Search

The pro-homeostatic lipid mediators elovanoids (ELVs) attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) as well as of the SARS-CoV-2 virus in human primary alveoli cells in culture. We uncovered that very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA, n-3) activate ELV biosynthesis in lung cells. Both ELVs and their precursors reduce the binding to RBD. ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulating defensive proteins against lung damage. In addition, ELVs and their precursors decreased the signal of spike (S) protein found in SARS-CoV-2 infected cells, suggesting that the lipids curb viral infection. These findings open avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.

Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57(KIP2) by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.

Colorectal cancer (CRC) is the third most common cancer and also the leading cause of death from gastrointestinal malignancy in the United States. Colorectal cancer ranks second after lung cancer in death rates in the United States (Siegel et al, 2011). Studies suggest that chemokines and their receptors serve as important regulators of various metastatic and advanced cancers (Coussens and Werb, 2001; Coussens and Werb, 2002). Among them, interleukin-8 (IL-8) and its receptor CXCR2 are two of the most significantly upregulated chemokines in colon cancer (Chen et al, 2004). The role of IL-8 and CXCR2 in tumour development and progression has been well documented in a wide range cancer cells (Brat et al, 2005; Singh et al, 2006; Araki et al, 2007; Yao et al, 2007; Merritt et al, 2008; Waugh and Wilson, 2008; Singh et al, 2009). Expression and secretion of IL-8 by tumour cells enhance proliferation and survival of the cells through autocrine activation, and promote angiogenesis and neutrophil infiltration into the tumour. The proangiogenic effects of IL-8 have been shown to be independent from its chemotactic activity for neutrophils and other pro-inflammatory effects (Strieter et al, 1992; Hu et al, 1993; Li et al, 2003). The IL-8/CXCR2-mediated autocrine properties have been demonstrated to activate the intrinsic mechanism of tumour cells to evade stress-induced apoptosis (Maxwell et al, 2007). Therefore, tumour cell-derived IL-8 can exert profound effects on tumour growth, survival, invasion, angiogenesis, metastases, resistance and recurrence. Nonetheless, studies on the effects of tumour microenvironment-encoded IL-8 and CXCR2 are rather limited, mostly due to the intuitive speculation for the equivalent roles regardless of their sources. Importantly, a common single-nucleotide polymorphism (SNP) in IL-8 at −251 bp (251-bp upstream of the IL-8 transcription start site) has been associated with increased plasma levels of IL-8 (Hull et al, 2000) and with IL-8 promoter activities (Lee et al, 2005; Ohyauchi et al, 2005). This allele has recently been correlated with an increased risk of developing breast, prostate and gastric cancers (McCarron et al, 2002; Taguchi et al, 2005; Snoussi et al, 2006). We – for the first time – demonstrated that this IL-8T −251A polymorphism was individually associated with risk of tumour recurrence (Gordon et al, 2006). Moreover, our classification and regression tree analyses of CRC produced a classification tree with node status and four marker genes (IL-8, intracellular adhesion molecule-1, transforming growth factor-β and fibroblast growth factor receptor-4) (Gordon et al, 2006). Our genotyping study of 12 biomarker genes in 125 patients with advanced CRC found that patients with vascular endothelial growth factor (VEGF) +936 C/C and IL-8 −251A/A genotype were at the greatest risk to develop tumour recurrence (Lurje et al, 2008), suggesting that polymorphisms in VEGF and IL-8 may serve as a key biomarker to identify stage III CRC patients who are at a great risk for tumour recurrence. In a separate study (Schultheis et al, 2008), we identified statistically significant four polymorphisms in CXCR2 and VEGF and demonstrated that the IL-8A −251T polymorphism may be a molecular predictor of response to anti-VEGF chemotherapy. The CXCR2 C+785T and VEGF C+936T SNPs can be used as molecular markers for progression-free survival (PFS) in cancer patients. Together, the polymorphisms and expression of IL-8 and CXCR2 are strongly associated with not only tumour progression, but also tumour recurrence and oxaliplatin chemoresistance in patients with various cancers, including CRC (Gordon et al, 2006; Lurje et al, 2008; Schultheis et al, 2008; Zhang et al, 2009). We have recently reported that IL-8 regulates proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer models (Ning et al, 2011). In addition, our clinical data showed that patients with stage IV CRC display more than 10 times higher serum level of IL-8 (1089 pg ml−1±311), compared with individuals with no evidence of disease (79 pg ml−1±56) (Ning et al, 2011). In the current study, we tested whether the in-vivo tissue microenvironment with either elevated IL-8 or CXCR2 deletion will promote colon cancer growth, invasion and metastases using a novel IL-8 transgenic mouse model and a CXCR2 knockout (KO) model. Our findings using these mouse models demonstrate the critical roles of IL-8/CXCR2 in the tumour environment, which is highly cohesive with our numerous previous experimental and clinical data, and further indicates that IL-8 and CXCR2 may be an important therapeutic target against colon cancer.

In cystic fibrosis, dysregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways. The underlying mechanisms have remained unclear. Lipoxins are anti-inflammatory lipid mediators that modulate neutrophilic inflammation. We report here that lipoxin concentrations in airway fluid were significantly suppressed in patients with cystic fibrosis compared to patients with other inflammatory lung conditions. We also show that administration of a metabolically stable lipoxin analog in a mouse model of the chronic airway inflammation and infection associated with cystic fibrosis suppressed neutrophilic inflammation, decreased pulmonary bacterial burden and attenuated disease severity. These findings suggest that there is a pathophysiologically important defect in lipoxin-mediated anti-inflammatory activity in the cystic fibrosis lung and that lipoxins have therapeutic potential in this lethal autosomal disease.

Eight-membered ring β-keto lactones were prepared from 2,2,6-trimethyl-4H-1,3-dioxin-4-one in three steps involving conjugate addition to α,β-unsaturated aldehydes or ketones, followed by conversion to an alcohol and thermolysis. The formation of these eight-membered rings involves the intramolecular trapping of a hydroxy acyl ketene intermediate and is facilitated by a suppressed ring strain and an unfavorable intramolecular hydrogen bond, which is suggested to favor the formation of oligomers. These aspects of the reaction were supported by molecular mechanics calculations.