play critical roles in colitis-associated CRC progression 150 . Furthermore, the role of proteases and their receptors on intestinal inflammation and cancer provide a rationale to explore the potential role of protease-activated receptor-induced PTGS2/COX2 in colitis-associated cancer 151 . American ginseng may have potential value in CRC chemoprevention via reduction of gene expression of inflammatory cytokines, including IL1A/IL1α (interleukin 1 α), IL1B, IL6, TNF, CSF3/G-CSF, and CSF2/GM-CSF in both the small intestine and the colon 152 …”

Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.

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Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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“…Proteases and phospholipases A 2 in snake venoms display up to 96% of homology with their human homologues (Pozzi, Chen, & Di Cera, ; Trusevych & MacNaughton, ). This high degree of structural and functional homology, could lead to similar in vitro inhibitions by our AB extract.…”

Section: Resultsmentioning

confidence: 99%

Fruit Bagasse Phytochemicals from Malpighia Emarginata Rich in Enzymatic Inhibitor with Modulatory Action on Hemostatic Processes

Marques

César

Braga

et al. 2018

Journal of Food Science

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Agro‐industrial wastes are promising sources of phytochemicals for the development of products to be used in health promotion and maintenance. In this study, extracts from acerola bagasse (AB) were characterized by HPLC, and evaluated according to its modulatory action on phospholipases A2 and proteases involved in processes such as inflammation and blood clotting. Snake venoms were used as biological tools once they have high functional and structural homology between their enzymes and human enzymes. Two types of extracts were prepared from AB: aqueous and methanolic. These extracts, evaluated at different proportions (venom:extract, w:w), significantly inhibited the phospholipase activity induced by the venoms of Bothrops moojeni, Bothrops atrox (11% to 31%), and Crotalus durissus terrificus (C. d. t.) (11% to 19%). The hemolytic activity induced by the venoms of B. moojeni and C. d. t. was better inhibited by the methanolic extract (inhibition between 23% and 48%). Thrombolysis induced by the venoms of B. moojeni and C. d. t. was inhibited by both extracts, with inhibition ranging from 13% to 63% for the aqueous extract, and from 12% to 92% for the methanolic one. Both extracts increased the time of coagulation induced by the venoms of B. moojeni and Lachesis muta muta in 26 and up to 68 s. These inhibitory actions were related to the following phenolic compounds present in the extract of AB: gallic acid, catechin, epigallocatechin gallate, epicatechin, syringic acid, p‐coumaric acid, and quercetin. Additional studies are needed to confirm their potential use for nutraceutical purposes. Practical Application Agro‐industrial wastes are promising sources of phytochemicals for the development of products that can be used by pharmaceutical, cosmetics, and food industries. Studies report the use of the acerola bagasse extract in health improvement. However, its toxic‐pharmacological characterization is still scarce. In this study, the extracts of acerola bagasse presented phenolic compounds that can modulate the activity of enzymes such as phospholipases A2 and proteases that act on the coagulant/anticoagulant and thrombotic/thrombolytic activities and the break of phospholipids, decreasing the inflammation and platelet aggregation. Although the in vivo effects of the extracts are not fully understood, this study shed light upon the possibilities of their usage.

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“…PAR2-activating proteases are abundant in the gut lumen, such as trypsin secreted primarily by the pancreas 35 , as well as trypsin-like enzymes produced by the bacteria 36 . Immune cells release various PAR2-activating proteases, such as tryptase and elastase, released by mast cells or neutrophils 37 . Coagulation involves the activation of coagulation factor V, XII and KLKs, all of which have been shown to activate PAR2 38 .…”

Section: Discussionmentioning

confidence: 99%

Protease-activated receptor 2 signaling modulates susceptibility of colonic epithelium to injury through stabilization of YAP in vivo

Han

et al. 2018

Cell Death Dis

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Hippo signaling plays critical roles in intestinal regeneration. However, the mechanisms which regulate its activity in vivo are largely unknown. We hypothesize that protease-activated receptor 2 (PAR2) signaling, which could be activated by trypsin, might affect YAP activity in the setting of tissue damage and regeneration. It is found that knockout of PAR2 severely aggravates the mucosal damage induced by dextran sodium sulfate (DSS) in mouse, which correlated with notable repression of YAP protein in colonic epithelial cells. Although the cytokine expression is reduced, the damage of colonic crypt is more severe after DSS-induced colitis in PAR2-/- mouse. In vitro, PAR2 activation causes the accumulation of YAP, while knockdown of PAR2 with shRNA dramatically represses the expression of YAP protein in different intestinal epithelial cell lines. Moreover, forced expression of YAP significantly reduces the production of reactive oxygen species (ROS) and the sensitivity to nitric oxide-induced apoptosis in PAR2-deficient condition. Further studies show that PAR2 signaling stabilizes YAP protein but independent of Lats. Nevertheless PAR2 activation increased the binding of YAP with protein phosphatase PP1. Inhibition of PP1 with specific siRNA blocked PAR2-induced dephosphorylation of YAP. Taken together, PAR2 signaling might modulate susceptibility of colonic epithelium to injury through stabilization of YAP.

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Proteases and their Receptors as Mediators of Inflammation-Associated Colon Cancer

Cited by 16 publications

References 0 publications

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

Fruit Bagasse Phytochemicals from Malpighia Emarginata Rich in Enzymatic Inhibitor with Modulatory Action on Hemostatic Processes

Protease-activated receptor 2 signaling modulates susceptibility of colonic epithelium to injury through stabilization of YAP in vivo

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