TRPA1 Inhibition Effects by 3-Phenylcoumarin Derivatives.

Transient receptor potential ankyrin 1 (TRPA1) protein plays an important role in the inflammatory response, and it has been associated with different pain conditions and pain-related diseases, making TRPA1 a valid target for painkillers. In this study, we identified potential TRPA1 inhibitors and located their binding sites utilizing computer-aided drug design (CADD) techniques. The designed 3-phenylcoumarin-based TRPA1 inhibitors were successfully synthesized using a microwave assisted synthetic strategy. 3-(3-Bromophenyl)-7-acetoxycoumarin (5), 7-hydroxy-3-(3-hydroxyphenyl)coumarin (12) and 3-(3-hydroxyphenyl)coumarin (23) all showed inhibitory activity toward TRPA1 in vitro. Compound 5 also decreased the size and formation of breast cancer cells. Hence, targeting TRPA1 may represent a promising alternative for the treatment of pain and inflammation.

Lingonberry (Vaccinium vitis-idaea L.) Skin Extract Prevents Weight Gain and Hyperglycemia in High-Fat Diet-Induced Model of Obesity in Mice.

The percentage of obese people is increasing worldwide, causing versatile health problems. Obesity is connected to diseases such as diabetes and cardiovascular diseases, which are preceded by a state called metabolic syndrome. Diets rich in fruits and vegetables have been reported to decrease the risk of metabolic syndrome and type 2 diabetes. Berries with a high polyphenol content, including lingonberry (Vaccinium vitis-idaea L.), have also been of interest to possibly prevent obesity-induced metabolic disturbances. In the present study, we prepared an extract from the by-product of a lingonberry juice production process (press cake/pomace) and investigated its metabolic effects in the high-fat diet-induced model of obesity in mice. The lingonberry skin extract partly prevented weight and epididymal fat gain as well as a rise in fasting glucose level in high-fat diet-fed mice. The extract also attenuated high-fat diet-induced glucose intolerance as measured by an intraperitoneal glucose tolerance test (IPGTT). The extract had no effect on the levels of cholesterol, triglyceride or the adipokines adiponectin, leptin, or resistin. The results extend previous data on the beneficial metabolic effects of lingonberry. Further research is needed to explore the mechanisms behind these effects and to develop further health-promoting lingonberry applications.

Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer.

BACKGROUND: Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). MATERIALS AND METHODS: An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. RESULTS: The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11-5.82, p = 0.02) and 3.11 (95% CI 1.30-7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97-19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02-8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19-0.98, p = 0.04)]. CONCLUSION: Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.

The glucocorticoid dexamethasone alleviates allergic inflammation through a mitogen-activated protein kinase phosphatase-1-dependent mechanism in mice.

Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti-allergic activity of glucocorticoids. Mitogen-activated protein kinase phosphatase-1 (MKP-1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP-1 is one of the anti-inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP-1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild-type and MKP-1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). Dexamethasone reduced the ovalbumin-induced paw edema at 1.5, 3 and 6 h time points in wild-type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP-1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin-induced inflammatory factors cyclooxygenase-2 (COX-2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1ß, 6 and 13; C-C motif chemokine 11 (CCL-11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild-type mice by more than 40%. In contrast, in MKP-1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP-1-dependent mechanism. The results also demonstrate MKP-1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin-induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP-1 enhancing compounds as potential novel anti-inflammatory and anti-allergic drugs.

Volume overload is a major characteristic in primary aldosteronism: a 3-year follow-up study.

OBJECTIVES: We examined haemodynamics, focusing on volume balance and forward and backward wave amplitudes, before and after 2.8 years of targeted treatment of primary aldosteronism. Patients with essential hypertension and normotensive individuals were examined for comparison ( n  = 40 in each group). METHODS: Recordings were performed using radial artery pulse wave analysis and whole-body impedance cardiography. Unilateral aldosteronism was treated with adrenalectomy ( n  = 20), bilateral aldosteronism with spironolactone-based medication ( n  = 20), and essential hypertension with standard antihypertensive agents. RESULTS: Aortic SBP and DBP, forward and backward wave amplitudes, and systemic vascular resistance were equally elevated in primary aldosteronism and essential hypertension. All these haemodynamic variables were similarly reduced by the treatments. Primary aldosteronism presented with 1 litre (∼10%) extracellular water excess ( P  < 0.001) versus the other groups, and this excess was normalized by treatment. Initial pulse wave velocity (PWV) was similarly increased in primary aldosteronism and essential hypertension, but final values remained higher in primary aldosteronism ( P  < 0.001). In regression analyses, significant explanatory factors for treatment-induced forward wave amplitude reduction were decreased systemic vascular resistance ( ß â€Š= 0.380) and reduced extracellular water volume ( ß â€Š= 0.183). Explanatory factors for backward wave amplitude reduction were changes in forward wave amplitude ( ß â€Š= 0.599), heart rate ( ß â€Š= -0.427), and PWV ( ß â€Š= 0.252). CONCLUSION: Compared with essential hypertension, the principal haemodynamic difference in primary aldosteronism was higher volume load. Volume excess elevated forward wave amplitude, which was subsequently reduced by targeted treatment of primary aldosteronism, along with normalization of volume load. We propose that incorporating extracellular water evaluation alongside routine diagnostics could enhance the identification and diagnosis of primary aldosteronism.