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Article ; Online: The discovery, structure, and function of 5-HTR1E serotonin receptor.

Sharma, Vinay Kumar / Loh, Y Peng

2023 Volume 21, Issue 1, Page(s) 235

Abstract: Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These serotonin receptors are divided into seven different classes based on their structure and ...

Abstract	Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These serotonin receptors are divided into seven different classes based on their structure and functions. Since these receptors co-express in various tissue and cell types and share the same ligand (5-HT), it has been a challenge for the researchers to define specific pathway and separate physiological role for each of these serotonin receptors. Though the evidence of operational diversity of these receptors is continuously emerging, much work remains to be done. 5-HTR1E is a member of 5-HT1 receptor family which belongs to G-protein coupled receptors (GPCRs). Even after three decades since its discovery, 5-HTR1E remains the least explored serotonin receptor. Very high similarity with another family member (5-HTR1F) and its non-existence in mice or rats makes 5-HTR1E a difficult target to study. Despite these challenges, recent findings on the role of 5-HTR1E in neuroprotection and diseases such as cancer, have excited many researchers to explore this receptor in detail. Here, we provide the first review of 5-HTR1E, since its discovery in 1989 to 2023. We highlight the structural and functional characteristics of this important serotonin receptor in detail and propose future directions in developing 5-HTR1E as a drug target. Video Abstract.
MeSH term(s)	Animals ; Mice ; Rats ; Serotonin ; Receptors, Serotonin ; Drug Delivery Systems
Chemical Substances	Serotonin (333DO1RDJY) ; Receptors, Serotonin
Language	English
Publishing date	2023-09-18
Publishing country	England
Document type	Video-Audio Media ; Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-023-01195-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Silencing of Carboxypeptidase E expression inhibits proliferation and invasion of Panc-1 pancreatic cancer cells [version 2; peer review

Y Peng Loh / Hong Lou

F1000Research, Vol

2 approved]

2022 Volume 10

Abstract: Background: Pancreatic cancer is one of the leading cause of cancer-related death globally. The molecular basis of this disease is complex and not fully understood. Previous studies have indicated that carboxypeptidase E (CPE) plays a role in promoting ... ...

Abstract	Background: Pancreatic cancer is one of the leading cause of cancer-related death globally. The molecular basis of this disease is complex and not fully understood. Previous studies have indicated that carboxypeptidase E (CPE) plays a role in promoting tumorigenesis in many cancer types. Here we have investigated the effect of carboxypeptidase E (CPE), including its isoform, in regulating the proliferation, migration and invasion of Panc-1 cells, a pancreatic cell line. Methods: Panc-1 cells were transfected with CPE siRNA which targets both CPE-wild type and its isoform, or scrambled siRNA, for 24 h and then assayed for proliferation by the MTT and colony formation assays, and migration and invasion by wound healing and matrigel assays, respectively. Results: CPE siRNA treatment of Panc-1 cells down-regulated the expression of CPE mRNA by 94.8%. Silencing of CPE mRNA expression resulted in a significant decrease in proliferation as revealed by the MTT assay and a 62.8% decrease in colony formation. Western blot analysis of expression of Cyclin D1 in Panc-1 cells treated with CPE siRNA showed a decrease of 32.5% compared to scr siRNA treated cells, indicating that CPE regulates proliferation through modulating this cell cycle protein. Additionally, suppression of CPE expression in Panc-1 cells significantly decreased migration and invasion. Conclusions: Our findings indicate that CPE may play an important role in regulating cell proliferation, migration and invasion to promote pancreatic cancer tumorigenesis.
Keywords	Carboxypeptidase E ; pancreatic cancer ; cell proliferation ; cell migration ; cell invasion ; eng ; Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Trafficking of hormones and trophic factors to secretory and extracellular vesicles: a historical perspective and new hypothesis.

Loh, Y Peng / Xiao, Lan / Park, Joshua J

Extracellular vesicles and circulating nucleic acids

2023 Volume 4, Issue 4, Page(s) 568–587

Abstract: It is well known that peptide hormones and neurotrophic factors are intercellular messengers that are packaged into secretory vesicles in endocrine cells and neurons and released by exocytosis upon the stimulation of the cells in a calcium-dependent ... ...

Abstract	It is well known that peptide hormones and neurotrophic factors are intercellular messengers that are packaged into secretory vesicles in endocrine cells and neurons and released by exocytosis upon the stimulation of the cells in a calcium-dependent manner. These secreted molecules bind to membrane receptors, which then activate signal transduction pathways to mediate various endocrine/trophic functions. Recently, there is evidence that these molecules are also in extracellular vesicles, including small extracellular vesicles (sEVs), which appear to be taken up by recipient cells. This finding raised the hypothesis that they may have functions differentiated from their classical secretory hormone/neurotrophic factor actions. In this article, the historical perspective and updated mechanisms for the sorting and packaging of hormones and neurotrophic factors into secretory vesicles and their transport in these organelles for release at the plasma membrane are reviewed. In contrast, little is known about the packaging of hormones and neurotrophic factors into extracellular vesicles. One proposal is that these molecules could be sorted at the trans-Golgi network, which then buds to form Golgi-derived vesicles that can fuse to endosomes and subsequently form intraluminal vesicles. They are then taken up by multivesicular bodies to form extracellular vesicles, which are subsequently released. Other possible mechanisms for packaging RSP proteins into sEVs are discussed. We highlight some studies in the literature that suggest the dual vesicular pathways for the release of hormones and neurotrophic factors from the cell may have some physiological significance in intercellular communication.
Language	English
Publishing date	2023-11-09
Publishing country	United States
Document type	Journal Article
DOI	10.20517/evcna.2023.34
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Article ; Online: Silencing of Carboxypeptidase E expression inhibits proliferation and invasion of Panc-1 pancreatic cancer cells.

Lou, Hong / Loh, Y Peng

F1000Research

2021 Volume 10, Page(s) 489

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Carboxypeptidase H/genetics ; Carboxypeptidase H/metabolism ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Pancreatic Neoplasms/genetics ; RNA, Messenger ; RNA, Small Interfering/genetics ; Pancreatic Neoplasms
Chemical Substances	RNA, Messenger ; RNA, Small Interfering ; Carboxypeptidase H (EC 3.4.17.10)
Language	English
Publishing date	2021-06-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2699932-8
ISSN	2046-1402 ; 2046-1402
ISSN (online)	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.53737.2
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Article ; Online: Carboxypeptidase E and its splice variants: Key regulators of growth and metastasis in multiple cancer types.

Hareendran, Sangeetha / Yang, Xuyu / Sharma, Vinay Kumar / Loh, Y Peng

Cancer letters

2022 Volume 548, Page(s) 215882

Abstract: Mechanisms driving tumor growth and metastasis are complex, and involve the recruitment of many genes working in concert with each other. The tumor is characterized by the expression of specific sets of genes depending on its environment. Here we review ... ...

Abstract	Mechanisms driving tumor growth and metastasis are complex, and involve the recruitment of many genes working in concert with each other. The tumor is characterized by the expression of specific sets of genes depending on its environment. Here we review the role of the carboxypeptidase E (CPE) gene which has been shown to be important in driving growth, survival and metastasis in many cancer types. CPE was first discovered as a prohormone processing enzyme, enriched in endocrine tumors, and later found to be expressed and secreted from many epithelial-derived tumors and cancer cell lines. Numerous studies have shown that besides wild-type CPE, a N-terminal truncated splice variant form of CPE (CPE-ΔN) has been cloned and found to be highly expressed in malignant tumors and cell lines derived from prostate, breast, liver and lung cancers and gliomas. The mechanisms of action of CPE and the splice variant in promoting tumor growth and metastasis in different cancer types are discussed. Mechanistically, secreted CPE activates the Erk/wnt pathways, while CPE-ΔN interacts with HDACs in a protein complex in the nucleus, to recruit various cell cycle genes and metastatic genes, respectively. Clinical studies suggest that CPE and CPE-ΔN mRNA and protein are potential diagnostic and prognostic biomarkers for multiple cancer types, assayed using solid tumors and secreted serum exosomes. CPE has been shown to be a therapeutic target for multiple cancer types. CPE/CPE-ΔN siRNA transported via exosomes and taken up by recipient high metastatic cancer cells, suppressed growth and proliferation of these cells. Thus future studies, delivering CPE/CPE-ΔN siRNA, perhaps via exosomes, to the tumor could be a novel treatment approach to suppress tumor growth and metastasis.
MeSH term(s)	Biomarkers ; Carboxypeptidase H/genetics ; Carboxypeptidase H/metabolism ; Cell Line, Tumor ; Humans ; Male ; Neoplasms/genetics ; RNA, Messenger/genetics ; RNA, Small Interfering
Chemical Substances	Biomarkers ; RNA, Messenger ; RNA, Small Interfering ; Carboxypeptidase H (EC 3.4.17.10)
Language	English
Publishing date	2022-08-18
Publishing country	Ireland
Document type	Journal Article ; Review ; Research Support, N.I.H., Intramural
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2022.215882
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Zs.A 1177: Show issues

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Article: Function of exosomes in neurological disorders and brain tumors.

Xiao, Lan / Hareendran, Sangeetha / Loh, Y Peng

Extracellular vesicles and circulating nucleic acids

2021 Volume 2, Page(s) 55–79

Abstract: Exosomes are a subtype of extracellular vesicles released from different cell types including those in the nervous system, and are enriched in a variety of bioactive molecules such as RNAs, proteins and lipids. Numerous studies have indicated that ... ...

Abstract	Exosomes are a subtype of extracellular vesicles released from different cell types including those in the nervous system, and are enriched in a variety of bioactive molecules such as RNAs, proteins and lipids. Numerous studies have indicated that exosomes play a critical role in many physiological and pathological activities by facilitating intercellular communication and modulating cells' responses to external environments. Particularly in the central nervous system, exosomes have been implicated to play a role in many neurological disorders such as abnormal neuronal development, neurodegenerative diseases, epilepsy, mental disorders, stroke, brain injury and brain cancer. Since exosomes recapitulate the characteristics of the parental cells and have the capacity to cross the blood-brain barrier, their cargo can serve as potential biomarkers for early diagnosis and clinical assessment of disease treatment. In this review, we describe the latest findings and current knowledge of the roles exosomes play in various neurological disorders and brain cancer, as well as their application as promising biomarkers. The potential use of exosomes to deliver therapeutic molecules to treat diseases of the central nervous system is also discussed.
Language	English
Publishing date	2021-03-30
Publishing country	United States
Document type	Journal Article
DOI	10.20517/evcna.2021.04
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Article ; Online: Carboxypeptidase E conditional knockout mice exhibit learning and memory deficits and neurodegeneration.

Fan, Fang-Cheng / Du, Yang / Zheng, Wen-Hui / Loh, Y Peng / Cheng, Yong

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 135

Abstract: Carboxypeptidase E (CPE) is a multifunctional protein with many nonenzymatic functions in various systems. Previous studies using CPE knock-out mice have shown that CPE has neuroprotective effects against stress and is involved in learning and memory. ... ...

Abstract	Carboxypeptidase E (CPE) is a multifunctional protein with many nonenzymatic functions in various systems. Previous studies using CPE knock-out mice have shown that CPE has neuroprotective effects against stress and is involved in learning and memory. However, the functions of CPE in neurons are still largely unknown. Here we used a Camk2a-Cre system to conditionally knockout CPE in neurons. The wild-type, CPE
MeSH term(s)	Mice ; Animals ; Mice, Knockout ; Carboxypeptidase H/genetics ; Carboxypeptidase H/metabolism ; Hippocampus/metabolism ; Learning ; Memory Disorders/genetics ; Memory Disorders/metabolism ; Maze Learning/physiology
Chemical Substances	Carboxypeptidase H (EC 3.4.17.10)
Language	English
Publishing date	2023-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02429-y
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Article: Characterization of serotonin-5-HTR1E signaling pathways and its role in cell survival.

Sharma, Vinay Kumar / Campbell, Kiersten / Yang, Xuyu / Dale, Ryan / Loh, Y Peng

Research square

2023

Abstract: 5-Hydroxy tryptamine receptor 1E (5-HTR1E) is reported to activate cAMP and ERK ... ...

Abstract	5-Hydroxy tryptamine receptor 1E (5-HTR1E) is reported to activate cAMP and ERK pathways
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2518076/v1
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Article ; Online: Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer's Disease male mice.

Xiao, Lan / Yang, Xuyu / Sharma, Vinay Kumar / Abebe, Daniel / Loh, Y Peng

Molecular psychiatry

2023 Volume 28, Issue 8, Page(s) 3332–3342

Abstract: Alzheimer's Disease (AD) is a prevalent neurodegenerative disease characterized by tau hyperphosphorylation, Aβ1-42 aggregation and cognitive dysfunction. Therapeutic agents directed at mitigating tau aggregation and clearing Aβ1-42, and delivery of ... ...

Abstract	Alzheimer's Disease (AD) is a prevalent neurodegenerative disease characterized by tau hyperphosphorylation, Aβ1-42 aggregation and cognitive dysfunction. Therapeutic agents directed at mitigating tau aggregation and clearing Aβ1-42, and delivery of growth factor genes (BDNF, FGF2), have ameliorated cognitive deficits, but these approaches did not prevent or stop AD progression. Here we report that viral-(AAV) delivery of Neurotrophic Factor-α1/Carboxypeptidase E (NF-α1/CPE) gene in hippocampus at an early age prevented later development of cognitive deficits as assessed by Morris water maze and novel object recognition assays, neurodegeneration, and tau hyperphosphorylation in male 3xTg-AD mice. Additionally, amyloid precursor protein (APP) expression was reduced to near non-AD levels, and insoluble Aβ1-42 was reduced significantly. Pro-survival proteins: mitochondrial Bcl2 and Serpina3g were increased; and mitophagy inhibitor Plin4 and pro-inflammatory protein Card14 were decreased in AAV-NF-α1/CPE treated versus untreated AD mice. Thus NF-α1/CPE gene therapy targets many regulatory components to prevent cognitive deficits in 3xTg-AD mice and has implications as a new therapy to prevent AD progression by promoting cell survival, inhibiting APP overexpression and tau hyperphosphorylation.
MeSH term(s)	Mice ; Male ; Animals ; Alzheimer Disease/metabolism ; Carboxypeptidase H/genetics ; Carboxypeptidase H/metabolism ; Neurodegenerative Diseases/metabolism ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism ; Memory Disorders/genetics ; Memory Disorders/prevention & control ; Memory Disorders/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Nerve Growth Factors/metabolism ; Amyloidosis/genetics ; Amyloidosis/metabolism ; Amnesia/metabolism ; Mice, Transgenic ; Disease Models, Animal ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Carboxypeptidase H (EC 3.4.17.10) ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Nerve Growth Factors ; tau Proteins
Language	English
Publishing date	2023-06-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-023-02135-7
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Zs.A 4812: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Characterization of serotonin-5-HTR1E signaling pathways and its role in cell survival.

Sharma, Vinay Kumar / Campbell, Kiersten / Yang, Xuyu / Dale, Ryan / Loh, Y Peng

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 37, Issue 5, Page(s) e22925

Abstract: 5-Hydroxytryptamine receptor 1E (5-HTR1E) is reported to activate cyclic AMP (cAMP) and extracellular-signal related kinases (ERK) pathways via its ligands and binding partners, but the detailed mechanism underlying the serotonin-induced 5-HTR1E ... ...

Abstract	5-Hydroxytryptamine receptor 1E (5-HTR1E) is reported to activate cyclic AMP (cAMP) and extracellular-signal related kinases (ERK) pathways via its ligands and binding partners, but the detailed mechanism underlying the serotonin-induced 5-HTR1E signaling is still not known. In the present study, we determined the cellular regulators of ERK and cAMP signaling pathways in response to serotonin-induced 5-HTR1E activation in 5-HTR1E overexpressing HEK293 cells. We found that Pertussis Toxin (PTX) treatment completely reversed the effect of serotonin-5-HTR1E mediated signaling on cAMP and ERK pathways, confirming the involvement of a Gαi-linked cascade. We also observed that Gβγ and Gq were not associated with 5-HTR1E activation, while blocking protein kinase A (PKA) inhibited ERK signaling only, and had no effect on cAMP. Additionally, serotonin-stimulated ERK1/2 phosphorylation was similar in 5-HTR1E overexpressing, β-arrestin-deficient HEK293 cells and is solely dependent on G protein signaling. siRNA mediated gene knockdown studies in SH-SY5Y cells revealed that the inhibition of 5-HTR1E reduced the expression of cMyc, Cyclin D1, Cyclin E and BCL2 genes which are related to cell cycle regulation and survival. MTT assays showed that 5-HTR1E knockdown in SHSY-5Y and U118 cells inhibited cell survival significantly. In addition to the signaling mechanism, we also performed RNA-seq analysis in 5-HTR1E overexpressing HEK293 cells and found that 5-HTR1E can regulate the expression of Receptor activity modifying protein 1 (RAMP1), Nuclear receptor 1 (NR4A1) and other Cyclin genes. These findings indicate that serotonin interaction with 5-HTR1E receptor simultaneously activates cAMP and ERK pathway in HEK293 cells and its expression is important for cell survival.
MeSH term(s)	Humans ; Serotonin/pharmacology ; Serotonin/metabolism ; Cell Survival ; HEK293 Cells ; Neuroblastoma ; Signal Transduction ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Phosphorylation ; MAP Kinase Signaling System
Chemical Substances	Serotonin (333DO1RDJY) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202300128R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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