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Recombinant Human Elafin Ameliorates Chronic Hyperoxia-Induced Lung Injury by Inhibiting Nuclear Factor-Kappa B Signaling in Neonatal Mice.
J Interferon Cytokine Res
Kexin Li, Fengmei Zhang, Li Wei +5 more
The study aimed to investigate whether recombinant human elafin can prevent hyperoxia-induced pulmonary inflammation in newborn mice, and to explore the mechanism underlying the inhibitory effects of elafin on nuclear factor-kappa B (NF-κB) signaling pathway. Neonatal C57BL/6J mice were exposed to 85% O2 for 1, 3, 7, 14, or 21 days. Then, elafin was administered daily for 20 days through intraperitoneal injection. After treatment, morphometric analysis, quantitative real-time polymerase chain reaction, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and Western blotting were carried out to determine the key markers involved in inflammatory process and the potential signaling pathways in hyperoxia-exposed newborn mice treated with elafin. In neonatal bronchopulmonary dysplasia (BPD) mice, hyperoxia induced apoptosis by increasing Bcl-2-associated X protein expression, and triggered inflammation by upregulating the expression levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α. Moreover, hyperoxia activated NF-κB signaling pathway by promoting the nuclear translocation of p65 in lung tissue. However, all these changes could be inhibited or reversed by elafin at least partially. Elafin reduced apoptosis, suppressed inflammation cytokines, and improved NF-κB p65 nuclear accumulation in hyperoxia-exposed neonatal mice, indicating that this recombinant protein can serve as a novel target for the treatment of BPD.
Thymosin β4 dynamics during chicken enteroid development.
Mol Cell Biochem
Mohan Acharya, Rohana Liyanage, Anamika Gupta +4 more
The sheared avian intestinal villus-crypts exhibit high tendency to self-repair and develop enteroids in culture. Presuming that this transition process involves differential biomolecular changes, we employed matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) to find whether there were differences in the spectral profiles of sheared villi versus the enteroids, assessed in the mass range of 2-18 kDa. The results showed substantial differences in the intensities of the spectral peaks, one particularly corresponding to the mass of 4963 Da, which was significantly low in the sheared villus-crypts compared with the enteroids. Based on our previous results with other avian tissues and further molecular characterization by LC-ESI-IT-TOF-MS, and multiple reaction monitoring (MRM), the peak was identified to be thymosin β4 (Tβ4), a ubiquitously occurring regulatory peptide implicated in wound healing process. The identity of the peptide was further confirmed by immunohistochemistry which showed it to be present in a very low levels in the sheared villi but replete in the enteroids. Since Tβ4 sequesters G-actin preventing its polymerization to F-actin, we compared the changes in F-actin by its immunohistochemical localization that showed no significant differences between the sheared villi and enteroids. We propose that depletion of Tβ4 likely precedes villous reparation process. The possible mechanism for the differences in Tβ4 profile in relation to the healing of the villus-crypts to developing enteroids is discussed.
Hypothalamic reproductive neurons communicate through signal transduction to control reproduction.
Mol Cell Endocrinol
Emma K McIlwraith, Denise D Belsham
Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus coordinate fertility and puberty. In order to achieve successful reproductive capacity, they receive signals from the periphery and from other hypothalamic neurons that coordinate energy homeostasis. Hormones, such as estradiol, insulin, leptin, and adiponectin, act directly or indirectly on GnRH and its associated reproductive neurons. Nutrients like glucose and fatty acids can also affect reproductive neurons to signal nutrient availability. Additionally, acute and chronic inflammation is reported to detrimentally affect GnRH and kisspeptin expression. All of these cues activate signal transduction pathways within neurons that lead to the changes in GnRH neuronal function. The signalling pathways can also be dysregulated by endocrine disrupting chemicals, which impair fertility by misappropriating common signalling pathways. The complex mechanisms controlling the levels of GnRH during the reproductive cycle rely on a carefully orchestrated set of signal transduction events to regulate the positive and negative feedback arms of the hypothalamic-pituitary-gonadal axis. If these signalling events are dysregulated, this will result is a downregulatory event leading to hypogonadal hypogonadism with decreased or absent fertility. Therefore, an understanding of the mechanisms involved in distinct neuronal signalling could provide an advantage to inform therapeutic interventions for infertility and reproductive disorders.
Pericyte-secreted IGF2 promotes breast cancer brain metastasis formation.
Mol Oncol
Kinga Molnár, Ádám Mészáros, Csilla Fazakas +9 more
Brain metastases are life-threatening complications of triple-negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple-negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin-like growth factor 2 (IGF2), which had a very significant pro-proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation-increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood-brain barrier-permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple-negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro-metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.
Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy-induced ventricular remodelling and dysfunction.
Br J Pharmacol
Chao Wang, Tracey A Gaspari, Dorota Ferens +3 more
Oxidative stress and fibrosis are hallmarks of cardiomyopathy-induced heart failure yet are not effectively targeted by current frontline therapies. Here, the therapeutic effects of the anti-oxidant, N-acetylcysteine (NAC), were compared and combined with an acute heart failure drug with established anti-fibrotic effects, serelaxin (RLX), in a murine model of cardiomyopathy.
Thymosin‑β 4 induces angiogenesis in critical limb ischemia mice via regulating Notch/NF‑κB pathway.
Int J Mol Med
Shumin Lv, Hongwen Cai, Yifei Xu +3 more
Thymosin‑β 4 (Tβ4) has been reported to exert a pro‑angogenic effect on endothelial cells. However, little is known on the role and underlying mechanisms of Tβ4 on critical limb ischemia (CLI). The present study aimed therefore to investigate the mechanisms and pro‑angiogenic effects of Tβ4 in CLI mice. Tβ4 overexpression lentiviral vector was first transfected into HUVEC and CLI mice model, and inhibitors of Notch pathway (DAPT) and NF‑κB pathway (BMS) were also applied to HUVEC and CLI mice. Subsequently, MTT, tube formation and wound healing assays were used to determine the cell viability, angiogenesis and migratory ablity of HUVEC, respectively. Western blotting, reverse transcription, quantitative PCR, immunofluorescence and immunohistochemistry were used to detect the expression of the angiogenesis‑related factors angiopoietin‑2 (Ang2), TEK receptor tyrosine kinase 2 (tie2), vascular endothelial growth factor A (VEGFA), CD31 and α‑smooth muscle actin (α‑SMA) and the Notch/NF‑κB pathways‑related factors NOTCH1 intracellular domain (N1ICD), Notch receptor 3 (Notch3), NF‑κB and p65 in HUVEC or CLI mice muscle tissues. The results demonstrated that Tβ4 not only enhanced the cell viability, angiogenesis and migratory ability of HUVEC but also promoted the expression of Ang2, tie2, VEGFA, N1ICD, Notch3, NF‑κB, and phosphorylated (p)‑p65 in HUVEC. In addition, Tβ4 promoted the expression of CD31, α‑SMA Ang2, tie2, VEGFA, N1ICD and p‑p65 in CLI mice muscle tissues. Treatment with DAPT and BMS had opposite effects of Tβ4, whereas Tβ4 reversed the effect of DAPT and BMS. The findings from the present study suggested that Tβ4 may promote angiogenesis in CLI mice via regulation of Notch/NF‑κB pathways.
Targeting the TLR2 Receptor With a Novel Thymopentin-Derived Peptide Modulates Immune Responses.
Front Immunol
Xubiao Wei, Lulu Zhang, Rijun Zhang +9 more
The innate and adaptive immune systems act in concert to protect us from infectious agents and other harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It takes a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases, with slow progress. Toll-like receptor 2 (TLR2) agonists have been reported as potential immunomodulatory candidates due to their effective activation of immune responses. It has been demonstrated that thymopentin (TP5) could modulate immunity by binding to the TLR2 receptor. However, the fairly short half-life of TP5 greatly reduces its pharmacological potential for immunosuppression therapy. Although peptide cathelicidin 2 (CATH2) has a long half-life, it shows poor immunomodulatory activity and severe cytotoxicity, which seriously hampers its clinical development. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In this study, to overcome all these challenges faced by the parental peptides, six hybrid peptides (CaTP, CbTP, CcTP, TPCa, TPCb, and TPCc) were designed by combining the full-length TP5 with different active fragments of CATH2. CbTP, the most potent TLR2 agonist among the six hybrid peptides, was effectively screened through in silico analysis and in vitro experiments. The CbTP peptide exhibited lower cytotoxicity than either CATH2 or TP5. Furthermore, the immunomodulatory effects of CbTP were confirmed in a CTX-immunosuppressed mouse model, which showed that CbTP has increased immunopotentiating activity and physiological stability compared to the parental peptides. CbTP successfully inhibited immunosuppression and weight loss, increased immune organ indices, and improved CD4+/CD8+ T lymphocyte subsets. In addition, CbTP significantly increased the production of the cytokine TNF-α and IL-6, and the immunoglobulins IgA, IgM, and IgG. The immunoenhancing effects of CbTP were attributed to its TLR2-binding activity, promoting the formation of the TLR2 cluster, the activation of the TLR2 receptor, and thus activation of the downstream MyD88-NF-кB signaling pathway.
Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease.
Clin Infect Dis
Lindsay T Fourman, Takara L Stanley, Isabel Zheng +12 more
Nonalcoholic fatty liver disease (NAFLD) affects more than one-third of people living with human immunodeficiency virus (HIV). Nonetheless, its natural history is poorly understood, including which patients are most likely to have a progressive disease course.
Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration.
J Food Biochem
Rui-Jun Li, Yang Liu, Huan-Qiu Liu +1 more
Ketogenic diet (KD), the "High-fat, low-carbohydrate, adequate-protein" diet strategy, replacing glucose with ketone bodies, is effective against several diseases, from intractable epileptic seizures, metabolic disorders, tumors, autosomal dominant polycystic kidney disease, and neurodegeneration to skeletal muscle atrophy and peripheral neuropathy. Key mechanisms include augmented mitochondrial efficiency, reduced oxidative stress, and regulated phospho-AMP-activated protein kinase, gamma-aminobutyric acid-glutamate, Na+/ K+ pump, leptin and adiponectin levels, ghrelin levels, lipogenesis, ketogenesis, lipolysis, and gluconeogenesis. In cancer cells, KD targets glucose metabolism, suppresses insulin-like growth factor-1 and PI3K/AKT/mTOR pathways, and reduces cancer cachexia and muscle waste and fatigue. An associated increased skeletal proliferator-activated receptor-γ coactivator-1α activity alters systemic ketone body homeostasis, contributing toward attenuated diabetic hyperketonemia. Antioxidative and anti-inflammatory properties enable KD enhance endurance and sports performances while preventing exercise-induced muscle and organ debility. KD reduces metabolic syndromes-associated allodynia and promotes peripheral axonal and sensory regeneration. This review enlightens effects of KD on various disease conditions. PRACTICAL APPLICATIONS: It is increasingly being realized that diet plays a very important role in our fight against several diseases. This can range from neurological disorders to diabetes and cancer. In this context, the potential of KD, the "High-fat, low-carbohydrate, adequate-protein" diet strategy, is increasingly being realized. In this article, we provide a comprehensive analysis of the benefits of KD against many diseases and discuss the underlying biochemical mechanisms. We hope that our write-up will stimulate further research on KD and help generate an interest for the populations to adopt this healthy diet. It can help overcome the problems associated with weight and dysregulated metabolism.
Evaluation of trappin-2 in cervicovaginal secretions as predictor of spontaneous preterm birth in asymptomatic high-risk women: Nested case-control study.
Int J Gynaecol Obstet
Deepika Negi, Kiran Guleria, Vipin Tyagi +2 more
To evaluate trappin-2 levels in cervicovaginal secretions for prediction of spontaneous preterm birth (sPTB) and compare it with transvaginal sonography (TVS) cervical length in asymptomatic women at risk of PTB.
A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer's disease mice.
J Control Release
Qian Guo, Shuting Xu, Peng Yang +7 more
The presence of blood-brain barrier (BBB) and specificity of neuron targeting remain two challenges in the effective delivery of nanotherapeutics for the treatment of Alzheimers disease (AD). Traditional strategy of nanocarriers for AD treatment involves co-decoration of both BBB-penetrating ligand and neuron-targeting ligand on the surface of the nanoparticles for "dual-stage" targeted delivery. Instead, we design and optimize a fusion peptide TPL comprising a BBB-penetrating peptide TGN and a neuron binding peptide Tet1 through a four-glycine linker. Compared to the mono-ligand Tet1 or CGN which is the retro-inverso isomer of TGN with higher brain targeting than TGN, the dual-ligand fusion peptide TPL has preferable blood stability and enhanced structural flexibility, resulting in higher binding affinity to either GT1b ganglioside receptor or brain capillary endothelial bEnd.3 cells. The TPL-modified nanoparticles (TPL-NP) increased the BBB-penetration and neuron-targeting efficacy than the nanoparticles co-decorated with the two mono-ligands. Encapsulation of a neuroprotective peptide NAP, TPL-NP significantly enhance reactive oxygen species scavenging ability and effectively protect microtubule from Aβ25-35-induced neurotoxicity. Meanwhile, TPL-NP inhibit okadaic acid-induced tau aggregation and neuronal apoptosis. Administration of TPL-NP in AD mice also significantly improves the cognitive performance, down-regulates the tau phosphorylation level, promotes axonal transport and attenuates microgliosis. Taken together, this work demonstrates that the rationally designed dual-ligand fusion peptides can greatly improve the delivery of drugs to the AD lesions, thereby markedly enhancing the efficacy of AD treatment.
Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice.
FASEB J
Zhengxiang Huang, Xuehan Lu, Lili Huang +4 more
Obese individuals often show low growth hormone (GH) secretion, which leads to reduced lipid mobilization and further fat accumulation. Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH-releasing hormone receptor agonist showed promising effects on fat reduction. However, side effects on glucose metabolism and the heavy costs on making large peptides hindered their clinical application. Here, we tested whether stimulation of endogenous GH secretion by a synthetic GH secretagogue receptor (GHSR) agonist, hexarelin, improved the metabolism in a hyperphagic obese mouse model. Male melanocortin 4 receptor knockout mice (MC4RKO) were pair-fed and received continuous hexarelin (10.56 μg/day) or vehicle infusion by an osmotic pump for 3-4 weeks. Hexarelin treatment significantly increased the pulsatile GH secretion without detectable alteration on basal GH secretion in MC4RKO mice. The treated mice showed increased lipolysis and lipid oxidation in the adipose tissue, and reduced de novo lipogenesis in the liver, leading to reduced visceral fat mass, reduced triglyceride content in liver, and unchanged circulating free fatty acid levels. Importantly, hexarelin treatment improved the whole-body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin-like growth factor 1 (IGF-1) levels. The metabolic effects of hexarelin were likely through the direct action of GH, as indicated by the increased expression level of genes involved in GH signaling pathways in visceral adipose tissues and liver. In conclusion, hexarelin treatment stimulated the pulsatile GH secretion and reduced the fat accumulation in visceral depots and liver in obese MC4RKO mice with improved insulin sensitivity without altered levels of insulin or IGF-1. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.
Impact of Aging on the Phenotype of Invariant Natural Killer T Cells in Mouse Thymus.
Front Immunol
Georgia Papadogianni, Inga Ravens, Oliver Dittrich-Breiholz +2 more
Invariant natural killer T (iNKT) cells represent a subclass of T cells possessing a restricted repertoire of T cell receptors enabling them to recognize lipid derived ligands. iNKT cells are continuously generated in thymus and differentiate into three main subpopulations: iNKT1, iNKT2, and iNKT17 cells. We investigated the transcriptomes of these subsets comparing cells isolated from young adult (6-10 weeks old) and aged BALB/c mice (25-30 weeks of age) in order to identify genes subject to an age-related regulation of expression. These time points were selected to take into consideration the consequences of thymic involution that radically alter the existing micro-milieu. Significant differences were detected in the expression of histone genes affecting all iNKT subsets. Also the proliferative capacity of iNKT cells decreased substantially upon aging. Several genes were identified as possible candidates causing significant age-dependent changes in iNKT cell generation and/or function such as genes coding for granzyme A, ZO-1, EZH2, SOX4, IGF1 receptor, FLT4, and CD25. Moreover, we provide evidence that IL2 differentially affects homeostasis of iNKT subsets with iNKT17 cells engaging a unique mechanism to respond to IL2 by initiating a slow rate of proliferation.
Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.
JCI Insight
Lindsay T Fourman, James M Billingsley, George Agyapong +12 more
Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction.
Proc Natl Acad Sci U S A
Angela C Rieger, Luiza L Bagno, Alessandro Salerno +13 more
Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.
[The Peptide Drug ACTH(4-7)PGP (Semax) Suppresses mRNA Transcripts Encoding Proinflammatory Mediators Induced by Reversible Ischemia of the Rat Brain].
Mol Biol (Mosk)
L V Dergunova, V G Dmitrieva, I B Filippenkov +9 more
Due to its nootropic, neuroprotective, and immunomodulatory effects, the peptide Semax is utilized in the treatment of ischemic stroke. Our earlier RNA-Seq analysis of the transcriptome in an ischemic model of transient occlusion of the middle cerebral artery showed an increase in the mRNA levels of many proinflammatory genes, and the suppression of their induction by Semax. However, for many relevant genes, including Il1a, Il1b, Il6 and Tnfa, the levels of their expression were too low for detailed quantitative evaluation. Here we utilize qRT-PCR to analyze the effects of the Semax peptide on the expression of weakly expressed mRNAs encoding several proinflammatory mediators, and show that exposure to Semax leads to a statistically significant decrease in the Il1a, Il1b, Il6, Ccl3, and Cxcl2 mRNAs, which compensates for the increase in the transcription of these genes induced by ischemia-reperfusion. We conclude that the observed protective effect of Semax in the model of stroke may be due to its anti-inflammatory effects. We also discuss the limitations of the RNA-Seq when applied to quantifying less abundant transcripts as compared to the real-time RT-PCR method.
Composition of Colon Microbiota in Rats Treated with ACTH(4-7)-PGP Peptide (Semax) under Conditions of Restraint Stress.
Bull Exp Biol Med
M V Svishcheva, A Yu Mukhina, O A Medvedeva +5 more
We studied the effect of Semax on the state of intestinal microbiota in rats subjected to restraint stress. Semax was injected to Wistar male rats intraperitoneally in doses of 5, 50, 150, 450 μg/kg 12-15 min before modelling chronic restraint stress. It was found that stress exposure reduced the number of obligate bacteria in the colon microbiota, but increased the content of opportunistic microorganisms. Semax in doses of 50 and 150 μg/kg prevented the stress-induced changes in the composition of colon microbiota. The observed effects of Semax might be mediated by the central neurotropic effects as well as by binding to peripheral melanocortin receptors of the intestine.
Real-world off-label use of icatibant for acute management of non-hereditary angioedema.
Intern Med J
Thanh-Thao Adriana Le, William Smith, Pravin Hissaria
We retrospectively examined the indications and efficacy of off-label use of the bradykinin B2 receptor antagonist icatibant. The clinical heterogeneity, variability of response to icatibant and lack of efficacy of adrenaline described in this audit highlights both the need for biomarkers that can rapidly distinguish between histaminergic and non-histaminergic angioedema, and for guidelines to improve the utility of icatibant in the non-hereditary angioedema setting.
The content of gonadotropin-releasing hormone (GnRH), kisspeptin, and estrogen receptors (ERα/ERβ) in the anteromedial hypothalamus displays daily variations throughout the rat estrous cycle.
Cell Tissue Res
Esteban Olvera-Juárez, Carlos-Camilo Silva, Angélica Flores +8 more
The content of gonadotropin-releasing hormone (GnRH), its mRNA, and estrogen receptor alpha (ERα) and beta (ERβ) in the hypothalamus varies throughout the estrous cycle. Furthermore, the abundance of these molecules displays asymmetry between the right and left side. In the present study, we investigated the changes in the content of ERα, ERβ, kisspeptin, and GnRH by western blot in the left and right anteromedial hypothalamus, at four different times during each stage of the rat estrous cycle. The serum levels of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were also measured. ERα and ERβ levels changed depending on the stage of the estrous cycle, meanwhile that of kisspeptin was modified according to both the hour of the day and the stage of the cycle. Except in estrus day, ERβ was higher in the right hypothalamus, while ERα was similar in both sides. During both proestrus and estrus, the content of kisspeptin and GnRH was higher in the right hypothalamus. The highest levels of FSH and LH occurred at 17:00 h of proestrus. But at estrus, the highest FSH levels were observed at 08:00 h and the lowest at 17:00 h. Thus, the current results show that the content of ERα, ERβ, kisspeptin, and GnRH in the anteromedial hypothalamus are regulated as a function of the stage of the estrous cycle and the hour of the day. Furthermore, the content of these proteins is regularly higher in the right anteromedial hypothalamus, regardless of the stage of the cycle or time of the day.
Ghrelin Receptors Enhance Fat Taste Responsiveness in Female Mice.
Nutrients
Ashley N Calder, Tian Yu, Naima S Dahir +2 more
Ghrelin is a major appetite-stimulating neuropeptide found in circulation. While its role in increasing food intake is well known, its role in affecting taste perception, if any, remains unclear. In this study, we investigated the role of the growth hormone secretagogue receptor's (GHS-R; a ghrelin receptor) activity in the peripheral taste system using feeding studies and conditioned taste aversion assays by comparing wild-type and GHS-R-knockout models. Using transgenic mice expressing enhanced green fluorescent protein (GFP), we demonstrated GHS-R expression in the taste system in relation phospholipase C ß2 isotype (PLCβ2; type II taste cell marker)- and glutamate decarboxylase type 67 (GAD67; type III taste cell marker)-expressing cells using immunohistochemistry. We observed high levels of co-localization between PLCβ2 and GHS-R within the taste system, while GHS-R rarely co-localized in GAD67-expressing cells. Additionally, following 6 weeks of 60% high-fat diet, female Ghsr-/- mice exhibited reduced responsiveness to linoleic acid (LA) compared to their wild-type (WT) counterparts, while no such differences were observed in male Ghsr-/- and WT mice. Overall, our results are consistent with the interpretation that ghrelin in the taste system is involved in the complex sensing and recognition of fat compounds. Ghrelin-GHS-R signaling may play a critical role in the recognition of fatty acids in female mice, and this differential regulation may contribute to their distinct ingestive behaviors.