bims-stacyt 2018-05-20 papers

Chem Biol Interact. 2018 May 10. pii: S0009-2797(17)30867-0. [Epub ahead of print]

Improvement of hyperglycemia in a murine model of insulin resistance and high glucose- and inflammasome-mediated IL-1β expressions in macrophages by silymarin.

Chun-Ping Lu, Chien-Yu Huang, Szu-Hsuan Wang, Chih-Hsien Chiu, Lan-Hui Li, Kuo-Feng Hua, Tzu-Hua Wu.

Macrophages and inflammasome pathway are involved in high-glucose toxicity and development of insulin resistance. Silymarin (SMR) was known to modulate glucose homeostasis and reduce inflammation. However, it is still unknown whether SMR possess anti-hyperglycemic effects in diabetic-like knockout mice (Hnf-1αkin/-/Ins.cre mice) with insulin resistance and also unclear how SMR regulates LPS induced stress markers and pro-inflammatory cytokines under stresses of high glucose (HG) or NLRP3 inflammasome activation. Current results show that oral administration of SMR (100 mg/kg) reduced hyperglycemia in the mouse model of maturity-onset diabetes of the young type 3-like mice. In cultured macrophages, SMR (5-20 μg/ml) reduces high glucose (HG)-enhanced expressions of inducible nitric oxide synthase, nitric oxide generation stimulated by LPS; however, no effects on COX-2 expressions. The enhanced interleukin-1β (ΙL-1β) secretions in the presence of HG or palmitate were also significantly down regulated by SMR in dose-dependent manner in LPS-treated macrophages. Such observations may result from the decreased extracellular signal-regulated kinase 1/2 phosphorylation, while without affecting protein kinase C-α phosphorylation and nuclear factor-κB activation. These findings together show that SMR acts as a protector against HG-related stresses not only by lowering hyperglycemia but also suppressing HG- and inflammasome-mediated IL-1β expressions to improve insulin resistance.

Keywords: High-glucose toxicity; Hyperglycemia; Insulin resistance; NLRP3 inflammasome; Silymarin

DOI: https://doi.org/10.1016/j.cbi.2018.05.004

Eur J Pharmacol. 2018 May 09. pii: S0014-2999(18)30264-4. [Epub ahead of print]

Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis.

Xiaoyu Liu, Xu Wan, Hao Kan, Yan Wang, Fan Yu, Lei Feng, Jian Jin, Peng Zhang, Xin Ma.

In colon cancer, hypoxia promotes metastasis and angiogenesis, but little is known about the mediators of these effects. Here, we reported that expression of Orai1 is up-regulated in colon cancer cells in response to hypoxia, and the increase in Orai1 is mediated by Notch1 pathway. We also showed upregulation of Orai1 contributes to hypoxia-induced invasion and angiogenesis, and inhibition or downregulation of Orai1 reverses these effects. Mechanistic study revealed that upregulation of Orai1 by hypoxia potentiates store-operated Ca2+ entry (SOCE), and then causes activation of nuclear factor of activated T cells isoform c3 (NFATc3) in colon cancer cells. Furthermore, expression of Orai1 was correlated with tumor metastasis in patients. These results identify Orai1 as a novel target gene of hypoxia and reveal the role of Orai1 signaling in regulating hypoxia-induced invasiveness and angiogenesis under hypoxic conditions. Strategies to target this signaling might be developed to treat colon cancer metastasis and angiogenesis associated with hypoxia.

Keywords: Angiogenesis; Colon cancer; Hypoxia; Invasiveness; Orai1

DOI: https://doi.org/10.1016/j.ejphar.2018.05.008

Drug Discov Today. 2018 May 14. pii: S1359-6446(17)30470-1. [Epub ahead of print]

Targeting HIF-2α as therapy for advanced cancers.

Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar.

Hypoxia-inducible factors (HIF-1α, -2α -3α, and -β) are key factors that control hypoxia-induced carcinogenic pathways. HIF-1α is predominantly involved in the early stages of cancer, whereas HIF-2α is actively involved in the later stages; in addition, chronic (prolonged) rather than acute (short) hypoxia is a feature of metastasis and chemoresistance that occur during the later stages of cancer. Oncometabolites, onco-miRNAs, glucose deprivation, pseudohypoxia, cytokine/chemokine secretion, and some unique upstream proteins are involved in the signaling switch from HIF-1α to HIF-2α; thus, understanding this signaling switch is critical for the treatment of advanced cancer. In this review, we highlight data relating to HIF-2α rather than HIF-1α signaling in cancer pathways and discuss prospective drugs that target this important factor.

DOI: https://doi.org/10.1016/j.drudis.2018.05.003