scholarly journals Co2+ Selectivity of Thermotoga maritima CorA and Its Inability to Regulate Mg2+ Homeostasis Present a New Class of CorA Proteins

2011 ◽  
Vol 286 (18) ◽  
pp. 16525-16532 ◽  
Author(s):  
Yu Xia ◽  
Anna-Karin Lundbäck ◽  
Newsha Sahaf ◽  
Gustav Nordlund ◽  
Peter Brzezinski ◽  
...  
Keyword(s):  
Structural Changes ◽  
Thermotoga Maritima ◽  
Main Role ◽  
Substrate Selection ◽  
New Class ◽  
Physiological Relevance ◽  
Structural Differences ◽  
High Concentrations

CorA is a family of divalent cation transporters ubiquitously present in bacteria and archaea. Although CorA can transport both Mg2+ and Co2+ almost equally well, its main role has been suggested to be that of primary Mg2+ transporter of prokaryotes and hence the regulator of Mg2+ homeostasis. The reason is that the affinity of CorA for Co2+ is relatively low and thus considered non-physiological. Here, we show that Thermotoga maritima CorA (TmCorA) is incapable of regulating the Mg2+ homeostasis and therefore cannot be the primary Mg2+ transporter of T. maritima. Further, our in vivo experiments confirm that TmCorA is a highly selective Co2+ transporter, as it selects Co2+ over Mg2+ at >100 times lower concentrations. In addition, we present data that show TmCorA to be extremely thermostable in the presence of Co2+. Mg2+ could not stabilize the protein to the same extent, even at high concentrations. We also show that addition of Co2+, but not Mg2+, specifically induces structural changes to the protein. Altogether, these data show that TmCorA has the role of being the transporter of Co2+ but not Mg2+. The physiological relevance and requirements of Co2+ in T. maritima is discussed and highlighted. We suggest that CorA may have different roles in different organisms. Such functional diversity is presumably a reflection of minor, but important structural differences within the CorA family that regulate the gating, substrate selection, and transport.

scholarly journals Oxidized LDLs as Signaling Molecules

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1184
Author(s):  
Jean-Marc Zingg ◽  
Adelina Vlad ◽  
Roberta Ricciarelli
Keyword(s):  
Free Radicals ◽  
Cellular Response ◽  
Vascular System ◽  
Signaling Molecules ◽  
Scavenger Receptors ◽  
Physiological Relevance ◽  
Reactive Radicals ◽  
Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

scholarly journals Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

1997 ◽  
Vol 186 (7) ◽  
pp. 999-1014 ◽  
Author(s):  
Hideaki Ishikawa ◽  
Daniel Carrasco ◽  
Estefania Claudio ◽  
Rolf-Peter Ryseck ◽  
Rodrigo Bravo
Keyword(s):  
T Cells ◽  
Lymphocyte Proliferation ◽  
Cytokine Production ◽  
Cell Types ◽  
Homozygous Deletion ◽  
Binding Activity ◽  
Activated T Cells ◽  
Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

scholarly journals Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4800-4812 ◽  
Author(s):  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Ana I. Pozo-Salas ◽  
Antonio J. Martínez-Fuentes ◽  
Luis de Lecea ◽  
...  
Keyword(s):  
Metabolic Phenotype ◽  
Somatostatin Analogue ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ancestral Gene ◽  
Ghrelin Receptor ◽  
Physiological Relevance

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

scholarly journals In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol

2011 ◽  
Vol 4 (2) ◽  
pp. 78-84 ◽  
Author(s):  
Galia Zamaratskaia ◽  
Martin Rasmussen ◽  
Isabelle Herbin ◽  
Bo Ekstrand ◽  
Vladimir Zlabek
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Effect ◽  
17Β Estradiol ◽  
Cyp2e1 Activity ◽  
High Concentrations ◽  
Testicular Steroids ◽  
Sexually Mature

In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol Sexually mature pigs are known to possess high concentrations of testicular steroids, which have been shown to change the activities of cytochrome P450 in vitro. The aim of the present study was to evaluate the regulation of CYP1A and CYP2E1 activity by the steroids dihydrotestosterone (DHT), 3β-androstenol, 17β-estradiol and 17α-estradiol. Catalytic activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) were used as markers of CYP1A activities, while p-nitrophenol hydroxylase (PNPH) was used as a marker of CYP2E1 activities. Of the steroids tested, only 17β-estradiol and 17α-estradiol inhibited EROD and MROD activities. This inhibition was observed when a steroid concentration of 100 μM was used, while lower concentrations showed no inhibitory effect. PNPH activities were inhibited only by 100 μM of 17β-estradiol. The significance of these results in vivo is unknown because inhibition was only found when concentrations of estrogens higher than physiological levels were used. Nevertheless, the results provided further evidence on the important role of estrogens in regulation of porcine cytochrome P450 activities.

scholarly journals Role of Emollients in Prevention of the Comorbid Allergic Diseases Development in Children with Atopic Dermatitis

2020 ◽  
Vol 17 (4) ◽  
pp. 334-339
Author(s):  
Nikolay N. Murashkin ◽  
Roman A. Ivanov ◽  
Dmitri V. Fedorov ◽  
Eduard T. Ambarchyan ◽  
Roman V. Epishev ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Inflammatory Diseases ◽  
Allergic Diseases ◽  
Main Role ◽  
Social Maladjustment ◽  
Active Components ◽  
Epidermal Barrier ◽  
New Class

Atopic dermatitis (AD) is one of the common multifactorial inflammatory diseases manifesting predominantly in childhood. There is significant number of cases of self-regression of the disease with aging. On the other hand, there is also another scenario ending with AD persistent course and/or development of comorbid allergic pathologies that can significantly worsen patient’s quality of life and finally lead to social maladjustment. The pathogenesis of such way includes epidermal barrier disturbance, transcutaneous sensibilisation and aberrant allergic (Th2) immune systemic response development. Main role in preventing of this pathological pathway is lying on the new class of moisturizers containing active components "emollients plus". They are considered as foundation for the therapy and prevention of the development of AD and other allergic diseases. This literature review provides relevant data on AD pathogenesis and development of comorbid allergic pathologies. This paper also covers data on the effect of emollients in restoration of the epidermal barrier and their use as preventive measures.

scholarly journals Regulation of Expression and Latency in BLV and HTLV

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1079
Author(s):  
Aneta Pluta ◽  
Juan P. Jaworski ◽  
Renée N. Douville
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Spastic Paraparesis ◽  
Viral Gene ◽  
Regulation Of Transcription ◽  
Main Role ◽  
Regulation Of Expression ◽  
Incurable Cancer

Human T-lymphotrophic virus type 1 (HTLV-1) and Bovine leukemia virus (BLV) belong to the Deltaretrovirus genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 5′ long terminal repeats (5′-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the cis-elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against Deltaretroviruses.

scholarly journals ICAMs Redistributed by Chemokines to Cellular Uropods as a Mechanism for Recruitment of T Lymphocytes

1997 ◽  
Vol 137 (2) ◽  
pp. 493-508 ◽  
Author(s):  
Miguel Angel del Pozo ◽  
Carlos Cabañas ◽  
María C. Montoya ◽  
Ann Ager ◽  
Paloma Sánchez-Mateos ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Fold Increase ◽  
Time Lapse ◽  
Cell Recruitment ◽  
T Cell Migration ◽  
Physiological Relevance ◽  
Amplification System

The recruitment of leukocytes from the bloodstream is a key step in the inflammatory reaction, and chemokines are among the main regulators of this process. During lymphocyte–endothelial interaction, chemokines induce the polarization of T lymphocytes, with the formation of a cytoplasmic projection (uropod) and redistribution of several adhesion molecules (ICAM-1,-3, CD43, CD44) to this structure. Although it has been reported that these cytokines regulate the adhesive state of integrins in leukocytes, their precise mechanisms of chemoattraction remain to be elucidated. We have herein studied the functional role of the lymphocyte uropod. Confocal microscopy studies clearly showed that cell uropods project away from the cell bodies of adhered lymphocytes and that polarized T cells contact other T cells through the uropod structure. Time-lapse videomicroscopy studies revealed that uropod-bearing T cells were able, through this cellular projection, to contact, capture, and transport additional bystander T cells. Quantitative analysis revealed that the induction of uropods results in a 5–10-fold increase in cell recruitment. Uropod-mediated cell recruitment seems to have physiological relevance, since it was promoted by both CD45R0+ peripheral blood memory T cells as well as by in vivo activated lymphocytes. Additional studies showed that the cell recruitment mediated by uropods was abrogated with antibodies to ICAM-1, -3, and LFA-1, whereas mAb to CD43, CD44, CD45, and L-selectin did not have a significant effect, thus indicating that the interaction of LFA-1 with ICAM-1 and -3 appears to be responsible for this process. To determine whether the increment in cell recruitment mediated by uropod may affect the transendothelial migration of T cells, we carried out chemotaxis assays through confluent monolayers of endothelial cells specialized in lymphocyte extravasation. An enhancement of T cell migration was observed under conditions of uropod formation, and this increase was prevented by incubation with either blocking anti– ICAM-3 mAbs or drugs that impair uropod formation. These data indicate that the cell interactions mediated by cell uropods represent a cooperative mechanism in lymphocyte recruitment, which may act as an amplification system in the inflammatory response.

scholarly journals Essentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Maria J. Bueno ◽  
Veronica Jimenez-Renard ◽  
Sara Samino ◽  
Jordi Capellades ◽  
Alejandra Junza ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Krebs Cycle ◽  
Tumor Development ◽  
Three Dimensional ◽  
Main Role ◽  
Prevention Studies ◽  
The Media

Abstract Upregulation of fatty acid synthase (FASN) is a common event in cancer, although its mechanistic and potential therapeutic roles are not completely understood. In this study, we establish a key role of FASN during transformation. FASN is required for eliciting the anaplerotic shift of the Krebs cycle observed in cancer cells. However, its main role is to consume acetyl-CoA, which unlocks isocitrate dehydrogenase (IDH)-dependent reductive carboxylation, producing the reductive power necessary to quench reactive oxygen species (ROS) originated during the switch from two-dimensional (2D) to three-dimensional (3D) growth (a necessary hallmark of cancer). Upregulation of FASN elicits the 2D-to-3D switch; however, FASN's synthetic product palmitate is dispensable for this process since cells satisfy their fatty acid requirements from the media. In vivo, genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth. These results render FASN as a potential target for cancer prevention studies.

scholarly journals New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

2020 ◽  
Vol 21 (22) ◽  
pp. 8718
Author(s):  
Alessandro Usiello ◽  
Maria Maddalena Di Fiore ◽  
Arianna De Rosa ◽  
Sara Falvo ◽  
Francesco Errico ◽  
...  
Keyword(s):  
Animal Studies ◽  
Endocrine System ◽  
Postnatal Life ◽  
Functional Development ◽  
The Central Nervous System ◽  
High Concentrations ◽  
System Physiology ◽  
Metabolizing Enzyme

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

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