STAT5 Is Necessary for the Metabolic Switch Induced by IL-2 in Cervical Cancer Cell Line SiHa.

The tumor cells reprogram their metabolism to cover their high bioenergetic demands for maintaining uncontrolled growth. This response can be mediated by cytokines such as IL-2, which binds to its receptor and activates the JAK/STAT pathway. Some reports show a correlation between the JAK/STAT pathway and cellular metabolism, since the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of genes related to energetic metabolism. However, the role of STAT proteins in the metabolic switch induced by cytokines in cervical cancer remains poorly understood. In this study, we analyzed the effect of IL-2 on the metabolic switch and the role of STAT5 in this response. Our results show that IL-2 induces cervical cancer cell proliferation and the tyrosine phosphorylation of STAT5. Also, it induces an increase in lactate secretion and the ratio of NAD+/NADH, which suggest a metabolic reprogramming of their metabolism. When STAT5 was silenced, the lactate secretion and the NAD+/NADH ratio decreased. Also, the expression of HIF1α and GLUT1 decreased. These results indicate that STAT5 regulates IL-2-induced cell proliferation and the metabolic shift to aerobic glycolysis by regulating genes related to energy metabolism. Our results suggest that STAT proteins modulate the metabolic switch in cervical cancer cells to attend to their high demand of energy required for cell growth and proliferation.

Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13, Asns, Hamp2, Hao2, and Pgc1a.

Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns, and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4, and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4, and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4, and Cyp2b9 in a sex- and gene-specific manner.

A new hope for early T cell precursor acute lymphoblastic leukemia therapy based on STAT5+ leukemic stem cell targeting.

Leukemia stem cells are known to drive tumor progression, drug resistance, microenvironmental shift, and relapse, which would make them a perfect therapeutic target. However, their phenotypic and functional similarity to their normal counterparts leaves limited road maps for their selective elimination. Tremblay et al. recently unraveled the fundamental role of overactivated pSTAT5 as a functional marker of early T cell precursor acute lymphoblastic leukemia stem cells driving leukemic progression and highlighted its potential use as a therapeutic target to prevent fatal outcomes.

Caveolae Microdomains Mediate STAT5 Signaling Induced by Insulin in MCF-7 Breast Cancer Cells.

Caveolae are small plasma membrane invaginations constituted for membrane proteins namely caveolins and cytosolic proteins termed cavins, which can occupy up to 50% of the surface of mammalian cells. The caveolae have been involved with a variety of cellular processes including regulation of cellular signaling. Insulin is a hormone that mediates a variety of physiological processes through activation of insulin receptor (IR), which is a tyrosine kinase receptor expressed in all mammalian tissues. Insulin induces activation of signal transducers and activators of transcription (STAT) family members including STAT5. In this study, we demonstrate, for the first time, that insulin induces phosphorylation of STAT5 at tyrosine-694 (STAT5-Tyr(P)694), STAT5 nuclear accumulation and an increase in STAT5-DNA complex formation in MCF-7 breast cancer cells. Insulin also induces nuclear accumulation of STAT5-Tyr(P)694, caveolin-1, and IR in MCF-7 cells. STAT5 nuclear accumulation and the increase of STAT5-DNA complex formation require the integrity of caveolae and microtubule network. Moreover, insulin induces an increase and nuclear accumulation of STAT5-Tyr(P)694 in MDA-MB-231 breast cancer cells. In conclusion, results demonstrate that caveolae and microtubule network play an important role in STAT5-Tyr(P)694, STAT5 nuclear accumulation and STAT5-DNA complex formation induced by insulin in breast cancer cells.

Association between somatotropic axis gene polymorphisms and reproductive efficiency of bovine females: a review / Associação entre polimorfismos de genes do eixo somatotrópico e eficiência reprodutiva de fêmeas bovinas: revisão de literatura

Reproductive characteristics directly reflect on productive performance, as they determine the number of calves born annually and the interval between generations, thereby affecting the selection intensity. This allows for the determination of the most important economic variables that directly affect the production system. The present study is a literature review of somatotropic axis gene polymorphisms that are associated with reproductive functions in heifers and cows (Bos taurus taurus and Bos taurus indicus). The following characteristics were analyzed from the various studies reviewed: number of services per pregnancy (Nº services/ pregnancy), age at first calving (AFC), calving interval (CI), and period of service calving conception interval (CCI). The research was conducted during the period from 2011 to 2021, and associations were found among all indicators of reproductive efficiency evaluated in heifers and cows, with 27 single nucleotide polymorphisms (SNPs): 18 in GHR, 5 in IGF-I, and 4 in STAT5A. This study revealed the relationships between SNPs and the reproductive efficiency indicators and demonstrated that molecular genetic techniques enhance the animal selection process, resulting in more profitable systems that are sustainable in the long term.

Características reprodutivas refletem diretamente no desempenho produtivo visto que são capazes de determinar o número de bezerros nascidos anualmente, além de afetar o intervalo entre gerações e, consequentemente, a intensidade de seleção, fazendo com o que tais atributos sejam apontados como variáveis econômicas das mais importantes que afetam diretamente o sistema de produção. O presente estudo propõe realizar uma revisão de literatura de polimorfismos de genes do eixo somatotrópico associados a funções reprodutivas em novilhas e vacas (Bos taurus taurus e Bos taurus indicus), indicadas pelos índices: número de serviços por gestação (Nº serviços/gestação), idade ao primeiro parto (IPP), intervalo de partos (IP) e período de serviço, como também denominado de intervalo parto-concepção (IPC). As pesquisas encontradas durante o período de 2011 a 2021 demonstraram associações entre todos os indicadores de eficiência reprodutiva analisados de novilhas e vacas com 27 polimorfismos de nucleotídeo único (SNPs), sendo 18 em GHR, 5 em IGF-I e 4 em STAT5A. Dessa forma, este estudo mostrou relação entre os SNPs e os indicadores de eficiência reprodutiva, demonstrando que técnicas de genética molecular potencializam o processo de seleção dos animais, resultando em sistemas mais lucrativos e que se sustentam a longo prazo.

Ovarian Cancer-Associated Ascites Have High Proportions of Cytokine-Responsive CD56bright NK Cells.

Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, we carried out flow cytometry-based analysis to readdress issues on NK and T lymphocyte subsets in women with advanced EOC, additionally evaluating phenotypic modulation of their intracellular pathways involved in interleukin (IL)-2 and IL-15 signaling. Results depicted ascites as an inflammatory and immunosuppressive environment, presenting significantly (p < 0.0001) higher amounts of IL-6 and IL-10 than in the patients' blood, as well as significantly (p < 0.05) increased expression of checkpoint inhibitory receptors (programmed death protein-1, PD-1) and ectonucleotidase (CD39) on T lymphocytes. However, NK lymphocytes from EOC-associated ascites showed higher (p < 0.05) pS6 phosphorylation compared with NK from blood. Additionally, in vitro treatment of lymphocytes with IL-2 or IL-15 elicited significantly (p < 0.001) phosphorylation of the STAT5 protein in NK, CD3 and CD8 lymphocytes, both from blood and ascites. EOC-associated ascites had a significantly (p < 0.0001) higher proportion of NK CD56bright lymphocytes than blood, which, in addition, were more responsive (p < 0.05) to stimulation by IL-2 than CD56dim NK. EOC-associated ascites allow studies on lymphocyte phenotype modulation in the tumor environment, where inflammatory profile contrasts with the presence of immunosuppressive elements and development of cellular self-regulating mechanisms.

The Genomic Landscape of a Restricted ALL Cohort from Patients Residing on the U.S./Mexico Border.

Next-generation sequencing (NGS) has identified unique biomarkers yielding new strategies in precision medicine for the treatment of Acute lymphoblastic leukemia (ALL). Hispanics show marked health disparities in ALL, often absent in clinical trials or cancer research. Thus, it is unknown whether Hispanics would benefit equally from curated data currently guiding precision oncology. Using whole-exome sequencing, nine ALL patients were screened for mutations within genes known to possess diagnostic, prognostic and therapeutic value. Genes mutated in Hispanic ALL patients from the borderland were mined for potentially pathogenic variants within clinically relevant genes. KRAS G12A was detected in this unique cohort and its frequency in Hispanics from the TARGET-ALL Phase II database was three-fold greater than that of non-Hispanics. STAT5B N642H was also detected with low frequency in Hispanic and non-Hispanic individuals within TARGET. Its detection within this small cohort may reflect a common event in this demographic. Such variants occurring in the MAPK and JAK/STAT pathways may be contributing to Hispanic health disparities in ALL. Notable variants in ROS1, WT1, and NOTCH2 were observed in the ALL borderland cohort, with NOTCH2 C19W occurring most frequently. Further investigations on the pathogenicity of these variants are needed to assess their relevance in ALL.

Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

Decoding signaling pathways involved in prolactin-induced neuroprotection: A review.

It has been well recognized that prolactin (PRL), a pleiotropic hormone, has many functions in the brain, such as maternal behavior, neurogenesis, and neuronal plasticity, among others. Recently, it has been reported to have a significant role in neuroprotection against excitotoxicity. Glutamate excitotoxicity is a common alteration in many neurological and neurodegenerative diseases, leading to neuronal death. In this sense, several efforts have been made to decrease the progression of these pathologies. Despite various reports of PRL's neuroprotective effect against excitotoxicity, the signaling pathways that underlie this mechanism remain unclear. This review aims to describe the most recent and relevant studies on the molecular signaling pathways, particularly, PI3K/AKT, NF-κB, and JAK2/STAT5, which are currently under investigation and might be implicated in the molecular mechanisms that explain the PRL effects against excitotoxicity and neuroprotection. Remarkable neuroprotective effects of PRL might be useful in the treatment of some neurological diseases.

Melatonin regulates maternal pancreatic remodeling and B-cell function during pregnancy and lactation.

The endocrine pancreas of pregnant rats shows evident plasticity, which allows the morphological structures to return to the nonpregnant state right after delivery. Furthermore, it is well-known the role of melatonin in the maintenance of the endocrine pancreas and its tropism. Studies indicate increasing nocturnal serum concentrations of maternal melatonin during pregnancy in both humans and rodents. The present study investigated the role of melatonin on energy metabolism and in pancreatic function and remodeling during pregnancy and early lactation in rats. The results confirm that the absence of melatonin during pregnancy impairs glucose metabolism. In addition, there is a dysregulation in insulin secretion at various stages of the development of pregnancy and an apparent failure in the glucose-stimulated insulin secretion during the lactation period, evidencing the role of melatonin on the regulation of insulin secretion. This mechanism seems not to be dependent on the antioxidant effect of melatonin and probably dependent on MT2 receptors. We also observed changes in the mechanisms of death and cell proliferation at the end of pregnancy and beginning of lactation, crucial periods for pancreatic remodeling. The present observations strongly suggest that both functionality and remodeling of the endocrine pancreas are impaired in the absence of melatonin and its adequate replacement, mimicking the physiological increase seen during pregnancy, is able to reverse some of the damage observed. Thus, we conclude that pineal melatonin is important to metabolic adaptation to pregnancy and both the functionality of the beta cells and the remodeling of the pancreas during pregnancy and early lactation, ensuring the return to nonpregnancy conditions.

Activation of the MAPK pathway (RASopathies) and partial growth hormone insensitivity.

RASopathies are a heterogeneous group of syndromes caused by germline mutations in genes encoding components of the RAS/MAPK pathway. Postnatal short stature is a cardinal feature of the RASopathies. Although the pathophysiology of these conditions is not fully understood to date, growth hormone insensitivity is one possibility, based on the observation of low IGF-1 values, generally preserved GH secretion and suboptimal growth response to recombinant human GH therapy. In this review, we will discuss the clinical and experimental evidence of GH insensitivity in patients with Noonan syndrome and other RASopathies, as well as their molecular basis.

Distribution of growth hormone-responsive cells in the brain of rats and mice.

A growth hormone (GH) injection is able to induce the phosphorylated form of the signal transducer and activator of transcription 5 (pSTAT5) in a large number of cells throughout the mouse brain. The present study had the objective to map the distribution of GH-responsive cells in the brain of rats that received an intracerebroventricular injection of GH and compare it to the pattern found in mice. We observed that rats and mice exhibited a similar distribution of GH-induced pSTAT5 in the majority of areas of the telencephalon, hypothalamus and brainstem. However, rats exhibited a higher density of GH-responsive cells than mice in the horizontal limb of the diagonal band of Broca (HDB), supraoptic and suprachiasmatic nuclei, whereas mice displayed more GH-responsive cells than rats in the hippocampus, lateral hypothalamic area and dorsal motor nucleus of the vagus (DMX). Since both HDB and DMX contain acetylcholine-producing neurons, pSTAT5 was co-localized with choline acetyltransferase in GH-injected animals. We found that 50.0 ± 4.5% of cholinergic neurons in the rat HDB coexpressed GH-induced pSTAT5, whereas very few co-localizations were observed in the mouse HDB. In contrast, rats displayed fewer cholinergic neurons responsive to GH in the DMX at the level of the area postrema. In summary, pSTAT5 can be used as a marker of GH-responsive cells in the rat brain. Although rats and mice exhibit a relatively similar distribution of GH-responsive neurons, some species-specific differences exist, as exemplified for the responsiveness to GH in distinct populations of cholinergic neurons.

A Bioinformatic Pipeline Places STAT5A as a miR-650 Target in Poorly Differentiated Aggressive Breast Cancer.

Breast cancer (BRCA) is a leading cause of mortality among women. Tumors often acquire aggressive features through genomic aberrations affecting cellular programs, e.g., the epithelial to mesenchymal transition (EMT). EMT facilitates metastasis leading to poor prognosis. We previously observed a correlation between an amplification of miR-650 (Amp-650) and EMT features in BRCA samples isolated from Mexican patients. In this study, we explored the cBioportal database aiming to extend that observation and better understand the importance of Amp-650 for BRCA aggressiveness. We found that Amp-650 is more frequent in aggressive molecular subtypes of BRCA, as well as in high grade poorly differentiated tumors, which we confirmed in an external miRNA expression database. We performed differential expression analysis on samples harboring Amp-650, taking advantage of gene target prediction tools and tumor suppressor gene databases to mine several hundreds of differentially underexpressed genes. We observed STAT5A as a likely putative target gene for miR-650 in aggressive poorly differentiated BRCA. Samples with both Amp-650 and low expression of STAT5A had less overall survival than samples with either or none of the alterations. No target gene has been described for miR-650 in BRCA, thus, this bioinformatic study provides valuable information that should be corroborated experimentally.

Effect of COQ9 and STAT5A polymorphisms on reproductive performance in a Holstein cow herd in Mexico.

Coenzyme Q9 (COQ9), a coenzyme Q (CoQ) precursor, is an essential component of the mitochondrial electron transport chain that drives adenosine triphosphate production. COQ9 polymorphism 18:25527339 is characterized by substitution of guanine (allele G) for adenine (allele A), which modifies the function of the protein encoded by the gene. In Holsteins, allele A has been associated with better reproductive performance in terms of the conception rate, number of services per conception (SPC) and days open (DO). The signal transducer and activator of transcription (STAT) protein is a transcription factor activated in the presence of cytokines and growth factors. STAT5A polymorphism 19:42407732 in exon 8 has been associated with higher fertility and embryonic survival rates. The objective of this study was to determine the relationship of COQ9 and STAT5A polymorphisms with reproductive parameters [calving to first heat interval (CFHI), DO and SPC]. Blood samples were taken from 112 lactating Holstein from a herd in México for allele genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). To estimate the association between reproductive parameters and genotypes, a linear mixed-effect model was performed. The COQ9 AG genotype was associated significantly with lower SPC (P<0.05) but not with DO or CFHI. No significant association with any reproductive parameter was found for STAT5A. Our findings suggest that the COQ9 18:25527339 polymorphism is a useful molecular marker for improvement of reproductive performance in dairy herds.

Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes.

A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells.

A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).

BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI. PATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

Regulation and neurochemical identity of melanin-concentrating hormone neurones in the preoptic area of lactating mice.

Neurones expressing the melanin-concentrating hormone (MCH) can be found in the medial preoptic area (mPOA) and ventral aspects of the periventricular preoptic nucleus of rats by mid-to-late lactation and this expression disappears after weaning. The transitory expression of MCH in the preoptic area suggests a role for these neurones in the control of the end of lactation. However, the neurochemical identity of mPOA MCH neurones and the regulatory factors that control the transient MCH expression remain largely unknown, especially in the mouse. In the present study, we showed that mice also present the transitory expression of MCH in the mPOA at late lactation. mPOA MCH cells did not colocalise significantly with markers of GABAergic (VGAT), glutamatergic (VGLUT2 and VGLUT3) or dopaminergic (tyrosine hydroxylase) neurones. mPOA MCH cells also did not express Kiss1 or oxytocin. By contrast, approximately 70% and 90% of mPOA MCH neurones colocalised with oestrogen receptor α and prolactin-induced phosphorylated signal transducer and activator of transcription 5 (STAT5), respectively. Finally, we demonstrated that the number of MCH neurones in the mPOA is significantly higher in females during the first lactation, compared to mice on the second lactation or pregnant mice during the first lactation or brain-specific STAT5 knockout mice during the first lactation. In summary, our findings indicate that MCH neurones in the mPOA of lactating mice are sensitive to oestrogens and prolactin. Thus, mPOA MCH expression is possibly influenced by hormonal variations. Furthermore, the STAT5 signalling pathway is likely involved in the regulation of MCH expression in the mPOA of lactating mice.

Effect of COQ9 and STAT5A polymorphisms on reproductive performance in a Holstein cow herd in Mexico

Coenzyme Q9 (COQ9), a coenzyme Q (CoQ) precursor, is an essential component of the mitochondrial electron transport chain that drives adenosine triphosphate production. COQ9 polymorphism 18:25527339 is characterized by substitution of guanine (allele G) for adenine (allele A), which modifies the function of the protein encoded by the gene. In Holsteins, allele A has been associated with better reproductive performance in terms of the conception rate, number of services per conception (SPC) and days open (DO). The signal transducer and activator of transcription (STAT) protein is a transcription factor activated in the presence of cytokines and growth factors. STAT5A polymorphism 19:42407732 in exon 8 has been associated with higher fertility and embryonic survival rates. The objective of this study was to determine the relationship of COQ9 and STAT5A polymorphisms with reproductive parameters [calving to first heat interval (CFHI), DO and SPC]. Blood samples were taken from 112 lactating Holstein from a herd in México for allele genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). To estimate the association between reproductive parameters and genotypes, a linear mixed-effect model was performed. The COQ9 AG genotype was associated significantly with lower SPC (P<0.05) but not with DO or CFHI. No significant association with any reproductive parameter was found for STAT5A. Our findings suggest that the COQ9 18:25527339 polymorphism is a useful molecular marker for improvement of reproductive performance in dairy herds.(AU)

Effect of COQ9 and STAT5A polymorphisms on reproductive performance in a Holstein cow herd in Mexico

Coenzyme Q9 (COQ9), a coenzyme Q (CoQ) precursor, is an essential component of the mitochondrial electron transport chain that drives adenosine triphosphate production. COQ9 polymorphism 18:25527339 is characterized by substitution of guanine (allele G) for adenine (allele A), which modifies the function of the protein encoded by the gene. In Holsteins, allele A has been associated with better reproductive performance in terms of the conception rate, number of services per conception (SPC) and days open (DO). The signal transducer and activator of transcription (STAT) protein is a transcription factor activated in the presence of cytokines and growth factors. STAT5A polymorphism 19:42407732 in exon 8 has been associated with higher fertility and embryonic survival rates. The objective of this study was to determine the relationship of COQ9 and STAT5A polymorphisms with reproductive parameters [calving to first heat interval (CFHI), DO and SPC]. Blood samples were taken from 112 lactating Holstein from a herd in México for allele genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). To estimate the association between reproductive parameters and genotypes, a linear mixed-effect model was performed. The COQ9 AG genotype was associated significantly with lower SPC (P<0.05) but not with DO or CFHI. No significant association with any reproductive parameter was found for STAT5A. Our findings suggest that the COQ9 18:25527339 polymorphism is a useful molecular marker for improvement of reproductive performance in dairy herds.

Effects of growth hormone in the central nervous system

ABSTRACT Growth hormone (GH) is best known for its effect stimulating tissue and somatic growth through the regulation of cell division, regeneration and proliferation. However, GH-responsive neurons are spread over the entire central nervous system, suggesting that they have important roles in the brain. The objective of the present review is to summarize and discuss the potential physiological importance of GH action in the central nervous system. We provide evidence that GH signaling in the brain regulates the physiology of numerous functions such as cognition, behavior, neuroendocrine changes and metabolism. Data obtained from experimental animal models have shown that disruptions in GH signaling in specific neuronal populations can affect the reproductive axis and impair food intake during glucoprivic conditions, neuroendocrine adaptions during food restriction, and counter-regulatory responses to hypoglycemia, and they can modify gestational metabolic adaptions. Therefore, the brain is an important target tissue of GH, and changes in GH action in the central nervous system can explain some dysfunctions presented by individuals with excessive or deficient GH secretion. Furthermore, GH acts in specific neuronal populations during situations of metabolic stress to promote appropriate physiological adjustments that restore homeostasis. Arch Endocrinol Metab. 2019;63(6):549-56