Identifying biomarkers for predicting successful embryo implantation: applying single to multi-OMICs to improve reproductive outcomes.

Background: Successful embryo implantation is a complex process that requires the coordination of a series of events, involving both the embryo and the maternal endometrium. Key to this process is the intricate cascade of molecular mechanisms regulated by endocrine, paracrine and autocrine modulators of embryonic and maternal origin. Despite significant progress in ART, implantation failure still affects numerous infertile couples worldwide and fewer than 10% of embryos successfully implant.

Renal delivery of adenovirus and antisense oligonucleotides in rats by retrograde renal vein injection.

Renal gene therapy may offer new strategies to treat diseases of native and transplanted kidneys. Several experimental techniques have been developed using viral, nonviral, and cellular vectors, although the effectiveness of such techniques varies widely depending upon the vector used, type of injection, species, and experimental model of renal disease. Here, we describe an optimized technique for renal delivery of DNA in rodents by retrograde renal vein injection as it is currently applied in our laboratory for adenovirus and nonviral vectors.

Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis.

Objective: Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development.

Methods And Results: Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area.

Fcgamma receptor deficiency confers protection against atherosclerosis in apolipoprotein E knockout mice.

IgG Fc receptors (FcgammaRs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E-deficient mice (apoE(-/-)) with FcgammaR gamma chain-deficient mice (gamma(-/-)). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE(-/-) control mice, without differences in serum lipid levels.

Parthenolide modulates the NF-kappaB-mediated inflammatory responses in experimental atherosclerosis.

Objective: Activation of transcription factor NF-kappaB is an important step in the development of vascular damage, because it controls inducible genes, including many inflammatory mediators. The pharmacological modulation of this process is the main objective in the design of new therapies for atherosclerosis. In this work we analyzed the effects of the natural compound parthenolide (PTN), an NF-kappaB inhibitor.

Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches.

The mesangium occupies a central anatomical position in the glomerulus, and also plays an important regulatory role in immune-mediated glomerular diseases, with an active participation in the response to local inflammation. In general, the mesangial cell responses to the pathological stimuli are associated with the main events of glomerular injury: leukocyte infiltration, cell proliferation and fibrosis. Leukocyte migration and infiltration into the glomerulus is responsible for the initiation and amplification of glomerular injury, and is mediated by adhesion molecules and chemokines, which can be locally synthesized by mesangial cells.

Suppressors of cytokine signaling regulate angiotensin II-activated Janus kinase-signal transducers and activators of transcription pathway in renal cells.

Suppressors of cytokine signaling (SOCS) family is constituted by cytokine-inducible proteins that modulate receptor signal transduction via tyrosine kinases, mainly the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Differential SOCS expression was noted in renal cells that were incubated with inflammatory stimuli, but the role of SOCS in the pathogenesis of renal diseases is not yet well defined. Because angiotensin II (Ang II) plays a key role in renal disease, SOCS proteins were studied as a novel mechanism involved in the negative regulation of Ang II-mediated processes.

Suppressors of cytokine signaling regulate Fc receptor signaling and cell activation during immune renal injury.

Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that modulate receptor signaling via tyrosine kinase pathways. We investigate the role of SOCS in renal disease, analyzing whether SOCS regulate IgG receptor (FcgammaR) signal pathways. In experimental models of immune complex (IC) glomerulonephritis, the renal expression of SOCS family genes, mainly SOCS-3, significantly increased, in parallel with proteinuria and renal lesions, and the proteins were localized in glomeruli and tubulointerstitium.

Differential activation of NF-kappa B, AP-1, and C/EBP in endotoxin-tolerant rats: mechanisms for in vivo regulation of glomerular RANTES/CCL5 expression.

Chemokines play a pivotal role in the regulation of inflammatory cell infiltration in glomerular immune injury. To characterize mechanisms relevant for the regulation of chemokine expression in vivo, the LPS-mediated model of renal inflammation in rats was used in which we have previously demonstrated that the chemokine RANTES/CCL5 is expressed and secreted in glomeruli. Glomerular RANTES/CCL5 expression in this model correlated with an increased glomerular binding activity of the transcription factors AP-1, C/EBP, and NF-kappaB.

Pre-existing glomerular immune complexes induce polymorphonuclear cell recruitment through an Fc receptor-dependent respiratory burst: potential role in the perpetuation of immune nephritis.

In immune complex (IC) diseases, FcR are essential molecules facilitating polymorphonuclear cell (PMN) recruitment and effector functions at the IC site. Although FcR-dependent initial tethering and FcR/integrin-dependent PMN accumulation were postulated, their underlying mechanisms remain unclear. We here addressed potential mechanisms involved in PMN recruitment in acute IC glomerulonephritis (nephrotoxic nephritis).

Nitric oxide production in renal cells by immune complexes: Role of kinases and nuclear factor-kappaB.

Background: Interaction of deposited immune complexes (IC) with Fc receptors (FcR) on tissue cells elicits the release of inflammatory mediators leading to tissue damage. Nitric oxide (NO) radicals generated by inducible NO synthase (iNOS) are important mediators in inflammatory processes. To analyze the role of NO in IC-mediated glomerular inflammation, we studied the in vitro and in vivo expression of iNOS in renal cells [resident mesangial cells (MC), and infiltrating monocytes] induced by IC, and the possible intermediate steps between FcR occupancy and iNOS induction.

Susceptibility to T cell-mediated injury in immune complex disease is linked to local activation of renin-angiotensin system: the role of NF-AT pathway.

FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (gamma(-/-)) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker.

Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis.

Nuclear factor (NF)-kappa B regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. In the anti-Thy 1.

Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells.

Inflammation is involved in the genesis and rupture of atherosclerotic plaques. We assessed the effect of atorvastatin (ATV) on the expression of cyclooxygenase-2 (COX-2) and other proinflammatory molecules in a rabbit model of atherosclerosis. Fourteen animals underwent injury of femoral arteries and 2 weeks of atherogenic diet.