https://digital.library.adelaide.edu.au/dspace/bitstream/2440/102889/2/hdl_102889.pdf

Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

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The role of Nrf2 in oxidative stress-induced endothelial injuries

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer 'hallmarks' through downstream activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Additionally, dysregulation of the interleukin (IL)-6-mediated JAK/STAT3 signaling pathway is closely related to the development of diverse human solid tumors including colorectal cancer (CRC). On this basis, modulation of the IL-6/JAK/STAT3 signaling pathway is currently being widely explored to develop novel therapies for CRC. The present review details the mechanisms and roles of the IL-6/JAK/STAT3 pathway in CRC, describes current therapeutic strategies, and the search for potential therapeutic approaches to treat CRC.

/pdf/the-il-6-jak-stat3-pathway-potential-therapeutic-strategies-ih046jensp.pdf

The IL-6/JAK/STAT3 pathway: Potential therapeutic strategies in treating colorectal cancer (Review)

Exploration of natural sources for novel bioactive compounds has been an emerging field of medicine over the past decades, providing drugs or lead compounds of considerable therapeutic potential. This research has provided exciting evidence on the isolation of microbe-derived metabolites having prospective biological activities. Mushrooms have been valued as traditional sources of natural bioactive compounds for many centuries and have been targeted as promising therapeutic agents. Many novel biologically active compounds have been reported as a result of research on medicinal mushrooms. In this review, we compile the information on bioactive structure-elucidated metabolites from macrofungi discovered over the last decade and highlight their unique chemical diversity and potential benefits to novel drug discovery. The main emphasis is on their anti-Alzheimer, anti-diabetic, anti-malarial, anti-microbial, anti-oxidant, anti-tumor, anti-viral and hypocholesterolemic activities which are important medicinal targets in terms of drug discovery today. Moreover, the reader’s attention is brought to focus on mushroom products and food supplements available in the market with claimed biological activities and potential human health benefits.

Bioactive metabolites from macrofungi: ethnopharmacology, biological activities and chemistry

Effect of ethanol on lipid metabolism

Ganoderic acid A is a lanostane triterpene isolated from Ganoderma lucidum. It has been reported to exhibit antitumor activity, which is mainly mediated through its inhibitory effect on nuclear transcription factor-kappaB and activator protein-1. But the role of ganoderic acid A in JAK-STAT3 signaling pathways is still unclear. In the present study, we investigated the effect of ganoderic acid A on the signal transducer and activator of the transcription 3 pathway and evaluated whether suppression of the signal transducer and activator of transcription 3 activity by ganoderic acid A could sensitize HepG2 cells to cisplatin. Our results show that ganoderic acid A significantly suppressed both the constitutively activated and IL-6-induced signal transducer and activator of transcription 3 phosphorylation in HepG2 cells. Inhibition of the signal transducer and activator of transcription 3 tyrosine phosphorylation was found to be achieved through suppression of JAK1 and JAK2. Furthermore, ganoderic acid A promoted cisplatin-induced cell death by enhancing the sensitivity of HepG2 cells to cisplatin mainly via the signal transducer and activator of transcription 3 suppression. These observations suggest a potential therapeutic strategy of using ganoderic acid A in combination with chemotherapeutic agents for cancer treatment.

Inhibition of the JAK-STAT3 signaling pathway by ganoderic acid A enhances chemosensitivity of HepG2 cells to cisplatin.

Taraxerol inhibits LPS-induced inflammatory responses through suppression of TAK1 and Akt activation.

Solanesol protects human hepatic L02 cells from ethanol-induced oxidative injury via upregulation of HO-1 and Hsp70.

Arctigenin promotes degradation of inducible nitric oxide synthase through CHIP-associated proteasome pathway and suppresses its enzyme activity.

The aim of the present study was to examine the anti-inflammatory effect of solanesol and to elucidate the underlying mechanisms. Heme oxygenase-1 (HO-1) plays an important role in cytoprotection against oxidative stress and inflammation. Solanesol induced HO-1 expression both at the level of mRNA and proteins, resulting in increased HO-1 activity. Solanesol treatment enhanced the level of the phosphorylated form, nuclear translocation, ARE-binding, and transcriptional activity of Nrf2. p38 and Akt contributed to ARE-driven HO-1 expression. Solanesol activated both p38 and Akt, and treatments with SB203580 (a p38 kinase inhibitor), LY294002 (an Akt inhibitor), specific p38 siRNA and Akt siRNA suppressed the solanesol-induced activation of Nrf2, resulting in a decrease in HO-1 expression. Solanesol also elevated the autophagic protein LC3B-II level. SnPP (a HO-1 inhibitor) and HO-1 siRNA markedly abolished the anti-inflammatory effect of solanesol against LPS-induced cell damage. Likewise, SB203580, LY294002, 3-MA and Baf-A1 inhibited the solanesol-induced anti-inflammatory effect. These studies demonstrate that solanesol attenuates inflammation by HO-1 induction via p38 and Akt signaling. Thus, it is quite plausible that HO-1 induction by solanesol could trigger anti-inflammatory pathways including limiting LPS-stimulated cytokine production through autophagic signaling via p38 and Akt.

Hui Xu

Papers

Inhibition of the JAK-STAT3 signaling pathway by ganoderic acid A enhances chemosensitivity of HepG2 cells to cisplatin.

Taraxerol inhibits LPS-induced inflammatory responses through suppression of TAK1 and Akt activation.

Solanesol protects human hepatic L02 cells from ethanol-induced oxidative injury via upregulation of HO-1 and Hsp70.

Arctigenin promotes degradation of inducible nitric oxide synthase through CHIP-associated proteasome pathway and suppresses its enzyme activity.

Solanesol induces the expression of heme oxygenase-1 via p38 and Akt and suppresses the production of proinflammatory cytokines in RAW264.7 cells