Search

Abstract: Vitamin E (α-tocopherol) has demonstrated antioxidant activity and gene-regulatory properties. d-Galactosamine (D-GalN)-induced cell death is mediated by nitric oxide in hepatocytes, and it is associated with hepatic steatosis. The beneficial properties of α-tocopherol and their relation to oxidative stress and gene regulation were assessed in D-GalN-induced cell death. Hepatocytes were isolated from human liver resections by a collagenase perfusion technique. α-Tocopherol (50 μM) was administered at the advanced stages (10 h) of D-GalN-induced cell death in cultured hepatocytes. Cell death, oxidative stress, α-tocopherol metabolism, and NF-κB-, pregnane X receptor (PXR)-, and peroxisome proliferator-activated receptor (PPAR-α)-associated gene regulation were estimated in the hepatocytes. D-GalN increased cell death and α-tocopherol metabolism. α-Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D-GalN. Induction (rifampicin) or inhibition (ketoconazole) of α-tocopherol metabolism and overexpression of PXR showed that the increase in PXR-related CYP3A4 expression caused by α-tocopherol enhanced cell death in hepatocytes. Nevertheless, the reduction in NF-κB activation and inducible nitric oxide synthase expression and the enhancement of PPAR-α and carnitine palmitoyl transferase gene expression by α-tocopherol may be relevant for cell survival. In conclusion, the cytoprotective properties of α-tocopherol are mostly related to gene regulation rather than to antioxidant activity in toxin-induced cell death in hepatocytes. [Copyright &y& Elsevier]

Abstract: The aim of present study was to clarify the role of female sex hormones in the development and course of neurodegenerative disease in an experimental model of Huntington''s disease induced by 3-nitropropionic acid (NPA) (30mg/kg intraperitoneally (i.p.)/day for 4 days) in ovariectomized rat. Gonadectomy prompted oxidative stress and cell death evaluated by the detection of caspase-3, whereas 3-nitropropionic acid enhanced the oxidative stress induced by ovariectomy and it triggered cell damage characterized by increases of LDH levels. These changes were prevented by administration of 17 β-estradiol. Our findings suggested that: (i) ovariectomy induced oxidative stress and apoptosis in the brain; (ii) 3-nitropropionic acid exacerbated oxidative stress induced by ovariectomy and shifting cell to cell death; and (iii) 17 β-estradiol administration decreased oxidative stress and cell death induced by ovariectomy and 3-nitropropionic acid. These results revealed that sex ovarian hormones play a important role in onset and development of neurodegenerative diseases, as well as neuroprotective effects of 17 β-estradiol against the changes induced ovariectomy and ovariectomy plus 3-nitropropionic acid. [Copyright &y& Elsevier]

The effects of ten natural cadinane sesquiterpenoids isolated from Heterotheca inuloides on the pathways of the NF-κB, Nrf2 and STAT3 transcription factors were studied for the first time. The main constituent in this species, 7-hydroxy-3,4-dihydrocadalene ( 1 ), showed anti-NF-κB activity and activated the antioxidant Nrf2 pathway, which may explain the properties reported for the traditional use of the plant. In addition to the main metabolite, a structurally similar compound, 7-hydroxy-cadalene ( 2 ), also displayed anti-NF-κB activity. Thus, both natural compounds were used as templates for the preparation of a novel semi-synthetic derivative set, including esters and carbamates, which were evaluated for their potential in vitro antiproliferative activities against six human cancer cell lines. Carbamate derivatives 32 and 33 were found to exhibit potent activity against human colorectal adenocarcinoma and showed important selectivity in cancer cells. Among ester derivatives, compound 13 was determined to be a more potent NF-κB inhibitor and Nrf2 activator than its parent, 7-hydroxy-3,4-dihydrocadalene ( 1 ). Furthermore, this compound decreases levels of phospho-IκBα, a protein complex involved in the NF-κB activation pathway. Molecular simulations suggest that all active compounds interact with the activation loop of the IKKβ subunit in the IKK complex, which is the responsible of IκBα phosphorylation. Thus, we identified two natural, and one semi-synthetic, NF-κB and Nrf2 modulators and two new promising cytotoxic compounds. [ABSTRACT FROM AUTHOR]

Highlights: [•] Galiellalactone inhibits HIV-1 transcriptional activity. [•] Galiellalactone inhibits NF-κB activation. [•] Galiellalactone binds p65. [•] Galiellalactone prevents p65/importin α3 interaction. [ABSTRACT FROM AUTHOR]

Abstract: This paper evaluates the effects of testosterone (0.5 mg/kg subcutaneously (s.c.) for 8 days) on oxidative stress and cell damage induced by 3-nitropropionic acid (20 mg/kg intraperitoneally (i.p.) for 4 days) in ovariectomized rats. Gonadectomy triggered oxidative damage and cell loss, evaluated by the detection of caspase-3, whereas 3-nitropropionic acid increased the levels of oxidative stress induced by ovariectomy and prompted cell damage characterized by enhanced levels of lactate dehydrogenase. These changes were blocked by testosterone administration. Our results support the following conclusions: i) ovariectomy triggers oxidative and cell damage via caspase-3 in the striatum; ii) 3-nitropropionic acid exacerbates oxidative stress induced by ovariectomy and leads to cell damage characterized by increased levels of lactate dehydrogenase; iii) testosterone administration decreases oxidative stress and cell damage. Additionally, these data support the hypothesis that testosterone might play an important role in the onset and development of neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract N -acyl-dopamines are endolipids with neuroprotective, antiinflammatory and immunomodulatory properties. Previously, we showed the ability of these compounds to induce HIF-1α stabilization. Hypoxia and HIF-1α play an important role in the most relevant stages of diabetic pathogenesis. This work analyzes the possible role of these molecules on beta cell differentiation, insulin production and diabetic foot ulcer. Hypoxia response pathway has been characterized in beta-cell differentiation in rat pancreatic acinar cell line and human islet-derived precursor cells. Protein and mRNA expression of key proteins in this process have been analyzed, as well as those involved in beta cells reprogramming. The effect of N -acyl-dopamines on hypoxia response pathway, beta cells reprogramming and insulin production have been studied in both cell types, as well as its role in angiogenesis models in vitro and wound closure in type 2 diabetic mice. Our results show how the hypoxia response pathway is altered during beta cells differentiation, accompanied by an induction of the transcription factor HIF-1α. We demonstrate how some N -acyl-dopamines induce beta cell differentiation and insulin production in two different cell models. In parallel, these endolipids promote angiogenesis in vitro and wound closure in type 2 diabetic mice. These results provide a biological mechanism through which some endolipids could induce beta cell differentiation. We demonstrate how N -acyl-dopamines can modulate insulin production and, in parallel, reverse HIF-1α inhibition in a wound healing model in diabetic mice. Therefore, the potential use of the pharmacological modulation of N -acyl-dopamines may have implications for diabetes prevention and treatment strategies. Highlights • N -acyl-dopamines present the ability to induce beta cell differentiation in AR42J and hIPCs cells. • N -acyl-dopamines induce HIF-1α and HIF-2α during beta cell differentiation. • N -palmitoyl-dopamine (PALDA) and N -stearoyl-dopamine (STEARDA) induce in vitro insulin production. • N -acyl-dopamines favor wound healing in type 2 diabetic mice. [ABSTRACT FROM AUTHOR]

Black chokeberry has been known to play a protective role in human health due to its high polyphenolic content including anthocyanins and caffeic acid derivatives. In the present study, we first characterized the polyphenolic content of a commercial chokeberry concentrate and investigated its effect on LPS-induced NF-κB activation and release of pro-inflammatory mediators in macrophages in the presence or the absence of sodium selenite. Examination of the phytochemical profile of the juice concentrate revealed high content of polyphenols (3.3%), including anthocyanins, proanthocyanidins, phenolic acids, and flavonoids. Among them, cyanidin-3- O -galactoside and caffeoylquinic acids were identified as the major compounds. Data indicated that chokeberry concentrate inhibited both the release of TNFα, IL-6 and IL-8 in human peripheral monocytes and the activation of the NF-κB pathway in RAW 264.7 macrophage cells. Furthermore, chokeberry synergizes with sodium selenite to inhibit NF-κB activation, cytokine release and PGE 2 synthesis. These findings suggest that selenium added to chokeberry juice enhances significantly its anti-inflammatory activity, thus revealing a sound approach in order to tune the use of traditional herbals by combining them with micronutrients. [ABSTRACT FROM AUTHOR]

[Display omitted] Polypharmacological targeting of lipid mediator networks offers potential for efficient and safe anti-inflammatory therapy. Because of the diversity of its biological targets, curcumin (1a) has been viewed as a privileged structure for bioactivity or, alternatively, as a pan-assay interference (PAIN) compound. Curcumin has actually few high-affinity targets, the most remarkable ones being 5-lipoxygenase (5-LOX) and microsomal prostaglandin E 2 synthase (mPGES)-1. These enzymes are critical for the production of pro-inflammatory leukotrienes and prostaglandin (PG)E 2 , and previous structure–activity-relationship studies in this area have focused on the enolized 1,3-diketone motif, the alkyl-linker and the aryl-moieties, neglecting the rotational state of curcumin, which can adopt twisted conformations in solution and at target sites. To explore how the conformation of curcuminoids impacts 5-LOX and mPGES-1 inhibition, we have synthesized rotationally constrained analogues of the natural product and its pyrazole analogue by alkylation of the linker and/or of the ortho aromatic position(s). These modifications strongly impacted 5-LOX and mPGES-1 inhibition and their systematic analysis led to the identification of potent and selective 5-LOX (3b , IC 50 = 0.038 µM, 44.7-fold selectivity over mPGES-1) and mPGES-1 inhibitors (2f , IC 50 = 0.11 µM, 4.6-fold selectivity over 5-LOX). Molecular docking experiments suggest that the C 2-methylated pyrazolocurcuminoid 3b targets an allosteric binding site at the interface between catalytic and regulatory 5-LOX domain, while the o, o '-dimethylated desmethoxycurcumin 2f likely binds between two monomers of the trimeric mPGES-1 structure. Both compounds trigger a lipid mediator class switch from pro-inflammatory leukotrienes to PG and specialized pro-resolving lipid mediators in activated human macrophages. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone and blood brain barrier (BBB) functions. Endogenous N-acyl-dopamines like N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA) have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we demonstrate that NADA differentially regulates the release of PGE2 and PGD2 in the microvascular brain endothelial cell line, b.end5. We found that NADA activates a redox-sensitive p38 MAPK pathway that stabilizes COX-2 mRNA resulting in the accumulation of the COX-2 protein, which depends on the dopamine moiety of the molecule and that is independent of CB1 and TRPV1 activation. In addition, NADA inhibits the expression of mPGES-1 and the release of PGE2 and upregulates the expression of L-PGD synthase enhancing PGD2 release. Hence, NADA and other molecules of the same family might be included in the group of lipid mediators that could prevent the BBB injury under inflammatory conditions and our findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the central nervous system and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases. [Copyright &y& Elsevier]