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These findings suggest that there could be an association of HDAC-1, HIF-1alpha, LL-37, VHL, and IAP-2 with angiogenic and apoptotic mechanisms in psoriasis.

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IntroductionGout is an inflammatory condition induced by the deposition of monosodium urate (MSU) crystals in the joints and soft tissues that can produce acute or chronic arthritis. Several animal models of crystal-induced inflammation have been proposed that involve direct injection of MSU-crystals into different anatomical structures; however, only a few of these models reflect a true diarthrodial joint microenvironment in which an acute gouty attack takes place. The aim of this study was to assess the inflammatory and structural joint changes in a rabbit model of acute gout attack by ultrasound (US), synovial fluid (SF) and histopathological analyses.MethodsUnder US guidance, 42 rabbit knees were randomly injected with a suspension of 50 mg/ml of either MSU or allopurinol synthetic crystals. The control group received intra-articular vehicle of phosphate-buffered saline (PBS). US evaluation, SF and histopathological analyses were performed at days 1, 3, and 7.ResultsA total of 21 rabbit knees were assigned to the control group, 12 to the MSU-crystals group, and 9 to the allopurinol crystals group. By US, the MSU crystals group displayed the double contour sign and bright stippled aggregates in 67% and 75% of joints, respectively. Neither control knees nor allopurinol crystals group displayed these US signs. Power Doppler (PD) signal was moderate to intense in the MSU-crystals group and greater than both the allopurinol crystal and control groups at day 1 (P <0.001) and 3 (P <0.05), with its practical disappearance by day 7. SF leukocyte count was 40,312 ± 6,369 cells/mm3 in the MSU-crystals group, higher than in controls (P = 0.004) and allopurinol crystal group (P = 0.006). At day 7, SF leukocyte count decreased in both MSU and allopurinol crystal groups reaching the non-inflammatory range. Histologically, at day 3 intense synovial polymorphonuclear cells infiltration and MSU aggregates were identified.ConclusionThe rabbit model of MSU crystal-induced acute arthritis efficiently reproduces the inflammatory, US, SF and histopathological changes of the human acute gouty attack.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0550-4) contains supplementary material, which is available to authorized users.

BackgroundColorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b. Thus, targeting the KRAS4b-PDEδ complex is a treatment strategy for colorectal cancer.MethodsUsing docking and molecular dynamics simulations coupled to molecular mechanics, the generalized born model and solvent accessibility (MMGBSA) approach to explore protein-ligand stability, we found that the compound ((2S)-N-(2,5-diclorofenil)-2-[(3,4-dimetoxifenil)metilamino]-propanamida), termed C19, bound and stabilized the KRAS4b-PDEδ complex. We investigated whether C19 decreases the viability and proliferation of colorectal cancer cells, in addition to knowing the type of cell death that it causes and if C19 decreases the activation of KRAS4b and their effectors.ResultsC19 showed high cytotoxicity in the colorectal cancer cell lines HCT116 and LoVo, with a stronger effect in KRAS-dependent LoVo cells. Importantly, C19 significantly decreased tumor size in a xenograft mouse model and showed lower side effects than 5-fluorouracil that is currently used as colorectal cancer treatment.ConclusionsMechanistically, the cytotoxic effect was due to increased apoptosis of tumor cells and decreased phosphorylation of Erk and Akt. Therefore, our results suggest that C19 may serve as a promising new treatment for colorectal cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4968-3) contains supplementary material, which is available to authorized users.

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In the inflammosome complex, NALP3 or NALP1 binds to ASC and activates caspase-1 which induces IL-1β. In murine LPS-induced ocular inflammation, the production of IL-1β is increased. We suggest that NALP3- or NALP1-inflammasome complex can be participating in the LPS-induced ocular inflammation. In this work, eye, brain, testis, heart, spleen, and lung were obtained from C3H/HeN mice treated with LPS for 3 to 48 hours, and the expression of NALP1b, NALP3, ASC, caspase-1, IL-1β, and IL-18 was determined. Infiltrated leukocytes producing IL-1β in the anterior chamber were found at 12-hour posttreatment. A high upregulated expression of NALP3, ASC, caspase-1, IL-1β, and IL-18 was found at the same time when infiltrated leukocytes were observed. NALP1b was not detected in the eye of treated mice. NALP3 was also overexpressed in heart and lung. These results suggest that NALP3-, but not NALP1-inflammosome complex, is participating in the murine LPS-induced ocular inflammation.

It is known that adrenaline promotes hydroxyl radical generation in isolated rat hepatocytes. The aim of this work was to investigate a potential role of NADPH oxidase (Nox) isoforms for an oxidative stress signal in response to adrenaline in hepatocytes. Enriched plasma membranes from isolated rat liver cells were prepared for this purpose. These membranes showed catalytic activity of Nox isoforms, probably Nox 2 based on its complete inhibition with specific antibodies. NADPH was oxidized to convert O(2) into superoxide radical, later transformed into H(2)O(2). This enzymatic activity requires previous activation with either 3 mM Mn(2+) or guanosine 5'-0-(3-thiotriphosphate) (GTPgammaS) plus adrenaline. Experimental conditions for activation and catalytic steps were set up: ATP was not required; S(0.5) for NADPH was 44 microM; S(0.5) for FAD was 8 microM; NADH up to 1 mM was not substrate, and diphenyleneiodonium was inhibitory. Activation with GTPgammaS plus adrenaline was dose- and Ca(2+)-dependent and proceeded through alpha(1)-adrenergic receptors (AR), whereas beta-AR stimulation resulted in inhibition of Nox activity. These results lead us to propose H(2)O(2) as additional transduction signal for adrenaline response in hepatic cells.