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Dive into the research topics where Fernando López-Barrera is active.

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Featured researches published by Fernando López-Barrera.


Journal of Cell Science | 2006

Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin

Yazmín Macotela; Manuel B. Aguilar; Jessica Guzmán-Morales; José Carlos Rivera; Consuelo Zermeño; Fernando López-Barrera; Gabriel Nava; Carlos Lavalle; Gonzalo Martínez de la Escalera; Carmen Clapp

The 16 kDa N-terminal fragment of prolactin (16K-prolactin) is a potent antiangiogenic factor. Here, we demonstrate that matrix metalloproteases (MMPs) produced and secreted by chondrocytes generate biologically functional 16K-prolactin from full-length prolactin. When incubated with human prolactin at neutral pH, chondrocyte extracts and conditioned medium, as well as chondrocytes in culture, cleaved the Ser155-Leu156 peptide bond in prolactin, yielding - upon reduction of intramolecular disulfide bonds - a 16 kDa N-terminal fragment. This 16K-prolactin inhibited basic fibroblast growth factor (FGF)-induced endothelial cell proliferation in vitro. The Ser155-Leu156 site is highly conserved, and both human and rat prolactin were cleaved at this site by chondrocytes from either species. Conversion of prolactin to 16K-prolactin by chondrocyte lysates was completely abolished by the MMP inhibitors EDTA, GM6001 or 1,10-phenanthroline. Purified MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 cleaved human prolactin at Gln157, one residue downstream from the chondrocyte protease cleavage site, with the following relative potency: MMP-8>MMP-13 >MMP-3>MMP-1=MMP-2>MMP-9. Finally, chondrocytes expressed prolactin mRNA (as revealed by RT-PCR) and they contained and released antiangiogenic N-terminal 16 kDa prolactin (detected by western blot and endothelial cell proliferation). These results suggest that several matrix metalloproteases in cartilage generate antiangiogenic 16K-prolactin from systemically derived or locally produced prolactin.


Laboratory Investigation | 2005

Prolactin stimulates integrin-mediated adhesion of circulating mononuclear cells to endothelial cells

Pável Montes de Oca; Yazmín Macotela; Gabriel Nava; Fernando López-Barrera; Gonzalo Martínez de la Escalera; Carmen Clapp

Attachment of leukocytes to endothelial cells is an essential step for the extravasation and recruitment of cells at sites of inflammation. The pituitary hormone prolactin (PRL) is involved in the inflammatory process. Here, we show that treatment with PRL of human peripheral blood mononuclear cells (PBMC) stimulates their adhesion to human umbilical vein endothelial cells (HUVEC) activated by interleukin-1β. Stimulation of adhesion by PRL is mediated via integrins leukocyte functional antigen-1 (LFA-1) and very late antigen-4 (VLA-4), because immunoneutralization of both integrins prevents PRL action. Also, PRL promotes the adhesion of PBMC to immobilized intercellular adhesion molecule-1 and fibronectin, ligands for LFA-1 and VLA-4, respectively. Stimulation of integrin-mediated cell adhesion by PRL may involve the activation of chemokine receptors, because PRL upregulates the expression of the G-protein-coupled chemokine receptor CXCR3 in PBMC, and pertussis toxin, a specific G-protein inhibitor, blocks PRL stimulation of PBMC adhesion to HUVEC. In addition, PRL stimulates tyrosine phosphorylation pathways leading to leukocyte adhesion. PRL triggered the tyrosine phosphorylation of Janus kinase-2, of signal transducer and activator of transcription-3 and 5, and of the focal adhesion protein paxillin. Furthermore, genistein, a tyrosine kinase inhibitor, blocked PRL-stimulated adhesion of PBMC and Jurkat T-cells to HUVEC. These results suggest that PRL promotes integrin-mediated leukocyte adhesion to endothelial cells via chemokine receptors and tyrosine phosphorylation signaling pathways.


Journal of Clinical Investigation | 2013

Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis

Norma Adán; Jessica Guzmán-Morales; Maria G. Ledesma-Colunga; Sonia I. Perales-Canales; Andrés Quintanar-Stephano; Fernando López-Barrera; Isabel Méndez; Bibiana Moreno-Carranza; Jakob Triebel; Nadine Binart; Gonzalo Martínez de la Escalera; Stéphanie Thebault; Carmen Clapp

Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3-dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor-null (Prlr(-/-)) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA.


Laboratory Investigation | 2003

Hypoxia Inhibits Expression of Prolactin and Secretion of Cathepsin-D by the GH4C1 Pituitary Adenoma Cell Line

Gabriela Cosío; Michael C. Jeziorski; Fernando López-Barrera; Gonzalo Martínez de la Escalera; Carmen Clapp

Diminished oxygen concentration within growing tumors may stimulate neovascularization by inducing both up-regulation of angiogenic factors and down-regulation of antiangiogenic agents. A potentially important molecule in the growth of pituitary adenomas is prolactin (PRL), which can be cleaved by cathepsin-D to yield a 16-kDa form (16K-PRL) with potent antiangiogenic effects. We examined the expression of PRL in cultured GH4C1 pituitary adenoma cells after exposure to hypoxia (0.1% oxygen) for periods of 12 to 36 hours. In contrast to increased expression of the angiogenic factor vascular endothelial growth factor in hypoxic cells, PRL mRNA and levels of intracellular and secreted PRL were significantly reduced under hypoxia. The reduction was not attributable to a general suppression of either transcription or protein synthesis. Although 16K-PRL was not evident in conditioned medium at physiologic pH, lowering the pH to mimic the acidic tumor microenvironment resulted in generation of 16K-PRL, which was sharply reduced in medium drawn from hypoxic cells. Production of 16K-PRL was blocked by the cathepsin-D inhibitor pepstatin-A, and the reduced 16K-PRL formation in hypoxic-conditioned medium correlated with a decrease in secretion of cathepsin-D and its precursor, procathepsin-D. Thus, hypoxia acts upon GH4C1 cells to increase vascular endothelial growth factor expression, decrease PRL synthesis, and suppress conversion of PRL to 16K-PRL via inhibition of cathepsin-D proteolysis. These mechanisms may act in concert to stimulate angiogenesis in prolactinomas.


American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2013

Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis

Bibiana Moreno-Carranza; Maite Goya-Arce; Claudia Vega; Norma Adán; Jakob Triebel; Fernando López-Barrera; Andrés Quintanar-Stephano; Nadine Binart; Gonzalo Martínez de la Escalera; Carmen Clapp

Prolactin (PRL) is a potent liver mitogen and proangiogenic hormone. Here, we used hyperprolactinemic rats and PRL receptor-null mice (PRLR(-/-)) to study the effect of PRL on liver growth and angiogenesis before and after partial hepatectomy (PH). Liver-to-body weight ratio (LBW), hepatocyte and sinusoidal endothelial cell (SEC) proliferation, and hepatic expression of VEGF were measured before and after PH in hyperprolactinemic rats, generated by placing two anterior pituitary glands (AP) under the kidney capsule. Also, LBW and hepatic expression of IL-6, as well as suppressor of cytokine signaling-3 (SOCS-3), were evaluated in wild-type and PRLR(-/-) mice before and after PH. Hyperprolactinemia increased the LBW, the proliferation of hepatocytes and SECs, and VEGF hepatic expression. Also, liver regeneration was increased in AP-grafted rats and was accompanied by elevated hepatocyte and SEC proliferation, and VEGF expression compared with nongrafted controls. Lowering circulating PRL levels with CB-154, an inhibitor of AP PRL secretion, prevented AP-induced stimulation of liver growth. Relative to wild-type animals, PRLR(-/-) mice had smaller livers, and soon after PH, they displayed an approximately twofold increased mortality and elevated and reduced hepatic IL-6 and SOCS-3 expression, respectively. However, liver regeneration was improved in surviving PRLR(-/-) mice. PRL stimulates normal liver growth, promotes survival, and regulates liver regeneration by mechanisms that may include hepatic downregulation of IL-6 and upregulation of SOCS-3, increased hepatocyte proliferation, and angiogenesis. PRL contributes to physiological liver growth and has potential clinical utility for ensuring survival and regulating liver mass in diseases, injuries, or surgery of the liver.


American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2015

Prolactin anterior pituitary expression and circulating levels are reduced in obese and diabetic rats: role of TGF-β and TNF-α

María Lemini; Xarubet Ruiz-Herrera; Maria G. Ledesma-Colunga; Nundehui Díaz-Lezama; Ericka A. de los Ríos; Fernando López-Barrera; Isabel Méndez; Gonzalo Martínez de la Escalera; Yazmín Macotela; Carmen Clapp

The levels of the hormone prolactin (PRL) are reduced in the circulation of patients with Type 2 diabetes and in obese children, and lower systemic PRL levels correlate with an increased prevalence of diabetes and a higher risk of metabolic syndrome. The secretion of anterior pituitary (AP) PRL in metabolic diseases may be influenced by the interplay between transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α), which inhibit and can stimulate AP PRL synthesis, respectively, and are known contributors to insulin resistance and metabolic complications. Here, we show that TGF-β and TNF-α antagonize the effect of each other on the expression and release of PRL by the GH4C1 lactotrope cell line. The levels of AP mRNA and circulating PRL decrease in high-fat diet-induced obese rats in parallel with increased and reduced AP levels of TGF-β and TNF-α mRNA, respectively. Likewise, AP expression and circulating levels of PRL are reduced in streptozotocin-induced diabetic rats and are associated with higher AP expression and protein levels of TGF-β and TNF-α. The opposing effects of the two cytokines on cultured AP cells, together with their altered expression in the AP of obese and diabetic rats suggest they are linked to the reduced PRL production and secretion characteristics of metabolic diseases.


Digestive Diseases and Sciences | 2006

Opposite association of serum prolactin and survival in patients with colon and rectal carcinomas: influence of preoperative radiotherapy.

Marcos Gutiéerrez De La Barrera; Belem Trejo; Pedro Luna-Péerez; Fernando López-Barrera; Gonzalo Martínez de la Escalera; Carmen Clapp

Prolactin (PRL) is a pleiotropic hormone associated with the progression of various cancers, including colorectal cancer (CRC). Here we investigate whether the association of serum PRL concentration and survival is affected by tumor location and preoperative radiotherapy (PRERT) in patients with CRC cancer. Serum PRL was determined in 82 CRC patients without previous treatment. Patients with PRL concentrations at and above the 75th percentile (high PRL) or below this level (low PRL), had a significant correlation with overall survival determined using the Kaplan–Meier method. In colon cancer, there was an increased risk of mortality when PRL values were at and above the highest quartile (22% vs. 73%; P = 0.01). In contrast, in rectal cancer, high PRL values were associated with a significant overall survival advantage (88% vs. 44%; P = 0.05), which became more significant (100% vs. 34%; P = 0.005) when only rectal cancer patients receiving PRERT were compared. These findings suggest that tumor location and adjuvant radiotherapy influence the association between circulating PRL and survival in CRC.


Endocrinology | 2016

Prolactin Promotes Adipose Tissue Fitness and Insulin Sensitivity in Obese Males

Xarubet Ruiz-Herrera; Ericka A. de los Ríos; Juan M. Díaz; Ricardo M. Lerma-Alvarado; Lucía Martínez de la Escalera; Fernando López-Barrera; María Lemini; Edith Arnold; Gonzalo Martínez de la Escalera; Carmen Clapp; Yazmín Macotela

Excessive accumulation of body fat triggers insulin resistance and features of the metabolic syndrome. Recently, evidence has accumulated that obesity, type 2 diabetes, and metabolic syndrome are associated with reduced levels of serum prolactin (PRL) in humans and rodents, raising the question of whether low PRL levels contribute to metabolic dysfunction. Here, we have addressed this question by investigating the role of PRL in insulin sensitivity and adipose tissue fitness in obese rodents and humans. In diet-induced obese rats, treatment with PRL delivered via osmotic mini-pumps, improved insulin sensitivity, prevented adipocyte hypertrophy, and reduced inflammatory cytokine expression in visceral fat. PRL also induced increased expression of Pparg and Xbp1s in visceral adipose tissue and elevated circulating adiponectin levels. Conversely, PRL receptor null mice challenged with a high-fat diet developed greater insulin resistance, glucose intolerance, and increased adipocyte hypertrophy compared with wild-type mice. In humans, serum PRL values correlated positively with systemic adiponectin levels and were reduced in insulin-resistant patients. Furthermore, PRL circulating levels and PRL produced by adipose tissue correlated directly with the expression of PPARG, ADIPOQ, and GLUT4 in human visceral and sc adipose tissue. Thus, PRL, acting through its cognate receptors, promotes healthy adipose tissue function and systemic insulin sensitivity. Increasing the levels of PRL in the circulation may have therapeutic potential against obesity-induced metabolic diseases.


The FASEB Journal | 2018

Impaired prolactin actions mediate altered offspring metabolism induced by maternal high-fat feeding during lactation

Ericka A. de los Ríos; Xarubet Ruiz-Herrera; Viridiana Tinoco-Pantoja; Fernando López-Barrera; Gonzalo Martínez de la Escalera; Carmen Clapp; Yazmín Macotela

Maternal diet during lactation affects offspring metabolic health throughout life. Prolactin (PRL) is present in high quantities in maternal milk; however, the effects of milk PRL on the offspring remain poorly characterized. In this study, we evaluated whether feeding a high‐fat diet (HFD) to rats during lactation alters PRL, both in the mothers serum and in milk, and whether this factor contributes to HFD‐induced metabolic dysfunction in the offspring. Maternal HFD resulted in decreased PRL levels in milk (but not in serum), reduced mammary gland (MG) PRL receptor expression, and altered MG structure and function. Offspring from HFD‐fed dams had increased body weight and adiposity, and developed fatty liver, hyperinsulinemia, and insulin resistance at weaning. Increasing PRL levels in the HFD‐fed mothers by subcutaneous osmotic minipumps releasing PRL normalized MG function and PRL levels in milk. Moreover, PRL treatment in HFD‐fed mothers, or directly in their pups via oral PRL administration, increased liver STAT5 phosphorylation, reduced visceral adiposity, ameliorated fatty liver, and improved insulin sensitivity in offspring. Our results show that HFD impairs PRL actions during lactation to negatively affect MG physiology and directly impair offspring metabolism.—De los Rios, E. A., Ruiz‐Herrera, X., Tinoco‐Pantoja, V., Lopez‐Barrera, F., Martinez de la Escalera, G., Clapp, C., Macotela, Y. Impaired prolactin actions mediate altered offspring metabolism induced by maternal high‐fat feeding during lactation. FASEB J. 32, 3457–3470 (2018). www.fasebj.org


Endocrinology | 2004

16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation

Carmen Lilia Sánchez González; Ana M. Corbacho; Jason P. Eiserich; Celina García; Fernando López-Barrera; Verónica Morales-Tlalpan; Alma Barajas-Espinosa; Mauricio Díaz-Muñoz; Rafael Rubio; Sue Hwa Lin; Gonzalo Martínez de la Escalera; Carmen Clapp

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Carmen Clapp

National Autonomous University of Mexico

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Gabriel Nava

National Autonomous University of Mexico

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Yazmín Macotela

National Autonomous University of Mexico

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Jorge Aranda

National Autonomous University of Mexico

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Hugo Quiroz-Mercado

University of Colorado Denver

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Andrés Quintanar-Stephano

Autonomous University of Aguascalientes

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Bibiana Moreno-Carranza

National Autonomous University of Mexico

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Celina García

National Autonomous University of Mexico

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