Neuroinflammation, immune system and Alzheimer disease: searching for the missing link.

Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-ß peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.

Evaluación de diferentes procedimientos de detección de anticuerpos anti Ro/SS-A 52 kDa y anti-Ro/SS-A 60 kDa en síndrome de Sjögren primario / Evaluation of the different procedures in the detection of anti RO/SS-A 52 kDa and anti-RO/SS-A 60 kDa antibodies in primary Sjögren's syndrome

Un grupo de pacientes con Síndrome de Sjögren primario fue analizado en el presente trabajo con el fin de evaluar diversas técnicas para la determinación de autoanticuerpos anti-Ro/SS-A de 52 y 60 kDa. Las técnicas evaluadas fueron: doble inmunodifusión en geles de agarosa utilizando como antígeno un extracto de bazo humano; enzimoinmuno análisis (ELISA) y Western Blot ambos realizados utilizando antígenos proteicos recombinantes (Ro/SS-A 52 y 60 kDa en ensayos individuales) como antígenos. Si bien las técnicas de ELISA y Western Blot poseen una mayor sensibilidad que la inmunodifusión, en ciertos casos esta última no puede ser completamente reemplazada por las primeras. Hay que tener en cuenta la naturaleza del antígeno utilizado para poder sacar conclusiones. Los antígenos recombinantes pueden mantener los epitopes lineales y conformacionales de las moléculas nativas, pero carecen de la interacción con las demás moléculas formadoras del complejo. En cambio, en el extracto antigénico utilizado en la inmunodifusión se podrían mantener epitopes formados por la interacción entre las distintas moléculas del complejo RoRNP. Nuestros resultados indican que, a pesar de su mayor sensibilidad, las técnicas de ELISA y Western Blot no serían capaces de desplazar totalmente a la inmunodifusión en geles (AU)

Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro.

Bisphosphonates (BPs) are analogues of pyrophosphate, which are widely used for the treatment of different pathologies associated with imbalances in bone turnover. Recent evidence suggested that cells of the osteoblastic lineage might be targets of the action of BPs. The objective of this work was to determine whether BPs induce proliferation of osteoblasts and whether this action involves activation of the extracellular signal-regulated kinases (ERKs). We have shown that three different BPs (olpadronate, pamidronate, and etidronate) induce proliferation in calvaria-derived osteoblasts and ROS 17/2.8 as measured by cell count and by [3H]thymidine uptake. Osteoblast proliferation induced by all BPs diminished to control levels in the presence of U0126, a specific inhibitor of the upstream kinase MEK 1 responsible for ERK phosphorylation. Consistent with this, BPs induced ERK activation as assessed by in-gel kinase assays. Phosphorylation of ERK1/2 was induced by the BPs olpadronate and pamidronate within 30 s, followed by rapid dephosphorylation, whereas etidronate induced phosphorylation of ERKs only after 90 s of incubation and returned to basal levels within 15-30 minutes. In addition, both BP-induced cell proliferation and ERK phosphorylation were reduced to basal levels in the presence of nifedipine, an L-type voltage-sensitive calcium channel (VSCC) inhibitor. These results show that BP-induced proliferation of osteoblastic cells is mediated by activation of ERKs and suggest that this effect requires influx of Ca2+ from the extracellular space through calcium channels.

Clomiphene and tamoxifen inhibit progesterone synthesis in granulosa cells: comparison with estradiol.

The actions of clomiphene, tamoxifen, and 17 beta-estradiol were studied in an isolated avian granulosa cell system during short term incubations. A dose-dependent inhibition of ovine LH-enhanced progesterone production was observed for all three compounds, with an IC50 of 3 X 10(-6) M and maximal inhibition (95%) at 5 X 10(-5) M. A similar inhibition was found when cells were stimulated by either 8-bromo-cAMP or forskolin. Neither clomiphene nor tamoxifen had an inhibitory effect on the conversion of pregnenolone to progesterone, a step that was blocked by 17 beta-estradiol and isoxazole , a known inhibitor of 3 beta-hydroxysteroid dehydrogenase. On the other hand, cells exposed to clomiphene failed to use [6-3H]25-hydroxycholesterol, while estradiol significantly increased the conversion of labeled substrate to pregnenolone at the expense of progesterone (30% vs. 7% of the total radioactivity). By comparison, in control cells, progesterone represented the major metabolite with 36% of the total radioactivity; pregnenolone had only 2.8%. The results demonstrate that these triphenylethylene compounds, which are used clinically as antiestrogens, inhibit steroidogenesis at a step before pregnenolone formation, probably at the site of the cholesterol side-chain cleavage enzyme complex, while 17 beta-estradiol inhibits 3 beta-hydroxysteroid dehydrogenase.

The prostanoid content in peritoneal fluid and plasma of women with endometriosis.

Peritoneal fluid and plasma collected at laparoscopy in women with and without endometriosis were evaluated for prostanoid content. 6-Keto-prostaglandin F1 alpha (6-keto-F1 alpha), thromboxane B2 (TxB2), 15-keto- 13, 14-dihydroprostaglandin F2 alpha (PGFM), prostaglandin F (PGF) and prostaglandin E (PGE) were assayed in peritoneal fluid, with 6-keto-F1 alpha, TxB2, and PGFM being studied in plasma. The concentrations of these prostanoids in women with endometriosis were not significantly different from the concentrations in the disease-free group, nor was a significant difference seen in any of the prostanoids studied in relationship to the severity of the endometriosis. The results suggest that routine study of prostanoid levels in patients with endometriosis may not be of a diagnostic or prognostic value.