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At least 127 records · Page 7Linked to original sources

PubMed2006

Adipose tissue in offspring of Lepr(db/+) mice: early-life environment vs. genotype.

Gravidas with obesity and diabetes ("diabesity") may transmit this syndrome to their children through genetic and nongenetic mechanisms. Here, we used the Lepr(db/+) diabese mouse to examine the magnitude of these transmission modes, focusing on adipose tissue (AT). We compared the following six groups: wild-type (+/+) offspring from +/+ or db/+ dams (different early life environment) and db/+ offspring from db/+ dams, fed a standard or high-fat diet. Weight gain (0-8 wk) was higher in +/+ offspring from db/+ vs. +/+ mothers, and even higher in db/+ vs. +/+ offspring from db/+ mothers. In addition, we observed a stepwise increase in AT and adipocyte size in +/+ from +/+ mice, +/+ from db/+ mice, and db/+ mice at 8 wk. Differences in weight and adiposity between +/+ offspring from db/+ vs. +/+ dams were more pronounced in males than in females. Leptin and apelin mRNA levels in white and brown AT were higher in +/+ offspring from db/+ vs. +/+ dams; however, leptin, apelin, and tumor necrosis factor-alpha expression were boosted more robustly in db/+ offspring. The high-fat diet amplified AT differences between db/+ vs. +/+ offspring from db/+ dams, but not between +/+ offspring from db/+ vs. +/+ dams. Moreover, db/+ but not +/+ offspring from db/+ mothers were insulin-resistant and hyperinsulinemic after a glucose challenge. In conclusion, the genetic transmission of the diabesity phenotype clearly prevailed, but the early-life diabesity environment had discernible effects on postnatal weight gain as well as on adipocyte size and adipokine expression at a postpubertal age.

Adipose Tissue↗

PubMed2000

Expression and coreceptor function of APJ for primate immunodeficiency viruses.

APJ is a seven transmembrane domain G-protein-coupled receptor that functions as a coreceptor for some primate immunodeficiency virus strains. The in vivo significance of APJ coreceptor function remains to be elucidated, however, due to the lack of an antibody that can be used to assess APJ expression, and because of the absence of an antibody or ligand that can block APJ coreceptor activity. Therefore, we produced a specific monoclonal antibody (MAb 856) to APJ and found that it detected this receptor in FACS, immunofluorescence, and immunohistochemistry studies. MAb 856 also recognized APJ by Western blot, enabling us to determine that APJ is N-glycosylated. Using this antibody, we correlated APJ expression with coreceptor activity and found that APJ had coreceptor function even at low levels of expression. However, we found that APJ could not be detected by FACS analysis on cell lines commonly used to propagate primate lentiviruses, nor was it expressed on human PBMC cultured under a variety of conditions. We also found that some viral envelope proteins could mediate fusion with APJ-positive, CD4-negative cells, provided that CD4 was added in trans. These findings indicate that in some situations APJ use could render primary cell types susceptible to virus infection, although we have not found any evidence that this occurs. Finally, the peptide ligand for APJ, apelin-13, efficiently blocked APJ coreceptor activity.

Adipokines↗

PubMed2003

Discovering orphan receptor function using human in vitro pharmacology.

mRNA encoding several recently discovered orphan receptors and their putative ligands has been identified in human tissues, suggesting the existence of new transmitter systems that may be important in the regulation of human cardiac and vascular function. Data obtained from in vitro pharmacological studies using healthy and pathological surgical samples of human arteries, veins and heart muscle are proving advantageous in the identification and characterisation of orphan receptor systems, such as urotensin-II, ghrelin, apelin and relaxin, which are most likely to provide novel targets for drugs to treat human cardiovascular disease.

Animals↗

PubMed2000

Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells.

APJ is a recently described seven-transmembrane (7TM) receptor that is abundantly expressed in the central nervous system (CNS). This suggests an important role for APJ in neural development and/or function, but neither its cellular distribution nor its function have been defined. APJ can also serve as a co-receptor with CD4 for fusion and infection by some strains of human immunodeficiency virus (HIV-1) in vitro, suggesting a role in HIV neuropathogenesis if it were expressed on CD4-positive CNS cells. To address this, we examined APJ expression in cultured neurons, astrocytes, oligodendrocytes, microglia and monocyte-derived macrophages utilizing both immunocytochemical staining with a polyclonal anti-APJ antibody and RT - PCR. We also analyzed the ability of a recently identified APJ peptide ligand, apelin, to induce calcium elevations in cultured neural cells. APJ was expressed at a high level in neurons and oligodendrocytes, and at lower levels in astrocytes. In contrast, APJ was not expressed in either primary microglia or monocyte-derived macrophages. Several forms of the APJ peptide ligand induced calcium elevations in neurons. Thus, APJ is selectively expressed in certain CNS cell types and mediates intracellular signals in neurons, suggesting that APJ may normally play a role in signaling in the CNS. However, the absence of APJ expression in microglia and macrophages, the prinicpal CD4-positive cell types in the brain, indicates that APJ is unlikely to mediate HIV-1 infection in the CNS.

Adult↗

PubMed2004

[Role of novel G-protein-coupled receptors and their ligands in the cardiovascular system].

INTRODUCTION: Despite current drug therapies, cardiovascular disease remains the major cause of morbidity and mortality, which suggests that yet unknown transmitter systems might be also involved in this disease. AIMS: Recent years discoveries have mainly focused on the most common type of cardiac receptors--the seven-transmembrane-spanning G-protein coupled receptors. mRNA encoding several recently discovered, orphan' receptors and their putative ligands has been identified in human tissues such as heart, vessels and plasma. RESULTS: Data obtained from in vitro pharmacological studies using healthy and pathological surgical samples of human arteries, veins and heart muscle as well as from subsequent in vivo studies are proving advantageous in characterization of potent vasoactive and direct cardiac effects of these peptide ligands, such as apelin, relaxin, ghrelin, and urotensin II. These novel peptides also have a clinical relevance as they are shown to be differentially expressed in human heart failure. CONCLUSIONS: The pharmacological characterization of these emerging peptide-receptor systems is therefore a tantalizing area of cardiovascular research, with the prospect of identifying new diagnostic and therapeutic targets.

Animals↗

PubMed2025

Multiomics Analysis Reveals Therapeutic Targets for Chronic Kidney Disease With Sarcopenia.

BACKGROUND: The presence of sarcopenia in patients with chronic kidney disease (CKD) is associated with poor prognosis. The mechanism underlying CKD-induced muscle wasting has not yet been fully explored. This study investigates the influence of renal secretions on muscles using multiomics sequencing. METHODS: The kidney transcriptome analysis by RNA-seq and protein profiling by tandem mass tag (TMT), serum TMT and muscle TMT were performed in CKD established using 0.2% adenine and control mice. Spp1 recombinant protein was used to study its effect on myotube atrophy in vitro. In animal experiments on CKD, pharmacological inhibition of Spp1 was used to explore the role of Spp1 in skeletal muscle wasting. Transcriptome analysis was performed to identify differentially expressed genes (DEGs) in the gastrocnemius muscle following Spp1 pharmacological inhibition. RESULTS: In the renal transcriptome and TMT, 503 and 377 proteins/genes respectively were co-upregulated and co-downregulated. In the serum TMT of CKD and normal control (NC) mice, 22 upregulated and 7 downregulated differentially expressed proteins (DEPs) showed the same expression patterns as those in the kidney transcriptome and TMT analysis. Based on bioinformatics analysis and reported studies, we selected Spp1 for further validation. Spp1 recombinant protein was added to C2C12 myotubes in vitro, and the results indicated that Spp1 significantly increased the protein levels of the muscle atrophy marker (Murf-1) and promoted the smaller myotubes (all p < 0.05). Compared with NC mice, Spp1 mRNA and protein levels were significantly upregulated in the kidneys of CKD mice, and the serum concentration of Spp1 was also markedly increased (all p < 0.05). In animal experiments, pharmacological inhibition of Spp1 increased the weights of gastrocnemius and tibialis anterior muscles (p < 0.05) and improved muscle atrophy phenotype. Transcriptome analysis showed that DEGs in the gastrocnemius muscle following Spp1 pharmacological inhibition were enriched in protein digestion and absorption, glucagon signalling pathway, apelin signalling pathway and ECM-receptor interaction pathway. CONCLUSIONS: Our study is the first to establish a regulatory network of kidney-muscle crosstalk to explore the potential mechanism of CKD-related sarcopenia. Employing multiomics analysis, cellular assessment and animal experiments, we have identified that Spp1 could potentialy serve as a promising therapeutic target for CKD patients with sarcopenia.

Sarcopenia↗

PubMed2004

Angiotensin-converting enzyme-2: a molecular and cellular perspective.

Angiotensin-converting enzyme-2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein which functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the C-terminus of its substrates. ACE2 efficiently hydrolyses the potent vasoconstrictor angiotensin II to angiotensin (1-7). It is a consequence of this action that ACE2 participates in the renin-angiotensin system. However, ACE2 also hydrolyses dynorphin A (1-13), apelin-13 and des-Arg(9) bradykinin. The role of ACE2 in these peptide systems has yet to be revealed. A physiological role for ACE2 has been implicated in hypertension, cardiac function, heart function and diabetes, and as a receptor of the severe acute respiratory syndrome coronavirus. This paper reviews the biochemistry of ACE2 and discusses key findings such as the elucidation of crystal structures for ACE2 and testicular ACE and the development of ACE2 inhibitors that have now provided a basis for future research on this enzyme.

Angiotensin-Converting Enzyme 2↗

PubMed2005

Rethinking the renin-angiotensin system and its role in cardiovascular regulation.

Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE(2) has been discovered. Both ACE and ACE(2) are emerging as key enzymes of the RAS, where ACE(2) may play a role as negative regulator of ACE. Moreover, ACE(2) appears to be an important enzyme outside the classical RAS, as it hydrolyzes apelins, dynorphin A 1-13, des-Arg-bradykinin and other peptide substrates. The precise interplay between tissue ACE, ACE(2), and their substrates and by-products are presently still unclear.ACE-inhibitors reduce angiotensin II formation and bradykinin degradation, but do not inhibit ACE(2) activity. Moreover, ACE-inhibitors differ in their affinity for tissue ACE, and it has been suggested that tissue ACE affinity might be responsible for some of the beneficial properties of these drugs. ACE-inhibitors also increase nitric oxide availability, and activate several kinases that may regulate protein synthesis by interacting with the nucleus of the cells (outside-in signaling). The outside-in signaling may also be activated by bradykinin itself. Although, the precise significance of the outside-in signaling is still unclear, this new role of ACE-inhibitors may represent a discriminant factor versus angiotensin II receptors antagonists. This mini review will summarize some new aspects concerning the recently discovered biological functions of RAS and in particular of ACE, ACE(2) and ACE-inhibitors in cardiovascular system.

Angiotensin II↗

PubMed2005

Angiogenesis and rhodopsin-like receptors: a role for N-terminal acidic residues?

Numerous rhodopsin-like G-protein coupling receptors induce or inhibit angiogenesis. The active human receptors include several chemokine receptors, apelin APJ receptor, neuropeptide Y Y2 receptor, Duffy antigen, and herpes virus-8 receptor. A common and striking feature of these receptors is the large fraction (up to 42%) of residues with anionic sidechains (Asp, Glu, and benzene anions Tyr, Trp, and Phe) in the N-terminal extracellular domain. These residues (which are frequently clustered) can assist the binding of ligand peptides, but should also support interactions that help tubular arraying of cells, e.g., via cationic bridges and/or hydrogen bonding with cell-connecting receptors such as integrins, or with proteins of the extracellular matrix.

Amino Acid Sequence↗

PubMed2006

Gene expression profiling of renal dysfunction in rats with experimental cirrhosis.

BACKGROUND/AIMS: Renal dysfunction is a frequent complication in advanced cirrhosis. The mechanisms underlying this complication have classically been addressed through conventional methods of study of candidate genes, but never on a genome-wide scale. In this investigation, we used microarrays to monitor global gene expression changes in the kidney of cirrhotic rats. METHODS: Renal samples were obtained from control and carbon tetrachloride-induced cirrhotic rats. RNA samples were reverse-transcribed into Cy5-labeled cDNA, combined with a Cy3-labeled reference and hybridized to oligonucleotide microarrays. Microarrays were scanned in a Genepix 4000B and data analyzed by Luminator v2.0 software. RESULTS: A total of 620 genes were differentially regulated (354 up and 266 down) in the cirrhotic kidney, accounting for approximately 11% of all analyzed transcripts. Functional grouping of these genes revealed that 47 were related to the category of vascular tone and 85 to transporters/channels. Among these, we identified genes and pathways already associated with renal dysfunction as well as a new subset of genes previously unknown to participate in this complication, including a G protein-coupled receptor that binds apelin, a protein phosphatase (calcineurin B) and a number of neuropeptide receptors and growth factors. CONCLUSIONS: These findings furnish new data for mechanistic investigation into renal dysfunction in cirrhosis.

Animals↗

PubMed2006

Zebrafish Angiotensin II Receptor-like 1a (agtrl1a) is expressed in migrating hypoblast, vasculature, and in multiple embryonic epithelia.

The human gene AGTRL1 is an angiotensin II receptor-like gene expressed in vasculature, which acts as the receptor for the small peptide APELIN, and a co-receptor for Human Immunodeficiency Virus. Mammalian AGTRL1 has been shown to modulate cardiac contractility, venous and arterial dilation, and endothelial cell migration in vitro, but no role in the development of the vasculature, or other tissues, has been described. We report the identification and expression of the zebrafish ortholog of the human gene AGTRL1. Zebrafish agtrl1a is first expressed before epiboly in dorsal precursors. During epiboly it is expressed in the enveloping layer, yolk syncytial layer and migrating mesendoderm. During segmentation stages, expression is observed in epithelial structures such as adaxial cells, border cells of the newly formed somites, developing lens, otic vesicles and venous vasculature.

Amino Acid Sequence↗

PubMed2005

Regulation of vascular reactivity by established and emerging GPCRs.

The vascular system is rich in G-protein-coupled receptors (GPCRs), particularly Class 1 GPCRs, which are activated by an eclectic range of chemical entities including peptides. These chemical messengers can function in blood vessels as directly acting vasoconstrictors, directly acting vasodilators or indirectly acting vasodilators. During the past ten years >50 receptors previously designated as 'orphan receptors' have been paired with their cognate ligands. New transmitter systems are emerging with some displaying potent activity in the vascular system, including the vasoconstrictors apelin, motilin, neuromedin U, sphingosine-1-phosphate and urotensin-II, and the vasodilators ghrelin and nociceptin. All Class 2 GPCRs are activated by peptides. Those displaying vasoactivity all function as directly acting vasodilators and include adrenomedullin and the emerging urocortin transmitters. Hypertension can persist despite treatment with combinations of blood-pressure-lowering drugs. Thus, it is likely that further as yet undiscovered transmitter systems will provide new targets for novel therapies or diagnosis.

Animals↗

PubMed2003

Emerging roles for orphan G-protein-coupled receptors in the cardiovascular system.

Despite current drug therapies, including those that target enzymes, channels and known G-protein-coupled receptors (GPCRs), cardiovascular disease remains the major cause of ill health, which suggests that other transmitter systems might be involved in this disease. In humans, approximately 175 genes have been predicted to encode 'orphan' GPCRs, where the endogenous ligand is not yet known. As a result of intensive screening using 'reverse pharmacology', an increasing number of orphan receptors are being paired with their cognate ligands, many of which are peptides. The existence of some of these peptides such as urotensin-II and relaxin had been known for some time but others, including ghrelin and apelin, represent novel sequences. The pharmacological characterization of these emerging peptide-receptor systems is a tantalising area of cardiovascular research, with the prospect of identifying new therapeutic targets.

Animals↗

PubMed2003

The role of ACE2 in cardiovascular physiology.

The renin-angiotensin system (RAS) is critically involved in cardiovascular and renal function and in disease conditions, and has been shown to be a far more complex system than initially thought. A recently discovered homologue of angiotensin-converting enzyme (ACE)--ACE2--appears to negatively regulate the RAS. ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively. ACE2 is highly expressed in kidney and heart and is especially confined to the endothelium. With quantitative trait locus (QTL) mapping, ACE2 was defined as a QTL on the X chromosome in rat models of hypertension. In these animal models, kidney ACE2 messenger RNA and protein expression were markedly reduced, making ACE2 a candidate gene for this QTL. Targeted disruption of ACE2 in mice failed to elicit hypertension, but resulted in severe impairment in myocardial contractility with increased angiotensin II levels. Genetic ablation of ACE in the ACE2 null mice rescued the cardiac phenotype. These genetic data show that ACE2 is an essential regulator of heart function in vivo. Basal renal morphology and function were not altered by the inactivation of ACE2. The novel role of ACE2 in hydrolyzing several other peptides-such as the apelin peptides, opioids, and kinin metabolites-raises the possibility that peptide systems other than angiotensin and its derivatives also may have an important role in regulating cardiovascular and renal function.

Angiotensin II↗

PubMed2003

Peptide and trace amine orphan receptors: prospects for new therapeutic targets.

Over 20 orphan receptors predicted to exist from the human genome have now been paired with their cognate peptide ligand. In human tissues, expression of mRNA encoding several of these peptides (including bovine adrenomedullary peptide, orexins, prolactin-releasing peptide, tuberoinfundibular peptide 39 and neuropeptide B and W) and their receptors is predominantly in the CNS, implying a central role. However, ligand-binding and functional studies suggest that urotensin II, apelin, ghrelin, relaxin and urocortins, together with the trace amine tyramine, may have a role in the human cardiovascular system, with the prospect of becoming new therapeutic targets.

Animals↗

PubMed2002

Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.

Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog is angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its catalytic activity was characterized. ACE2 proteolytic activity has a pH optimum of 6.5 and is enhanced by monovalent anions, which is consistent with the activity of ACE. ACE2 activity is increased approximately 10-fold by Cl(-) and F(-) but is unaffected by Br(-). ACE2 was screened for hydrolytic activity against a panel of 126 biological peptides, using liquid chromatography-mass spectrometry detection. Eleven of the peptides were hydrolyzed by ACE2, and in each case, the proteolytic activity resulted in removal of the C-terminal residue only. ACE2 hydrolyzes three of the peptides with high catalytic efficiency: angiotensin II () (k(cat)/K(m) = 1.9 x 10(6) m(-1) s(-1)), apelin-13 (k(cat)/K(m) = 2.1 x 10(6) m(-1) s(-1)), and dynorphin A 1-13 (k(cat)/K(m) = 3.1 x 10(6) m(-1) s(-1)). The ACE2 catalytic efficiency is 400-fold higher with angiotensin II () as a substrate than with angiotensin I (). ACE2 also efficiently hydrolyzes des-Arg(9)-bradykinin (k(cat)/K(m) = 1.3 x 10(5) m(-1) s(-1)), but it does not hydrolyze bradykinin. An alignment of the ACE2 peptide substrates reveals a consensus sequence of: Pro-X((1-3 residues))-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid.

Amino Acid Sequence↗

PubMed2006

Endocrine receptors as targets for new drugs.

Increasingly detailed knowledge of cellular signalling pathways is providing a sound basis for the development of specific drugs aimed at selected components of the pathways. Many of these targets are receptors and the multitude of hormone receptors makes endocrine functions a rich proving ground for this research. This article reviews a recent meeting (Insights into Receptor Function and New Drug Development Targets; 5th Endocrinology Colloquium of the Fondation Ipsen, Paris, December 5, 2005) where progress in defining suitable targets for drug therapies in the endocrine system and in designing drugs for some of these targets was discussed. Although the family of G-protein-coupled receptors, ubiquitous in the endocrine system, was the central focus, comparisons with other receptor families were made. Many mutations affecting genes coding for receptors or other components of signalling pathways have been found in a wide range of endocrine disorders including obesity, parathyroid malfunction, disorders involving thyroid-stimulating hormone and follicle-stimulating hormone, and tumours in the anterior pituitary, as well as in many types of cancer. These are being used to dissect the normal control mechanisms as well as to provide information for the development of selective drugs. Recently identified mutations that affect the intracellular traffic in newly synthesised receptors open up possibilities of another dimension of cellular regulation of signalling. Both the discovery of hormones such as apelin and its pairing with an 'orphan' receptor, and the unexpected action of a drug against cannabinoid receptors point to further levels of complexity in cardiovascular regulation. Deeper understanding of the evolution of receptor families and of the molecular mechanisms of signal transduction is enabling the design of highly specific agonists and antagonists. Pharmacological intervention is not limited to the ligand-receptor interaction but can extend to inhibition of selected steps in the intracellular pathway, such as the regulation of G protein deactivation. The progress in this area is both leading to improved treatment for a range of endocrine disorders and serving as a model for the study of signalling in other physiological systems.

Animals↗

PubMed2024

Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Humans↗