bims-stacyt 2018-08-19 papers

Cancer Lett. 2018 Aug 08. pii: S0304-3835(18)30513-5. [Epub ahead of print]435 80-91

Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.

Xin Chen, Jieru Zhou, Xiaoduan Li, Xinjing Wang, Yingying Lin, Xipeng Wang.

Recently, cancer has been considered to be a complex system that includes the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most common immune-related stromal cells in the TME, and communication between cancer cells and TAMs is crucial for the progression of epithelial ovarian cancer (EOC). In this study, we revealed that exosomes derived from EOC cells remodel macrophages to a tumor-promoted phenotype, namely TAMs. In addition, hypoxic microenvironments have been postulated to facilitate this process in the TME, and hypoxia-inducible factors (HIFs) play an important role in this process. We found that TAMs educated by hypoxic exosomes derived from EOC cells promote tumor proliferation and migration in a feedback loop. Based on microarray analysis of normoxic and hypoxic exosomes, we discovered that a panel of miRNAs was enriched in hypoxic exosomes. And these three highly expressed miRNAs were induced by hypoxia via HIFs. In this study, we revealed that under hypoxic conditions, EOC cell-derived exosomes deliver miRNAs to induce M2 macrophage polarization, which promotes EOC cell proliferation and migration. This study suggests that these exosomes and associated miRNAs might serve as targets for novel treatments or diagnostic biomarkers for EOC.

Keywords: EOC; Exosomes; Hypoxia; TAMs; miRNAs

DOI: https://doi.org/10.1016/j.canlet.2018.08.001

Biomed Pharmacother. 2018 Aug 08. pii: S0753-3322(18)32240-6. [Epub ahead of print]107 306-328

Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity.

Biplab Giri, Sananda Dey, Tanaya Das, Mrinmoy Sarkar, Jhimli Banerjee, Sandeep Kumar Dash.

Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.

Keywords: Cancer; Diabetes; Glucose toxicity; Hyperglycemia; Infection; Organ dysfunction

DOI: https://doi.org/10.1016/j.biopha.2018.07.157

Mol Cancer. 2018 Aug 11. 17(1): 120

Role of hypoxia-induced exosomes in tumor biology.

Chuchu Shao, Fengming Yang, Suyu Miao, Weitao Liu, Chaoshan Wang, Yongqian Shu, Hua Shen.

PURPOSE: Hypoxia is a major regulator of angiogenesis and always influences the release of exosomes in various types of tumors. The present review aimed to assess the role of hypoxia-induced exosomes in the tumor biology.
METHODS: The relevant publications were retrieved from PubMed using keywords such as hypoxia, exosome, extracellular vesicles, tumor, cancer, and other similar terms.
RESULTS: Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Hypoxia-induced exosomes play critical roles in tumor angiogenesis, invasion, metastasis, and the immune system.
CONCLUSIONS: These findings provide new insights into the complex networks underlying cellular and genomic regulation in response to hypoxia and might provide novel and specific targets for future therapies.

Keywords: Cancer; Exosome; Extracellular vesicles; Hypoxia

DOI: https://doi.org/10.1186/s12943-018-0869-y

Sleep Breath. 2018 Aug 11.

Toll-like receptor-4 deficiency alleviates chronic intermittent hypoxia-induced renal injury, inflammation, and fibrosis.

Yan Zhang, Xiaoli Su, Fangfang Zou, Tengjuan Xu, Pinhua Pan, Chengping Hu.

BACKGROUND: Obstructive sleep apnea (OSA)-associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered renal damage. This study aims to investigate the role of toll-like receptor-4 (TLR4) in underlying mechanism involved chronic intermittent hypoxia (CIH)-induced renal damage.
METHODS: C57BL/6J mice with normal TLR4 (TLR4 WT) or deficient TLR4 (TLR4 KO) were divided into four groups and exposed to normal air (NA) and CIH: TLR4 WT + NA, TLR4 KO + NA, TLR4 WT + CIH, and TLR4 KO + CIH. CIH lasted for 8 h/day and 7 days/week for 6 weeks. Renal injury and inflammation were evaluated by histology and ELISA. Renal tubular apoptosis, macrophages, and fibroblasts recruitment were determined by TUNEL assay, immunofluorescence, and western blot.
RESULTS: In response to CIH, TLR4 deficiency alleviated renal histological injury, renal dysfunction, and fibrosis. TLR4 deficiency ameliorated renal dysfunction (serum BUN and creatinine) and tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL, and western blot of apoptotic protein (caspase-3, c-caspase-3, and Bax/Bcl-2 ratio). Furthermore, we also found TLR4 deficiency abrogated CIH-induced macrophages (CD68) and fibroblasts (α-SMA) recruitment, further reducing expression of extra-cellular matrix protein (collagen I and collagen IV) and inflammatory cytokines release (IL-6, TNF-α, and MCP-1). Finally, we used immunohistochemistry to demonstrate that TLR4 deficiency attenuated increased expression of MyD88 and NF-kB p65 after CIH treatment.
CONCLUSIONS: Our data suggest that TLR4 plays a vital role in CIH-induced renal injury, inflammation and fibrosis, and inhibition of TLR4 probably provides a therapeutic potential for CIH-induced kidney damage.

Keywords: Chronic intermittent hypoxia; Obstructive sleep apnea; Renal damage; Toll-like receptor 4

DOI: https://doi.org/10.1007/s11325-018-1704-9