The gonadal expression pattern of lipocalin­2 and 24p3 receptor is modified in the gonads of the offspring of obese rats.

Obesity represents a global health and economic burden, affecting millions of individuals worldwide. This pathology is associated with a chronic low­grade inflammatory state that is partially responsible for the development of other cardiometabolic complications. Clinical studies have reported an association between high circulating levels of lipocalin­2 (Lcn2) and increased body weight. Additionally, there is scientific evidence demonstrating the impact of maternal obesity on fetal programming. The latter and the fact that the authors previously found that Lcn2 and its receptor (24p3R) are expressed in the gonads of wild­type rats, led to the analysis of their mRNA profile and cellular localization in gonads collected from the offspring of obese rats at 21 days postconception (dpc), and 0, 2, 4, 6, 12, 20 and 30 days postnatal (dpn) in the present study. Semi­quantitative PCR revealed a statistically significant downregulation of Lcn2 and 24p3R mRNA at 21 dpc in the ovaries (P<0.01) and testicles (P<0.001) of the offspring of obese mothers. At 30 dpn, the relative expression of Lcn2 mRNA decreased significantly in the ovaries of the experimental group (P<0.05), while Lcn2 mRNA expression was not detectable in testicles. Regarding 24p3R, its mRNA was only significantly decreased at 21 dpc in ovaries of pups of obese mothers. At 30 dpn, the change in females was not significant. Conversely, in testicles, 24p3R mRNA levels increased slightly in the experimental group at 30 dpn. The Lcn2 protein signal was less intense in gonadal tissue sections from 30 dpn offspring of obese rats (P<0.001), whereas the 24p3R signal was downregulated in ovaries (P<0.001) and slightly upregulated in testicles. It was concluded that maternal obesity changes the expression of Lcn2 and 24p3R in the gonads of the offspring of obese rats, possibly through fetal programming. The consequences of this dysregulation for the offspring's gonadal function remains to be determined.

Expression profiling of lipocalin-2 and 24p3 receptor in murine gonads at different developmental stages.

Numerous clinical studies have reported the association between high circulating levels of lipocalin-2 (LCN2) and metabolic diseases. However, only few studies have addressed sexually dimorphic, either in its circulating concentration or in its expression in other organs. To the best of our knowledge, LCN2 and the 24p3 receptor (24p3R), have not been identified in gonads; therefore, the present study analyzed their mRNA expression profile and cellular localization in gonads collected from fetal rats at 21 days post coitum, as well as from neonatal rats at 0, 2, 4, 6, 12, 20 and 30 postnatal days. Semiquantitative polymerase chain reaction and immunohistochemical assays revealed that the LCN2 mRNA during perinatal and pre-pubertal stages presented a sex-specific expression pattern, being higher in ovaries than in testes collected at these stages. Furthermore, the mRNA levels of the long and short isoforms of the 24p3R (507 and 350 bp, respectively), were lower in female gonads from postnatal day 0 onwards in comparison with the levels observed in males, but before birth, the short isoform of the 24p3R was higher in ovaries than in testes. In addition, in females, the abundance of mRNA of this isoform was drastically diminished at 24 h after birth. Furthermore, this specific expression profile of LCN2 and 24p3R at perinatal and prepubertal stages coincides with events of cellular proliferation and apoptosis within both gonads. Immunohistochemical assays revealed that in ovaries, LCN2 and 24p3R are present in germinal and somatic cells of follicles, while in testes, this adipokine and its receptor are only located in germinal cells. These findings suggest that in murine gonads, LCN2/24p3R signaling may be involved either in cell proliferation or cell death driven by gonadotropin-independent or -dependent mechanisms.

[Gender differences in lipocalin 2 plasmatic levels are correlated with age and the triglyceride/high-density lipoprotein ratio in healthy individuals]. / Las diferencias de género en los niveles plasmáticos de la lipocalina 2 se correlacionan con la edad y con la proporción de triglicéridos y lipoproteínas de alta densidad en individuos sanos.

INTRODUCTION: The increment of lipocalin 2, also called neutrophil gelatinase-associated lipocalin, plasmatic levels is associated with cardiometabolic and nefrologic alterations. Nonetheless, there is much controversy about lipocalin 2 plasmatic concentrations among healthy individuals. AIM: The aim of this study was to quantify lipocalin 2 in plasma of healthy men and women and to assess a possible correlation with cardiometabolic risk factors. METHODS: Fifty-three subjects (24 men and 29 women) were included. By means of an ELISA, a higher concentration of lipocalin 2 was observed in men than in women (91 ± 9 vs. 57 ± 7 ng/ml). Such difference was statistically significant (p < 0.0001). RESULTS: Lipocalin 2 levels were significantly correlated with body mass index, homeostasis model assessment index-insulin resistance index, triglycerides, high-density lipoprotein, and age. CONCLUSION: Lipocalin 2 plasmatic concentrations present a gender-specific profile in healthy subjects and its circulating levels appear to be age-dependent and associated with several cardiometabolic risk factors, including the triglycerides/high-density lipoprotein cholesterol ratio, which has proven to be a reliable marker for cardiometabolic risk among the global population.

Colesterol y aterosclerosis. Consideraciones históricas y tratamiento / Cholesterol and atherosclerosis. Historical considerations and treatment

Resumen El colesterol es un esteroide precursor de hormonas, componente esencial de la membrana celular, sin embargo, alteraciones en la regulación de la síntesis, absorción y excreción del colesterol predisponen al desarrollo de enfermedades cardiovasculares de origen aterosclerótico. De esta manera, reconociendo los acontecimientos históricos desde hace 200 años, con Michel Chevreul que le dio el nombre "colesterina", más tarde Lobstein que acuñó el término aterosclerosis y Marchand que lo introduce, Anichkov que identifica el colesterol en las placas de ateroma, y el descubrimiento del receptor LDL por Brown y Goldstein; además de la aparición de los diferentes fármacos que han surgido desde los fibratos, las estatinas y en esta década cetrapibs, muy prometedores para aumentar el HDL, en forma más reciente, ezetimibe y anti-PCSK9 para inhibir el proceso de degradación del receptor LDL; no obstante, estos avances no han sido suficientes para disminuir la morbilidad en enfermedades cardiovasculares.

Abstract Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming "cholesterol"; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.

[Cholesterol and atherosclerosis. Historical considerations and treatment]. / Colesterol y aterosclerosis. Consideraciones históricas y tratamiento.

Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming «cholesterol¼; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.

FBXW12, a novel F box protein-encoding gene, is deleted or methylated in some cases of epithelial ovarian cancer.

Epithelial ovarian cancer is one of the most lethal of gynecological malignancies. Due to its lack of early symptoms, detection usually occurs when the tumor is no longer confined to the ovary. We previously identified Fbxw15, a gene encoding an F-box protein in the mouse ovary, and showed that its expression is developmentally regulated. Here we report the molecular analysis of its human homologue, FBXW12 in epithelial ovarian tumors. To search for FBXW12 gene mutations, we PCR-amplified and sequenced the coding region of FBXW12, the gene's 5-untranslated region and the proximal promoter in each of 30 EOC tumors. Promoter methylation was determined by DNA bisulfite conversion, followed by methylation specific PCR. FBXW12 intracellular localization was identified by means of immunohistochemistry. A complete deletion of the gene's coding region, the 5'-UTR and the proximal promoter, was observed in 3 EOC samples. Eight of the remaining 27, had a deletion of the 5'-UTR, and the proximal promoter. FBXW12 mRNA was detected in 2 of the 19 samples without deletions. The methylation specific PCR results demonstrated CpGs methylation in the FBXW12 proximal promoter. Immunohistochemistry assay revealed that within the normal ovary, FBXW12 has an oocyte specific expression, whereas in EOC samples it is present in the ovarian surface epithelium. Our results indicate that the FBXW12 gene is deleted in approximately ten percent of the EOC cases studied; such deletions comprised either the FBXW12 promoter or the mRNA-encoding region. Moreover, FBXW12 could be epigenetically silenced by CpGs methylation in some of these EOC cases.

Lipocalin-2 plasmatic levels are reduced in patients with long-term type 2 diabetes mellitus.

BACKGROUND: De-regulation of adipocytokines synthesis and secretion appears to be involved in the pathogenesis of different metabolic diseases. AIMS: We assessed a possible association between plasmatic levels of lipocalin-2 (LCN2) and type 2 diabetes mellitus (T2DM), as well as among levels of LCN2 and those of adiponectin, ghrelin, leptin and resistin, in Mexican diabetic patients. SUBJECTS AND METHODS: Fifty-three healthy individuals and fifty-three with long-term T2DM were included. Measurements from all patients for BMI, fasting glucose, insulin, lipids and adipocytokine profiles were obtained. RESULTS: Comparison of data between the corresponding for diabetic subjects and those of healthy individuals showed significant differences in every anthropometric and metabolic parameter analyzed (P < 0.001). In diabetic subjects, lipocalin-2 and ghrelin plasmatic levels were statistically diminished (P < 0.001) in comparison with the levels registered in healthy subjects. In conclusion, in this study we found that LCN2 plasmatic levels are reduced in Mexican subjects with long-term diabetes and this reduction in circulating concentrations is similar to the one reported for anti-inflammatory adipocytokines, which suggests that lipocalin-2 is somehow involved in insulin resistance and cardiometabolic alterations through an uncharacterized mechanism generated by the inflammation process.

Aspectos genéticos y neuroendocrinos en el trastorno del espectro autista / Genetic and neuroendocrine aspects in autism spectrum disorder

El autismo, hoy en día definido como trastornos del espectro autista, fue descrito inicialmente en 1943. Se caracteriza por alteraciones en la comunicación, la interacción social y un espectro restringido de intereses del paciente. Generalmente se identifica en etapas tempranas del desarrollo a partir de los 18 meses de edad. Actualmente el autismo se considera un desorden neurológico con un espectro que abarca diferentes grados que se asocian con factores genéticos, no genéticos y del medio ambiente. Dentro de los factores genéticos se han referido diversos síndromes relacionados con este trastorno. Asimismo, el autismo se ha estudiado a nivel genético, neurofisiológico, neuroquímico y neuropatológico. Las técnicas de neuroimagen han mostrado múltiples anormalidades estructurales en estos pacientes. También se han observado alteraciones relacionadas en los sistemas serotoninérgico, GABAérgico, catecolaminérgico y colinérgico. En este trabajo se presenta una actualización de la información de los aspectos genéticos y neuroendocrinos del trastorno del espectro autista.

The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder.

[Genetic and neuroendocrine aspects in autism spectrum disorder]. / Aspectos genéticos y neuroendocrinos en el trastorno del espectro autista.

The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder.

The transcription factors Sox5 and Sox9 regulate Catsper1 gene expression.

Catsper is a Ca(2+)permeable channel required for sperm hyperactivation. In spite of its central role in male fertility, the transcriptional mechanisms that regulate Catsper1 expression are ill defined. In this work, we describe the identification and characterization of important regulatory elements in the murine Catsper1 gene proximal promoter. Four transcription start sites and three functional Sox-binding sites were identified in the Catsper1 promoter. Interestingly, transcription factors Sox5 and Sox9 caused a significant increase in transactivation of the Catsper1 promoter in heterologous systems, and chromatin immunoprecipitation assays showed that both transcription factors interact with the Catsper1 promoter in vivo. These results provide new insights into the molecular mechanisms that control Catsper channel expression.

Fbxw15/Fbxo12J is an F-box protein-encoding gene selectively expressed in oocytes of the mouse ovary.

In recent years, several factors required for follicular assembly and/or early growth of newly formed primordial follicles have been characterized, but additional factors likely remain to be identified. We have used cDNA arrays to compare gene expression in the neonatal mouse ovary at 48 h (when primordial follicles are being assembled) and at 96 h (when early follicular growth is taking place) after birth to that of ovaries collected <24 h after birth (when follicles have not yet been formed). Segregating genes according to their pattern of expression revealed the presence of one cluster of 24 genes for which expression consistently increased at 48 and 96 h. The top increaser in this cluster encodes a approximately 1.5-kb mRNA containing an open reading frame of 1401 bp that encodes a protein of 466 amino acids. The predicted 52.3-kDa protein is a member of the F-box-only (FBXO) protein family, termed FBXW15 or FBXO12J. It has a cytoplasmic localization that includes the endoplasmic reticulum. Expression of Fbxw15/Fbxp12J mRNA is oocyte-specific; the mRNA is first detected on Gestational Day 18, decreasing thereafter to minimal levels on the day of birth. The prevalence of Fbxw15/Fbxp12J mRNA increases again at 48 and 96 h after birth, coinciding with the time of follicular assembly and the initiation of early follicular growth, respectively. The specific expression of Fbxw15/Fbxp12J in oocytes and its developmental pattern of expression suggest a role for this gene in the regulation of oocyte physiology.

Analysis of C-850T and G-308A polymorphisms of the tumor necrosis factor-alpha gene in Maya-Mestizo women with preeclampsia.

OBJECTIVE: To determine whether polymorphisms in the TNF-alpha promoter gene are associated with preeclampsia. METHODS: 105 women with preeclampsia and 200 controls were genotyped for the G-308A and C-850T polymorphisms by RFLP. Differences in allele, genotype, and haplotype frequencies between groups were assessed. RESULTS: The genotypic and allelic distribution of both polymorphisms was similar between groups. Moreover, the estimated overall pair of loci haplotype frequencies did not differ significantly. CONCLUSION: We did not find any association between these polymorphisms and the risk for preeclampsia. However, we found that both the genotypic and allelic distribution in our population differed from those reported in other populations.