Nrf2 plays a critical role in the metabolic response during and after spaceflight

AbstractSpace travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

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Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00296.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G419-G427 ◽

Cited By ~ 3

Author(s):

Tatsuhide Nabeshima ◽

Shin Hamada ◽

Keiko Taguchi ◽

Yu Tanaka ◽

Ryotaro Matsumoto ◽

...

Keyword(s):

Oxidative Stress ◽

Cancer Progression ◽

Stress Responses ◽

Target Genes ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Related Factor ◽

Loss Of Function ◽

P53 Expression ◽

Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

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Regulation of the cognitive aging process by the transcriptional repressor RP58

10.1101/2021.09.18.460879 ◽

2021 ◽

Author(s):

Tomoko Tanaka ◽

Shinobu Hirai ◽

Hiroyuki Manabe ◽

Kentaro Endo ◽

Hiroko Shimbo ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Knockout Mice ◽

Cognitive Aging ◽

Critical Role ◽

Harmful Effect ◽

Transcriptional Repressor ◽

Repair Pathway ◽

Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

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Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

Scientific Reports ◽

10.1038/s41598-019-56933-7 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Yuanbo Wu ◽

Changlong An ◽

Xiaogao Jin ◽

Zhaoyong Hu ◽

Yanlin Wang

Keyword(s):

Knockout Mice ◽

Critical Role ◽

Kidney Injury ◽

Wild Type ◽

Salt Treatment ◽

Hypertensive Nephropathy ◽

Deoxycorticosterone Acetate ◽

Kidney Fibrosis ◽

Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

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Plasma Transcortin Influences Endocrine and Behavioral Stress Responses in Mice

Endocrinology ◽

10.1210/en.2009-0862 ◽

2010 ◽

Vol 151 (2) ◽

pp. 649-659 ◽

Cited By ~ 66

Author(s):

Elodie M. Richard ◽

Jean-Christophe Helbling ◽

Claudine Tridon ◽

Aline Desmedt ◽

Amandine M. Minni ◽

...

Keyword(s):

Stress Response ◽

Stress Responses ◽

Learned Helplessness ◽

Critical Role ◽

Adaptive Responses ◽

Adrenal Axis ◽

Response To Stress ◽

Hypothalamus Pituitary Adrenal Axis ◽

Deficient Mice ◽

Pituitary Adrenal Axis

Glucocorticoids are released after hypothalamus-pituitary-adrenal axis stimulation by stress and act both in the periphery and in the brain to bring about adaptive responses that are essential for life. Dysregulation of the stress response can precipitate psychiatric diseases, in particular depression. Recent genetic studies have suggested that the glucocorticoid carrier transcortin, also called corticosteroid-binding globulin (CBG), may have an important role in stress response. We have investigated the effect of partial or total transcortin deficiency using transcortin knockout mice on hypothalamus-pituitary-adrenal axis functioning and regulation as well as on behaviors linked to anxiety and depression traits in animals. We show that CBG deficiency in mice results in markedly reduced total circulating corticosterone at rest and in response to stress. Interestingly, free corticosterone concentrations are normal at rest but present a reduced surge after stress in transcortin-deficient mice. No differences were detected between transcortin-deficient mice for anxiety-related traits. However, transcortin-deficient mice display increased immobility in the forced-swimming test and markedly enhanced learned helplessness after prolonged uncontrollable stress. The latter is associated with an approximately 30% decrease in circulating levels of free corticosterone as well as reduced Egr-1 mRNA expression in hippocampus in CBG-deficient mice. Additionally, transcortin-deficient mice show no sensitization to cocaine-induced locomotor responses, a well described corticosterone-dependent test. Thus, transcortin deficiency leads to insufficient glucocorticoid signaling and altered behavioral responses after stress. These findings uncover the critical role of plasma transcortin in providing an adequate endocrine and behavioral response to stress.

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PASTA kinase-dependent control of peptidoglycan synthesis via ReoM is required for cell wall stress responses, cytosolic survival, and virulence in Listeria monocytogenes

PLoS Pathogens ◽

10.1371/journal.ppat.1009881 ◽

2021 ◽

Vol 17 (10) ◽

pp. e1009881

Author(s):

Jessica L. Kelliher ◽

Caroline M. Grunenwald ◽

Rhiannon R. Abrahams ◽

McKenzie E. Daanen ◽

Cassandra I. Lew ◽

...

Keyword(s):

Cell Wall ◽

Listeria Monocytogenes ◽

Stress Responses ◽

Pathogenic Bacteria ◽

Critical Role ◽

Wall Stress ◽

Wild Type ◽

Comprehensive Overview ◽

Bacterial Physiology ◽

Cell Wall Stress

Pathogenic bacteria rely on protein phosphorylation to adapt quickly to stress, including that imposed by the host during infection. Penicillin-binding protein and serine/threonine-associated (PASTA) kinases are signal transduction systems that sense cell wall integrity and modulate multiple facets of bacterial physiology in response to cell envelope stress. The PASTA kinase in the cytosolic pathogen Listeria monocytogenes, PrkA, is required for cell wall stress responses, cytosolic survival, and virulence, yet its substrates and downstream signaling pathways remain incompletely defined. We combined orthogonal phosphoproteomic and genetic analyses in the presence of a β-lactam antibiotic to define PrkA phosphotargets and pathways modulated by PrkA. These analyses synergistically highlighted ReoM, which was recently identified as a PrkA target that influences peptidoglycan (PG) synthesis, as an important phosphosubstrate during cell wall stress. We find that deletion of reoM restores cell wall stress sensitivities and cytosolic survival defects of a ΔprkA mutant to nearly wild-type levels. While a ΔprkA mutant is defective for PG synthesis during cell wall stress, a double ΔreoM ΔprkA mutant synthesizes PG at rates similar to wild type. In a mouse model of systemic listeriosis, deletion of reoM in a ΔprkA background almost fully restored virulence to wild-type levels. However, loss of reoM alone also resulted in attenuated virulence, suggesting ReoM is critical at some points during pathogenesis. Finally, we demonstrate that the PASTA kinase/ReoM cell wall stress response pathway is conserved in a related pathogen, methicillin-resistant Staphylococcus aureus. Taken together, our phosphoproteomic analysis provides a comprehensive overview of the PASTA kinase targets of an important model pathogen and suggests that a critical role of PrkA in vivo is modulating PG synthesis through regulation of ReoM to facilitate cytosolic survival and virulence.

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PAX5/TEL Causes Down Modulation of B-Lineage Specific Genes, and Enhances Migration to CXCL12 in preBI Cells.

Blood ◽

10.1182/blood.v110.11.980.980 ◽

2007 ◽

Vol 110 (11) ◽

pp. 980-980

Author(s):

Grazia Fazio ◽

Chiara Palmi ◽

Antonius G. Rolink ◽

Giovanni Cazzaniga ◽

Andrea Biondi

Keyword(s):

B Cell ◽

Target Genes ◽

Fusion Gene ◽

Wild Type Mouse ◽

Leukemic Cells ◽

Wild Type ◽

Cell Precursor ◽

Childhood All ◽

B Lineage ◽

Lineage Specific Genes

Abstract PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as frequent target of abnormalities in childhood ALL (30% of B-cell precursor ALL cases), showing monoallelic loss, point mutations or chromosomal translocations. The role of these lesions is still poorly understood. We previously cloned the PAX5/TEL fusion gene in a patient affected by B-cell precursor ALL with t(9;12) translocation. We investigated the functional roles of PAX5/TEL protein in vitro, in murine wild type preBI cells, primary cells derived from a wild type mouse and positive for B220, cKIT and CD19 antigens.We demonstrated that the PAX5/TEL protein acts as a transcriptional repressor, down regulating not only CD19, but also other B-lineage specific genes, such as BLNK and MB-1. In addition, PAX5/TEL down regulates FLT3, B220 and μ heavy chain expression, and it does not activate MCSFR. Moreover in PAX5−/− preBI cells, PAX5/TEL did not restore CD19 expression. Comprehensively, these findings suggest that the fusion protein functions as a dominant repressor of transcription on many PAX5-target genes. It is known that CXCL12/SDF1 is a growth factor promoting B-cell progenitor proliferation, acting as a chemo attractant to the bone marrow. In several hematopoietic malignancies, tumor cells express CXCR4, and that the CXCL12-CXCR4 axis may influence the biology of tumor, favoring the metastasis process and the tumor proliferation. Indeed, we demonstrated that PAX5/TEL enhances cell migration towards CXCL12, with over-expression of CXCR4. These phenomena could indicate that leukemic cells carrying PAX5/TEL are able to access to niches that are normally restricted to progenitor cells, and thereby reside in a microenvironment that favours their growth and survival, although this finding must be proved in vivo. Together with previous evidences on the PAX5/TEL capacity to overcome IL7 withdrawal and to interfere with TGFbeta1 pathway, we conclude that PAX5/TEL induces resistance to apoptosis and interferes with the processes of B-cell differentiation and migration. Taken together, these phenomena likely represent key events in the process of B-cell transformation.

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Modulation of Myeloid-Derived Dendritic Cell Maturity: Unmasking a Novel Role for the Tumor Suppressor p15Ink4b in Immunity

Blood ◽

10.1182/blood.v118.21.2469.2469 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2469-2469

Author(s):

Joanna Fares ◽

Linda Wolff ◽

Juraj Bies

Keyword(s):

T Cells ◽

Tumor Suppressor ◽

Knockout Mice ◽

Myeloid Leukemia ◽

Critical Role ◽

Conditional Knockout ◽

Maturation Process ◽

Wild Type ◽

Antigen Presenting ◽

Specific Deletion

Abstract Abstract 2469 p15Ink4b, an inhibitor of cyclin-dependent kinases, is a tumor suppressor frequently associated with hematological malignancies. Its inactivation through DNA methylation is one of the most prevalent epigenetic alterations reported in up to 80% of all acute myeloid leukemia (AML) patients. p15Ink4b is also silenced in 50% of patients diagnosed with myelodysplastic syndromes and its silencing correlates with frequent disease progression into AML. During the leukemogenesis process, escape of pre-leukemic cells from immune clearance represents an important step in the establishment of leukemic disease. Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the regulation of immune responses. In immune surveillance, their primary function is to stimulate naïve T cells against pathogens and cancerous cells leading to their effective clearance. However, whether p15Ink4b plays a role in DC development has never been addressed. In this study, we found that expression of p15Ink4b is strongly induced in mouse splenic DCs and during the development of bone marrow-derived DCs (BM-DCs). Increased expression levels were also found during the development of human CD34-derived DCs suggesting an important role for p15Ink4b in DC maturation. To investigate the function of p15Ink4b during the differentiation and maturation of DCs we used the previously generated p15Ink4bfl/fl-LysMcre conditional knockout mice, where a myeloid-specific deletion of p15Ink4b closely mimics inactivation of the gene in AML. The knockout mice developed nonreactive monocytosis and were predisposed to retrovirus-induced AML. These results provided strong experimental evidence for a role of the gene as a tumor suppressor for myeloid leukemia. Myeloid-specific deletion of p15Ink4b in mice resulted in a reduction in the common DC progenitor pool as compared to wild type mice. p15Ink4bfl/fl-LysMcre mice had significantly fewer and less mature myeloid DCs (mDCs) than the wild type mice whereas other DC subtypes were not affected. Consistent with this data, BM cells from the p15Ink4bfl/fl-LysMcre mice cultured in vitro, generated BM-DCs that express lower levels of the antigen presenting (MHCII) and the co-stimulatory (CD80, CD86) molecules when activated with LPS. Re-expression of p15Ink4b in knockout BM-DCs resulted in an increase in the expression of both co-stimulatory molecules confirming a role for p15Ink4b in the regulation of the maturation process of DCs. The incomplete maturation of BM-DCs correlated with a reduced ability to activate T cells in a MHCII-mismatched mixed leukocyte reaction, and to uptake antigen suggesting that loss of p15Ink4b affects the function of BM-DCs. Taken together, our results indicate a novel role for p15Ink4b in mDC development, and suggest that frequent inactivation of p15Ink4b in myeloid malignancies could lead to an inefficient anti-leukemic immune response during leukemogenesis. Our data also have an important translational significance. AML blasts isolated from patients and differentiated ex-vivo into DCs represent a powerful immunotherapy tool. However, AML-DCs have reportedly a partially impaired maturation process as compared to DCs from healthy donors. We propose that re-expression of p15 in AML-DCs may overcome some of the limitations of a DC-based immunotherapy for AML patients. Disclosures: No relevant conflicts of interest to declare.

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Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis

Cell Death and Disease ◽

10.1038/cddis.2013.448 ◽

2013 ◽

Vol 4 (11) ◽

pp. e921-e921 ◽

Cited By ~ 34

Author(s):

S Tanigawa ◽

C H Lee ◽

C S Lin ◽

C C Ku ◽

H Hasegawa ◽

...

Keyword(s):

Oxidative Stress ◽

Transcriptional Activation ◽

Leucine Zipper ◽

Target Genes ◽

Critical Role ◽

Notch Receptor ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Mobility Shift ◽

Basic Leucine Zipper

Abstract Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.

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Copper proteins and ferroxidases in human plasma and that of wild-type and ceruloplasmin knockout mice

Biochemical Journal ◽

10.1042/bj20081983 ◽

2009 ◽

Vol 419 (1) ◽

pp. 237-245 ◽

Cited By ~ 26

Author(s):

Lawrence W. Gray ◽

Theodros Z. Kidane ◽

Anh Nguyen ◽

Sheryl Akagi ◽

Kristina Petrasek ◽

...

Keyword(s):

Human Plasma ◽

Knockout Mice ◽

Oxidase Activity ◽

Wild Type Mouse ◽

Size Exclusion ◽

Copper Binding ◽

Copper Proteins ◽

Wild Type ◽

Native Page ◽

Ferroxidase Activity

In the blood plasma of humans and rats, ceruloplasmin is the major copper-binding protein and ferroxidase, accounting for 70% of the copper present in the plasma, with the rest binding primarily to albumin and a macroglobulin. Systematic studies with fresh plasma were carried out to compare what occurs in the mouse. C57BL6 mice had half as much copper and pPD (p-phenylene diamine) oxidase activity as humans and rats, 20–40% as much ferroxidase activity as humans (determined using three different assays) and less inhibition by azide. Plasma from ceruloplasmin knockout mice had no pPD oxidase activity, but retained >50% ferroxidase activity (which was not as affected by azide). Modelling of mouse ceruloplasmin against the known X-ray structure of human ceruloplasmin indicated subtle but potentially significant changes in the pPD- and azide-binding sites. Purification and in-gel assays after native PAGE confirmed that mouse ceruloplasmin had ferroxidase activity but revealed an additional ferroxidase in ceruloplasmin knockout mouse plasma, which is also seen in size-exclusion chromatography. In the wild-type mouse, the ‘ceruloplasmin’ peak contained ∼55% of the total copper, but ceruloplasmin knockout plasma exposed a major additional peak (180 kDa) which co-eluted with ferroxidase activity. Two other ferroxidases (700 and 2000 Da) were also detected in mouse and human plasma. Mammalian blood thus contains copper components and ferroxidases not reported previously.

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Role of endothelin-1 in stress response in the central nervous system

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.279.2.r515 ◽

2000 ◽

Vol 279 (2) ◽

pp. R515-R521 ◽

Cited By ~ 16

Author(s):

Yukiko Kurihara ◽

Hiroki Kurihara ◽

Hiroyuki Morita ◽

Wei-Hua Cao ◽

Guang-Yi Ling ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Stress Responses ◽

Knockout Mice ◽

Biological Activities ◽

Close Association ◽

Immunohistochemical Analysis ◽

Catecholamine Metabolism ◽

Wild Type ◽

The Central Nervous System

Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distributed in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to emotional and physical stressors are differentially affected in heterozygous ET-1-knockout mice, which exhibited diminished aggressive and autonomic responses toward intruders (emotional stressors) but responded to restraint-induced (physical) stress more intensely than wild-type mice. This suggests differing roles of ET-1 in the central pathways mediating responses to different types of stress. Hypothalamic levels of ET-1 and the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were both increased in wild-type mice subjected to intruder stress, whereas MHPG levels were not significantly affected in ET-1-knockout mice. Furthermore, immunohistochemical analysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catecholamine synthesis pathway, were colocalized within certain neurons of the hypothalamus and amygdala. Our findings suggest that ET-1 modulates central coordination of stress responses in close association with catecholamine metabolism.

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