Lipoxygenase (LOX) Pathway: A Promising Target to Combat Cancer.

Leukotrienes are one of the major eicosanoid lipid mediators produced due to an oxidative transformation of arachidonic acid. Subsequently, they get converted into various cellular signaling hormones by a series of enzymes of myeloid origin to mediate or debilitate inflammation. Interestingly, the available literature demonstrates the pivotal role of eicosanoids in neurodegenerative, obesity, diabetes, cardiovascular diseases, and cancers as well. The aberrant metabolism of arachidonic acid by the LOX pathway is a common feature of epithelial-derived malignancies and suggests the contributory role of dietary fats in carcinogenesis. The enzymes and receptors of the LOX pathway play a significant role in cell proliferation, differentiation and regulation of apoptosis through multiple signaling pathways and have been reported to be involved in various cancers, including prostate, colon, lung and pancreatic cancers. So far, leukotriene receptor antagonists and 5-LOX inhibitors have reached up to the clinical trials for treating various diseases. Keeping its various roles in cancer, the review highlights the components of the leukotriene synthesizing machinery, emerging opportunities for pharmacological intervention, and the probability of considering lipoxygenases and leukotriene receptors as good candidates for clinical chemoprevention studies.

Protective effects of luteolin against oxidative stress and mitochondrial dysfunction in endothelial cells.

BACKGROUND AND AIMS: Luteolin is a common flavonoid that is abundantly present in various edible plants, it is known to exhibit beneficial effects on cardiovascular system. However, the mechanisms which underlie the protective effects of luteolin on endothelial cell damage caused by oxidative stress remains unclear. The purpose of this study is to test the hypothesis which states that luteolin protects against H2O2-induced oxidative stress via modulating ROS-mediated P38 MAPK/NF-κB and calcium-evoked mitochondrial apoptotic signalling pathways. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were pretreated with luteolin prior to being stimulated by 600 µM H2O2 for another 24 h. The expression of native and phosphorylated-P38, IκB, NF-κB, native eNOS, phosphorylated-eNOS, iNOS and several apoptosis-related proteins were analyzed by Western blot. In addition, intracellular calcium was determined by fura-2 AM and mitochondrial membrane potential was examined by using JC1. Using the data gathered, we found indications that H2O2 induced P38 MAPK/NF-κB activation. H2O2 downregulated the expression of eNOS and upregulated iNOS, which in turn contribute to an elevated NO generation and protein nitrosylation. However, pretreatment with luteolin markedly reversed all of these alterations dose-dependently. Additionally, an intracellular calcium rise and subsequent mitochondrial membrane potential collapse, P53 phosphorylation, reduced BcL-2/Bax ratio in the mitochondrial membrane, release cytochrome c from mitochondria, leading to the subsequent activation of caspase 3 activation by H2O2 were all markedly suppressed in the presence of luteolin. CONCLUSION: Results from this study may provide the possible molecular mechanisms underlying cardiovascular protective effects of luteolin.

Tid1-S attenuates LPS-induced cardiac hypertrophy and apoptosis through ER-a mediated modulation of p-PI3K/p-Akt signaling cascade.

Myocardial dysfunction is clinically relevant? repercussion that follows sepsis. Tid 1 protein has been implicated in many biological process. However, the role of Tid 1 in lipopolysaccharide (LPS)-induced cardiomyocyte hypertrophy and apoptosis remains elusive. In the current research endeavor, we have elucidated the role of Tid1-S on LPS-induced cardiac hypertrophy and apoptosis. Interestingly, we found that overexpression of Tid1-S suppressed TLR-4, NFATc3, and BNP protein expression which eventually led to inhibition of LPS-induced cardiac hypertrophy. Moreover, Tid1-S overexpression attenuated cellular apoptosis and activated survival proteins p-PI3K and pser473 Akt. Besides this, Tid1-S overexpression enhanced ER-a protein expression. Collectively, our data suggest that Tid1-S plausibly enhance ER-a protein and further activate p-PI3K and p ser473 Akt survival protein expression; which thereby led to attenuation of LPS-induced apoptosis in cardiomyoblast cells. Interestingly, our data suggest that Tid1-S is involved in attenuation of cardiomyoblast cells damages induced by LPS.

Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression.

Osteosarcoma (OS) is a tumor entity that can cause a large number of cancer-related deaths. Although chemotherapy can decrease proliferation and increase apoptosis of human OS cells, the clinical prognosis remains poor. Fisetin is a flavonol found in fruits and vegetables and is reported to inhibit cell growth in numerous cancers. But the molecular mechanism underlying fisetin in human OS cells is not clear. It is known that sterile-alpha motif and leucine zipper containing kinase (ZAK), a kinase in the MAP3K family, is involved in various cell processes, including proliferation and apoptosis. In our lab, we have demonstrated that overexpression of ZAK can induce apoptosis in human OS cells. In the previous studies, MAP4K, the upstream of MAP3K, can act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Turning on the Hippo pathway can decrease proliferation and otherwise cause cell apoptosis in cancer cells. In this study, we found that fisetin can upregulate ZAK expression to induce the Hippo pathway and mediate the activation of JNK/ERK, the downstream of ZAK, to trigger cell apoptosis via AP-1 dependent manner in human OS cells. These findings reveal a novel molecular mechanism underlying fisetin effect on human OS cells.

The multifaceted link between inflammation and human diseases.

Increasing reports on epidemiological, diagnostic, and clinical studies suggest that dysfunction of the inflammatory reaction results in chronic illnesses such as cancer, arthritis, arteriosclerosis, neurological disorders, liver diseases, and renal disorders. Chronic inflammation might progress if injurious agent persists; however, more typically than not, the response is chronic from the start. Distinct to most changes in acute inflammation, chronic inflammation is characterized by the infiltration of damaged tissue by mononuclear cells like macrophages, lymphocytes, and plasma cells, in addition to tissue destruction and attempts to repair. Phagocytes are the key players in the chronic inflammatory response. However, the important drawback is the activation of pathological phagocytes, which might result from continued tissue damage and lead to harmful diseases. The longer the inflammation persists, the greater the chance for the establishment of human diseases. The aim of this review was to focus on advances in the understanding of chronic inflammation and to summarize the impact and involvement of inflammatory agents in certain human diseases.