Topic Editors

Department of Hematologic Malignancies Translational Science, City of Hope, Monrovia, CA, USA
Dr. Vishnu Suresh Babu
Hematology/Oncology Division, Department of Medicine, University of California San Francisco, San Francisco, USA
Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA

Cell Signaling Pathways

Abstract submission deadline
closed (30 November 2022)
Manuscript submission deadline
closed (31 January 2023)
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Topic Information

Dear Colleagues,

Cell signaling or cell communication explores how a cell receives and sends messages to other cells in the environment to regulate its internal workings to survive. The study of cell signaling includes all biological disciplines, such as cancer biology, developmental biology, immunology, neurobiology, plant cell signaling and pathogenesis. Two major areas of cell signaling are membrane signaling initiated by membrane-bound receptors and signaling between and within intracellular compartments. The downstream effects of signaling pathways include enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, ubiquitinylation, and changes in gene expression. Despite emerging technical advances, a thorough apprehension of cell signaling pathways and their precise contributions to different biological disciplines is largely lacking. In this Topic, the most recent findings on the contribution of cell signaling pathways to developmental biology, cancer hallmarks, plant cell signaling, pathogenesis, immunology, homeostasis, endocrinology, and neurobiology will be outlined.

Dr. Majid Momeny
Dr. Vishnu Suresh Babu
Dr. Avisek Majumder
Topic Editors

Keywords

  • cancer
  • endocrinology
  • immunology
  • diabetes
  • neurobiology
  • development
  • pathogenesis
  • plant cell signaling
  • allergies
  • behavioral biology

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
Journal of Developmental Biology
jdb
2.7 3.7 2013 19.1 Days CHF 1800
Journal of Respiration
jor
- - 2021 21.9 Days CHF 1000
Pathogens
pathogens
3.7 5.1 2012 16.4 Days CHF 2700

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Published Papers (49 papers)

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9 pages, 250 KiB  
Review
Current Advances in Bovine In Vitro Maturation and Embryo Production Using Different Antioxidants: A Review
by Roksana Naspinska, Maria Helena Moreira da Silva and Fernando Moreira da Silva
J. Dev. Biol. 2023, 11(3), 36; https://doi.org/10.3390/jdb11030036 - 29 Aug 2023
Cited by 2 | Viewed by 1840
Abstract
In vitro maturation (IVM) is one of the most important steps in in vitro embryo production (IVEP). It is a complicated procedure in which nuclear and cytoplasmatic changes in oocytes appear. In order to carry out the in vitro maturation procedure correctly, it [...] Read more.
In vitro maturation (IVM) is one of the most important steps in in vitro embryo production (IVEP). It is a complicated procedure in which nuclear and cytoplasmatic changes in oocytes appear. In order to carry out the in vitro maturation procedure correctly, it is necessary to provide the oocytes with as close to a natural (in vivo) environment as possible. Many factors contribute to the overall poor quality of in vitro-matured oocytes. One important factor may be oxidative stress (OS). The generation of oxidants, such as reactive oxygen species, is common under culture conditions. The solution for OC treatment and prevention is antioxidants. In the last 5 years, many studies have examined different antioxidants and their effects on in vitro maturation of oocytes and embryo production. The aim of this systematic review was to present the achievements of scientific research in the last five years, in which the effects of many antioxidants were tested on bovine oocyte maturation and embryo production. Full article
(This article belongs to the Topic Cell Signaling Pathways)
34 pages, 6838 KiB  
Article
Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability
by Nafiseh Chalabi Hagkarim, Morteza Chalabi Hajkarim, Toru Suzuki, Toshinobu Fujiwara, G. Sebastiaan Winkler, Grant S. Stewart and Roger J. Grand
Cells 2023, 12(14), 1868; https://doi.org/10.3390/cells12141868 - 17 Jul 2023
Viewed by 1671
Abstract
The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, [...] Read more.
The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4–Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4–Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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12 pages, 6063 KiB  
Article
Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients
by Carter Norton, Derek Clarke, Joshua Holmstrom, Isaac Stirland, Paul R. Reynolds, Tim G. Jenkins and Juan A. Arroyo
Cells 2023, 12(8), 1130; https://doi.org/10.3390/cells12081130 - 11 Apr 2023
Cited by 5 | Viewed by 1759
Abstract
Intrauterine growth restriction (IUGR) and preeclampsia (PE) are placental pathologies known to complicate pregnancy and cause neonatal disorders. To date, there is a limited number of studies on the genetic similarity of these conditions. DNA methylation is a heritable epigenetic process that can [...] Read more.
Intrauterine growth restriction (IUGR) and preeclampsia (PE) are placental pathologies known to complicate pregnancy and cause neonatal disorders. To date, there is a limited number of studies on the genetic similarity of these conditions. DNA methylation is a heritable epigenetic process that can regulate placental development. Our objective was to identify methylation patterns in placental DNA from normal, PE and IUGR-affected pregnancies. DNA was extracted, and bisulfite was converted, prior to being hybridized for the methylation array. Methylation data were SWAN normalized and differently methylated regions were identified using applications within the USEQ program. UCSC’s Genome browser and Stanford’s GREAT analysis were used to identify gene promoters. The commonality among affected genes was confirmed by Western blot. We observed nine significantly hypomethylated regions, two being significantly hypomethylated for both PE and IGUR. Western blot confirmed differential protein expression of commonly regulated genes. We conclude that despite the uniqueness of methylation profiles for PE and IUGR, the similarity of some methylation alterations in pathologies could explain the clinical similarities observed with these obstetric complications. These results also provide insight into the genetic similarity between PE and IUGR and suggest possible gene candidates plausibly involved in the onset of both conditions. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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18 pages, 5326 KiB  
Article
Photobiomodulation at 660 nm Stimulates In Vitro Diabetic Wound Healing via the Ras/MAPK Pathway
by Patricia Kasowanjete, Heidi Abrahamse and Nicolette N. Houreld
Cells 2023, 12(7), 1080; https://doi.org/10.3390/cells12071080 - 04 Apr 2023
Cited by 4 | Viewed by 1436
Abstract
Diabetic foot ulcers (DFUs) are open chronic wounds that affect diabetic patients due to hyperglycaemia. DFUs are known for their poor response to treatment and frequently require amputation, which may result in premature death. The present study evaluated the effect of photobiomodulation (PBM) [...] Read more.
Diabetic foot ulcers (DFUs) are open chronic wounds that affect diabetic patients due to hyperglycaemia. DFUs are known for their poor response to treatment and frequently require amputation, which may result in premature death. The present study evaluated the effect of photobiomodulation (PBM) at 660 nm on wound healing via activation of Ras/MAPK signalling in diabetic wounded cells in vitro. This study used four human skin fibroblast cell (WS1) models, namely normal (N), wounded (W), diabetic (D), and diabetic wounded (DW). Cells were irradiated at 660 nm with 5 J/cm2. Non-irradiated cells (0 J/cm2) served as controls. Cells were incubated for 24 and 48 h post-irradiation, and the effect of PBM on cellular morphology and migration rate, viability, and proliferation was assessed. Basic fibroblast growth factor (bFGF), its phosphorylated (activated) receptor FGFR, and phosphorylated target proteins (Ras, MEK1/2 and MAPK) were determined by enzyme-linked immunosorbent assay (ELISA) and Western blotting; nuclear translocation of p-MAPK was determined by immunofluorescence. PBM resulted in an increase in bFGF and a subsequent increase in FGFR activation. There was also an increase in downstream proteins, p-Ras, p-MEK1/2 and p-MAPK. PBM at 660 nm led to increased viability, proliferation, and migration as a result of increased bFGF and subsequent activation of the Ras/MAPK signalling pathway. Therefore, this study can conclude that PBM at 660 nm stimulates in vitro diabetic wound healing via the bFGF-activated Ras/MAPK pathway. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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15 pages, 2133 KiB  
Article
JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model
by Erica Cecilia Priori, Clara Alice Musi, Arianna Giani, Luca Colnaghi, Ivana Milic, Andrew Devitt, Tiziana Borsello and Mariaelena Repici
Cells 2023, 12(6), 904; https://doi.org/10.3390/cells12060904 - 15 Mar 2023
Cited by 1 | Viewed by 1754
Abstract
The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, [...] Read more.
The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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33 pages, 8679 KiB  
Review
Domain Architecture of the Nonreceptor Tyrosine Kinase Ack1
by Yagmur Kan, YiTing Paung, Markus A. Seeliger and W. Todd Miller
Cells 2023, 12(6), 900; https://doi.org/10.3390/cells12060900 - 15 Mar 2023
Viewed by 2293
Abstract
The nonreceptor tyrosine kinase (NRTK) Ack1 comprises a distinct arrangement of non-catalytic modules. Its SH3 domain has a C-terminal to the kinase domain (SH1), in contrast to the typical SH3-SH2-SH1 layout in NRTKs. The Ack1 is the only protein that shares a region [...] Read more.
The nonreceptor tyrosine kinase (NRTK) Ack1 comprises a distinct arrangement of non-catalytic modules. Its SH3 domain has a C-terminal to the kinase domain (SH1), in contrast to the typical SH3-SH2-SH1 layout in NRTKs. The Ack1 is the only protein that shares a region of high homology to the tumor suppressor protein Mig6, a modulator of EGFR. The vertebrate Acks make up the only tyrosine kinase (TK) family known to carry a UBA domain. The GTPase binding and SAM domains are also uncommon in the NRTKs. In addition to being a downstream effector of receptor tyrosine kinases (RTKs) and integrins, Ack1 can act as an epigenetic regulator, modulate the degradation of the epidermal growth factor receptor (EGFR), confer drug resistance, and mediate the progression of hormone-sensitive tumors. In this review, we discuss the domain architecture of Ack1 in relation to other protein kinases that possess such defined regulatory domains. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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13 pages, 2739 KiB  
Communication
Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK
by Sarah Borkowsky, Maximilian Gass, Azadeh Alavizargar, Johannes Hanewinkel, Ina Hallstein, Pavel Nedvetsky, Andreas Heuer and Michael P. Krahn
Cells 2023, 12(5), 812; https://doi.org/10.3390/cells12050812 - 06 Mar 2023
Cited by 1 | Viewed by 2782
Abstract
The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 [...] Read more.
The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1’s kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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18 pages, 3968 KiB  
Article
Full-Length Transcriptomes and Sex-Based Differentially Expressed Genes in the Brain and Ganglia of Giant River Prawn Macrobrachium rosenbergii
by Dong Liu, Zhenzhen Hong, Lang Gui, Li Zhao, Yude Wang, Shengming Sun and Mingyou Li
Biomolecules 2023, 13(3), 460; https://doi.org/10.3390/biom13030460 - 02 Mar 2023
Cited by 3 | Viewed by 1875
Abstract
Macrobrachium rosenbergii is an important aquaculture prawn that exhibits sexual dimorphism in growth, with males growing much faster than females. However, the mechanisms controlling these complex traits are not well understood. The nervous system plays an important role in regulating life functions. In [...] Read more.
Macrobrachium rosenbergii is an important aquaculture prawn that exhibits sexual dimorphism in growth, with males growing much faster than females. However, the mechanisms controlling these complex traits are not well understood. The nervous system plays an important role in regulating life functions. In the present work, we applied PacBio RNA-seq to obtain and characterize the full-length transcriptomes of the brains and thoracic ganglia of female and male prawns, and we performed comparative transcriptome analysis of female and male prawns. A total of 159.1-Gb of subreads were obtained with an average length of 2175 bp and 93.2% completeness. A total of 84,627 high-quality unigenes were generated and annotated with functional databases. A total of 6367 transcript factors and 6287 LncRNAs were predicted. In total, 5287 and 6211 significantly differentially expressed genes (DEGs) were found in the brain and thoracic ganglion, respectively, and confirmed by qRT-PCR. Of the 435 genes associated with protein processing pathways in the endoplasmic reticula, 42 DEGs were detected, and 21/26 DEGs with upregulated expression in the male brain/thoracic ganglion. The DEGs in this pathway are regulated by multiple LncRNAs in polypeptide folding and misfolded protein degradation in the different organs and sexes of the prawn. Our results provide novel theories and insights for studying the nervous system, sexual control, and growth dimorphism. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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21 pages, 2047 KiB  
Article
A Role for the V0 Sector of the V-ATPase in Neuroexocytosis: Exogenous V0d Blocks Complexin and SNARE Interactions with V0c
by Christian Lévêque, Yves Maulet, Qili Wang, Marion Rame, Léa Rodriguez, Sumiko Mochida, Marion Sangiardi, Fahamoe Youssouf, Cécile Iborra, Michael Seagar, Nicolas Vitale and Oussama El Far
Cells 2023, 12(5), 750; https://doi.org/10.3390/cells12050750 - 26 Feb 2023
Cited by 3 | Viewed by 1364
Abstract
V-ATPase is an important factor in synaptic vesicle acidification and is implicated in synaptic transmission. Rotation in the extra-membranous V1 sector drives proton transfer through the membrane-embedded multi-subunit V0 sector of the V-ATPase. Intra-vesicular protons are then used to drive neurotransmitter uptake by [...] Read more.
V-ATPase is an important factor in synaptic vesicle acidification and is implicated in synaptic transmission. Rotation in the extra-membranous V1 sector drives proton transfer through the membrane-embedded multi-subunit V0 sector of the V-ATPase. Intra-vesicular protons are then used to drive neurotransmitter uptake by synaptic vesicles. V0a and V0c, two membrane subunits of the V0 sector, have been shown to interact with SNARE proteins, and their photo-inactivation rapidly impairs synaptic transmission. V0d, a soluble subunit of the V0 sector strongly interacts with its membrane-embedded subunits and is crucial for the canonic proton transfer activity of the V-ATPase. Our investigations show that the loop 1.2 of V0c interacts with complexin, a major partner of the SNARE machinery and that V0d1 binding to V0c inhibits this interaction, as well as V0c association with SNARE complex. The injection of recombinant V0d1 in rat superior cervical ganglion neurons rapidly reduced neurotransmission. In chromaffin cells, V0d1 overexpression and V0c silencing modified in a comparable manner several parameters of unitary exocytotic events. Our data suggest that V0c subunit promotes exocytosis via interactions with complexin and SNAREs and that this activity can be antagonized by exogenous V0d. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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22 pages, 2717 KiB  
Review
Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?
by Ruolei Wang, Lirong Liang, Misaki Matsumoto, Kazumi Iwata, Atsushi Umemura and Feng He
Biomolecules 2023, 13(2), 353; https://doi.org/10.3390/biom13020353 - 11 Feb 2023
Cited by 21 | Viewed by 3138
Abstract
The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and [...] Read more.
The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and growth or causing cell death. Cells developed evolutionarily conserved programs to sense and adapt redox the fluctuations to regulate ROS as either signaling molecules or toxic insults. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2)-KEAP1 system is the master regulator of cellular redox and metabolic homeostasis. NRF2 has Janus-like roles in carcinogenesis and cancer development. Short-term NRF2 activation suppresses tissue injury, inflammation, and cancer initiation. However, cancer cells often exhibit constitutive NRF2 activation due to genetic mutations or oncogenic signaling, conferring advantages for cancer cells’ survival and growth. Emerging evidence suggests that NRF2 hyperactivation, as an adaptive cancer phenotype under stressful tumor environments, regulates all hallmarks of cancer. In this review, we summarized the source of ROS, regulation of ROS signaling, and cellular sensors for ROS and oxygen (O2), we reviewed recent progress on the regulation of ROS generation and NRF2 signaling with a focus on the new functions of NRF2 in cancer development that reach beyond what we originally envisioned, including regulation of cancer metabolism, autophagy, macropinocytosis, unfolded protein response, proteostasis, and circadian rhythm, which, together with anti-oxidant and drug detoxification enzymes, contributes to cancer development, metastasis, and anticancer therapy resistance. Full article
(This article belongs to the Topic Cell Signaling Pathways)
(This article belongs to the Section Biomacromolecules: Proteins)
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14 pages, 802 KiB  
Opinion
The Dynamic Poly(A) Tail Acts as a Signal Hub in mRNA Metabolism
by Guiying Zhang, Haolin Luo, Xinyi Li, Zhangli Hu and Quan Wang
Cells 2023, 12(4), 572; https://doi.org/10.3390/cells12040572 - 10 Feb 2023
Cited by 2 | Viewed by 2129
Abstract
In eukaryotes, mRNA metabolism requires a sophisticated signaling system. Recent studies have suggested that polyadenylate tail may play a vital role in such a system. The poly(A) tail used to be regarded as a common modification at the 3′ end of mRNA, but [...] Read more.
In eukaryotes, mRNA metabolism requires a sophisticated signaling system. Recent studies have suggested that polyadenylate tail may play a vital role in such a system. The poly(A) tail used to be regarded as a common modification at the 3′ end of mRNA, but it is now known to be more than just that. It appears to act as a platform or hub that can be understood in two ways. On the one hand, polyadenylation and deadenylation machinery constantly regulates its dynamic activity; on the other hand, it exhibits the ability to recruit RNA-binding proteins and then interact with diverse factors to send various signals to regulate mRNA metabolism. In this paper, we outline the main complexes that regulate the dynamic activities of poly(A) tails, explain how these complexes participate polyadenylation/deadenylation process and summarize the diverse signals this hub emit. We are trying to make a point that the poly(A) tail can metaphorically act as a “flagman” who is supervised by polyadenylation and deadenylation and sends out signals to regulate the orderly functioning of mRNA metabolism. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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14 pages, 4120 KiB  
Article
CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2
by Yeong Chan Ryu, Jiyeon Park, You-Rin Kim, Sehee Choi, Geon-Uk Kim, Eunhwan Kim, Yumi Hwang, Heejene Kim, Gyoonhee Han, Soung-Hoon Lee and Kang-Yell Choi
Cells 2023, 12(4), 555; https://doi.org/10.3390/cells12040555 - 09 Feb 2023
Cited by 5 | Viewed by 2929
Abstract
The number of people suffering from hair loss is increasing, and hair loss occurs not only in older men but also in women and young people. Prostaglandin D2 (PGD2) is a well-known alopecia inducer. However, the mechanism by which PGD [...] Read more.
The number of people suffering from hair loss is increasing, and hair loss occurs not only in older men but also in women and young people. Prostaglandin D2 (PGD2) is a well-known alopecia inducer. However, the mechanism by which PGD2 induces alopecia is poorly understood. In this study, we characterized CXXC5, a negative regulator of the Wnt/β-catenin pathway, as a mediator for hair loss by PGD2. The hair loss by PGD2 was restored by Cxxc5 knock-out or treatment of protein transduction domain–Dishevelled binding motif (PTD-DBM), a peptide activating the Wnt/β-catenin pathway via interference with the Dishevelled (Dvl) binding function of CXXC5. In addition, suppression of neogenic hair growth by PGD2 was also overcome by PTD-DBM treatment or Cxxc5 knock-out as shown by the wound-induced hair neogenesis (WIHN) model. Moreover, we found that CXXC5 also mediates DHT-induced hair loss via PGD2. DHT-induced hair loss was alleviated by inhibition of both GSK-3β and CXXC5 functions. Overall, CXXC5 mediates the hair loss by the DHT-PGD2 axis through suppression of Wnt/β-catenin signaling. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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24 pages, 3443 KiB  
Article
Lateral Diffusion of NKCC1 Contributes to Chloride Homeostasis in Neurons and Is Rapidly Regulated by the WNK Signaling Pathway
by Etienne Côme, Simon Blachier, Juliette Gouhier, Marion Russeau and Sabine Lévi
Cells 2023, 12(3), 464; https://doi.org/10.3390/cells12030464 - 31 Jan 2023
Cited by 2 | Viewed by 1551
Abstract
An upregulation of the Na+-K+-2Cl cotransporter NKCC1, the main chloride importer in mature neurons, can lead to depolarizing/excitatory responses mediated by GABA type A receptors (GABAARs) and, thus, to hyperactivity. Understanding the regulatory mechanisms of NKCC1 [...] Read more.
An upregulation of the Na+-K+-2Cl cotransporter NKCC1, the main chloride importer in mature neurons, can lead to depolarizing/excitatory responses mediated by GABA type A receptors (GABAARs) and, thus, to hyperactivity. Understanding the regulatory mechanisms of NKCC1 would help prevent intra-neuronal chloride accumulation that occurs in pathologies with defective inhibition. The cell mechanisms regulating NKCC1 are poorly understood. Here, we report in mature hippocampal neurons that GABAergic activity controls the membrane diffusion and clustering of NKCC1 via the chloride-sensitive WNK lysine deficient protein kinase 1 (WNK1) and the downstream Ste20 Pro-line Asparagine Rich Kinase (SPAK) kinase that directly phosphorylates NKCC1 on key threonine residues. At rest, this signaling pathway has little effect on intracellular Cl concentration, but it participates in the elevation of intraneuronal Cl concentration in hyperactivity conditions associated with an up-regulation of NKCC1. The fact that the main chloride exporter, the K+-Cl cotransporter KCC2, is also regulated in mature neurons by the WNK1 pathway indicates that this pathway will be a target of choice in the pathology. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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13 pages, 1588 KiB  
Article
Sphingosylphosphorylcholine (SPC), a Causative Factor of SPC-Induced Vascular Smooth Muscle Cells Contraction, Is Taken Up via Endocytosis
by Natsuko Tsurudome, Yuji Minami and Katsuko Kajiya
Cells 2023, 12(2), 265; https://doi.org/10.3390/cells12020265 - 09 Jan 2023
Viewed by 1545
Abstract
The reaction field of abnormal vascular contraction induced by sphingosylphosphorylcholine (SPC) and the action point of SPC around the plasma membranes remain unknown. However, we found in a previous study that fisetin prevents SPC-induced vascular smooth muscle cells contraction, while the mechanism remains [...] Read more.
The reaction field of abnormal vascular contraction induced by sphingosylphosphorylcholine (SPC) and the action point of SPC around the plasma membranes remain unknown. However, we found in a previous study that fisetin prevents SPC-induced vascular smooth muscle cells contraction, while the mechanism remains unknown. Therefore, in this study, we aimed to address the action point of SPC around the plasma membranes and the involvement of fisetin. We focused on microdomains and evaluated their markers flotillin-1 and caveolin-1 and the localization of SPC to investigate their action point. The results showed that microdomains of vascular smooth muscle cells were not involved in SPC-induced contraction. However, we found that after SPC had been affected on the plasma membrane, cells took up SPC via endocytosis. Moreover, SPC remained in the cells and did not undergo transcytosis, and SPC-induced contracting cells produced exosomes. These phenomena were similar to those observed in fisetin-treated cells. Thus, we speculated that, although not involved in the reaction field of SPC-induced contractions, the microdomain induced the endocytosis of SPCs, and fisetin prevented the contractions by directly targeting vascular smooth muscle cells. Notably, this preventive mechanism involves the cellular uptake of SPC via endocytosis. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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18 pages, 1879 KiB  
Review
Isthmin—A Multifaceted Protein Family
by Hosen Md Shakhawat, Zaman Hazrat and Zhongjun Zhou
Cells 2023, 12(1), 17; https://doi.org/10.3390/cells12010017 - 21 Dec 2022
Cited by 4 | Viewed by 1486
Abstract
Isthmin (ISM) is a secreted protein family with two members, namely ISM1 and ISM2, both containing a TSR1 domain followed by an AMOP domain. Its broad expression pattern suggests diverse functions in developmental and physiological processes. Over the past few years, multiple studies [...] Read more.
Isthmin (ISM) is a secreted protein family with two members, namely ISM1 and ISM2, both containing a TSR1 domain followed by an AMOP domain. Its broad expression pattern suggests diverse functions in developmental and physiological processes. Over the past few years, multiple studies have focused on the functional analysis of the ISM protein family in several events, including angiogenesis, metabolism, organ homeostasis, immunity, craniofacial development, and cancer. Even though ISM was identified two decades ago, we are still short of understanding the roles of the ISM protein family in embryonic development and other pathological processes. To address the role of ISM, functional studies have begun but unresolved issues remain. To elucidate the regulatory mechanism of ISM, it is crucial to determine its interactions with other ligands and receptors that lead to the activation of downstream signalling pathways. This review provides a perspective on the gene organization and evolution of the ISM family, their links with developmental and physiological functions, and key questions for the future. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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24 pages, 8903 KiB  
Article
Effects of Simvastatin on Cartilage Homeostasis in Steroid-Induced Osteonecrosis of Femoral Head by Inhibiting Glucocorticoid Receptor
by Yaling Yu, Lishan Lin, Kangping Liu, Yixin Jiang and Zhenlei Zhou
Cells 2022, 11(24), 3945; https://doi.org/10.3390/cells11243945 - 07 Dec 2022
Cited by 3 | Viewed by 1522
Abstract
Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain [...] Read more.
Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain to be determined. In this study, pulse methylprednisolone (MP) treatment was used to induce SONFH in broilers, and then MP-treated birds were administrated with simvastatin simultaneously to investigate the changes in cartilage homeostasis. Meanwhile, chondrocytes were isolated, cultured, and treated with MP, simvastatin, or GR inhibitor in vitro. The changes in serum homeostasis factors, cell viability, and expression of GR were analyzed. The results showed that the morbidity of SONFH in the MP-treated group increased significantly compared with the simvastatin-treated and control group. Furthermore, MP treatment induced apoptosis and high-level catabolism and low-level anabolism in vitro and vivo, while simvastatin significantly decreased catabolism and slightly recovered anabolism via inhibiting GR and the hypoxia-inducible factor (HIF) pathway. The GR inhibitor or its siRNA mainly affected the catabolism of cartilage homeostasis in vitro. In conclusion, the occurrence of SONFH in broilers was related to the activation of GR and HIF pathway, and imbalance of cartilage homeostasis. Simvastatin and GR inhibitor maintained cartilage homeostasis via GR and the HIF pathway. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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21 pages, 15509 KiB  
Article
Exploring the Characteristics of Monkeypox-Related Genes in Pan-Cancer
by Yong Liao, Zhiping Liu, Weile Ye, Zunnan Huang and Jiaojiao Wang
Cells 2022, 11(23), 3909; https://doi.org/10.3390/cells11233909 - 02 Dec 2022
Cited by 2 | Viewed by 1862
Abstract
Monkeypox, an infectious virus that is a member of the Poxviridae family, has raised great threats to humans. Compared to the known oncoviruses, the relationship between monkeypox and cancer still remains obscure. Hence, in this study, we analyzed the multi-omics data from the [...] Read more.
Monkeypox, an infectious virus that is a member of the Poxviridae family, has raised great threats to humans. Compared to the known oncoviruses, the relationship between monkeypox and cancer still remains obscure. Hence, in this study, we analyzed the multi-omics data from the Cancer Genome Atlas (TCGA) database by using genomic and transcriptomic approaches to comprehensively assess the monkeypox-related genes (MRGs) in tumor samples from 33 types of cancers. Based on the results, the expression of MRGs was highly correlated with the immune infiltration and could be further utilized to predict survival in cancer patients. Furthermore, it was shown that tumorigenesis and patient survival were frequently associated with the genomic alterations of MRGs. Moreover, pathway analysis showed that MRGs participated in the regulation of apoptosis, cell cycle, Epithelial to Mesenchymal Transition (EMT), DNA damage, and hormone androgen receptor (AR), as well as RAS/MAPK and RTK signaling pathways. Besides, we also developed the prognostic features and consensus clustering clusters of MRGs in cancers. Lastly, by mining the cancer drug sensitivity genomics database, we further identified a series of candidate drugs that may target MRGs. Collectively, this study revealed genomic alterations and clinical features of MRGs, which may provide new hints to explore the potential molecular mechanisms between viruses and cancers as well as to provide new clinical guidance of cancer patients who also face the threats during the monkeypox epidemic. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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25 pages, 5702 KiB  
Article
UBA52 Is Crucial in HSP90 Ubiquitylation and Neurodegenerative Signaling during Early Phase of Parkinson’s Disease
by Shubhangini Tiwari, Abhishek Singh, Parul Gupta and Sarika Singh
Cells 2022, 11(23), 3770; https://doi.org/10.3390/cells11233770 - 25 Nov 2022
Cited by 6 | Viewed by 2176
Abstract
Protein aggregation is one of the major pathological events in age-related Parkinson’s disease (PD) pathology, predominantly regulated by the ubiquitin–proteasome system (UPS). UPS essentially requires core component ubiquitin; however, its role in PD pathology is obscure. This study aimed to investigate the role [...] Read more.
Protein aggregation is one of the major pathological events in age-related Parkinson’s disease (PD) pathology, predominantly regulated by the ubiquitin–proteasome system (UPS). UPS essentially requires core component ubiquitin; however, its role in PD pathology is obscure. This study aimed to investigate the role of ubiquitin-encoding genes in sporadic PD pathology. Both cellular and rat models of PD as well as SNCA C57BL/6J-Tg (Th-SNCA*A30P*A53T)39 Eric/J transgenic mice showed a decreased abundance of UBA52 in conjunction with significant downregulation of tyrosine hydroxylase (TH) and neuronal death. In silico predictions, mass spectrometric analysis, and co-immunoprecipitation findings suggested the protein–protein interaction of UBA52 with α-synuclein, HSP90 and E3-ubiquitin ligase CHIP, and its co-localization with α-synuclein in the mitochondrion. Next, in vitro ubiquitylation assay indicated an imperative requirement of the lysine-63 residue of UBA52 in CHIP-mediated HSP90 ubiquitylation. Myc-UBA52 expressed neurons inhibited alteration in PD-specific markers such as α-synuclein and TH protein along with increased proteasome activity in diseased conditions. Furthermore, Myc-UBA52 expression inhibited the altered protein abundance of HSP90 and its various client proteins, HSP75 (homolog of HSP90 in mitochondrion) and ER stress-related markers during early PD. Taken together, the data highlights the critical role of UBA52 in HSP90 ubiquitylation in parallel to its potential contribution to the modulation of various disease-related neurodegenerative signaling targets during the early phase of PD pathology. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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20 pages, 1627 KiB  
Review
Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives
by Yue Yu, Ailin Yang, Ganggang Yu and Haoyan Wang
Biomolecules 2022, 12(11), 1637; https://doi.org/10.3390/biom12111637 - 04 Nov 2022
Cited by 3 | Viewed by 2247
Abstract
The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, [...] Read more.
The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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14 pages, 1775 KiB  
Review
The Function and Therapeutic Implications of TNF Signaling in MDSCs
by Kun Yu, Chengxin Yu, Liping Jiao, Kun Miao, Li Ni, Xiaoquan Rao, Ling Zhou and Chunxia Zhao
Biomolecules 2022, 12(11), 1627; https://doi.org/10.3390/biom12111627 - 03 Nov 2022
Cited by 1 | Viewed by 1628
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of immature and heterogeneous myeloid cells with immunosuppressive functions. MDSCs play important roles in the pathogenesis of cancer, chronic inflammatory diseases, and many autoimmune disorders. The accumulation and activation of MDSCs can be regulated by tumor [...] Read more.
Myeloid-derived suppressor cells (MDSCs) are a group of immature and heterogeneous myeloid cells with immunosuppressive functions. MDSCs play important roles in the pathogenesis of cancer, chronic inflammatory diseases, and many autoimmune disorders. The accumulation and activation of MDSCs can be regulated by tumor necrosis factor α (TNF-α). In this review, we summarize the roles played by TNF-α in the recruitment, immunosuppressive functions, and chemotaxis of MDSCs, and discuss the potential therapeutic effects of TNF-α upon these cells in tumor growth and some inflammatory disorders. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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22 pages, 5951 KiB  
Review
The DNA Methylation in Neurological Diseases
by Samareh Younesian, Amir-Mohammad Yousefi, Majid Momeny, Seyed H. Ghaffari and Davood Bashash
Cells 2022, 11(21), 3439; https://doi.org/10.3390/cells11213439 - 31 Oct 2022
Cited by 21 | Viewed by 3817
Abstract
DNA methylation is critical for the normal development and functioning of the human brain, such as the proliferation and differentiation of neural stem cells, synaptic plasticity, neuronal reparation, learning, and memory. Despite the physical stability of DNA and methylated DNA compared to other [...] Read more.
DNA methylation is critical for the normal development and functioning of the human brain, such as the proliferation and differentiation of neural stem cells, synaptic plasticity, neuronal reparation, learning, and memory. Despite the physical stability of DNA and methylated DNA compared to other epigenetic modifications, some DNA methylation-based biomarkers have translated into clinical practice. Increasing reports indicate a strong association between DNA methylation profiles and various clinical outcomes in neurological diseases, making DNA methylation profiles valuable as novel clinical markers. In this review, we aim to discuss the latest evidence concerning DNA methylation alterations in the development of neurodegenerative, neurodevelopmental, and neuropsychiatric diseases. We also highlighted the relationship of DNA methylation alterations with the disease progression and outcome in many neurological diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and autism. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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20 pages, 2632 KiB  
Article
Modification of Hinge/Transmembrane and Signal Transduction Domains Improves the Expression and Signaling Threshold of GXMR-CAR Specific to Cryptococcus spp.
by Matheus Henrique dos Santos, Michele Procópio Machado, Pappanaicken R. Kumaresan and Thiago Aparecido da Silva
Cells 2022, 11(21), 3386; https://doi.org/10.3390/cells11213386 - 26 Oct 2022
Cited by 5 | Viewed by 2169
Abstract
Chimeric antigen receptors (CARs) redirect T cells to recognize a specific target. CAR components play a pivotal role in antigen specificity, structure stability, expression on cell surface, and induction of cellular activation, which together determine the success of CAR T-cell therapy. CAR products [...] Read more.
Chimeric antigen receptors (CARs) redirect T cells to recognize a specific target. CAR components play a pivotal role in antigen specificity, structure stability, expression on cell surface, and induction of cellular activation, which together determine the success of CAR T-cell therapy. CAR products targeting B-cell lymphoma encouraged the development of new CAR applications beyond cancer. For example, our group developed a CAR to specifically target glucuronoxylomannan (GXM) in the capsule of Cryptococcus species, called GXMR-CAR or GXMR-IgG4-28ζ. Cryptococcus are fungi that cause the life-threatening disease cryptococcosis, and GXMR-IgG4-28ζ redirected T cells to target yeast and titan cell forms of Cryptococcus spp. Here, we replaced the IgG4-hinge and CD28-transmembrane domains from GXMR-CAR with a CD8α molecule as the hinge/transmembrane and used CD28 or 4-1BB molecules as co-stimulatory domains, creating GXMR-8-28ζ and GXMR-8-BBζ, respectively. Jurkat cells expressing GXMR-CAR containing CD8α as the hinge/transmembrane improved the CAR expression and induced a tonic signaling. GXMR-8-28ζ and GXMR-8-BBζ induced high levels of IL-2 and up-regulation of CD69 expression in the presence of reference strains of C. neoformans and C. gattii. Moreover, GXMR-8-28ζ and GXMR-8-BBζ showed increased strength in response to incubation with clinical isolates of Cryptococcuss spp., and 4-1BB co-stimulatory domain triggered a more pronounced cellular activation. Dasatinib, a tyrosine kinase inhibitor, attenuated the GXMR-CAR signaling cascade’s engagement in the presence or absence of its ligand. This study optimized novel second-generation GXMR-CARs containing the CD8-hinge/transmembrane domain that improved CAR expression, antigen recognition, and signal strength in T-cell activation. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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14 pages, 1131 KiB  
Article
Crosstalk between Extracellular Matrix Stiffness and ROS Drives Endometrial Repair via the HIF-1α/YAP Axis during Menstruation
by Tao Zhang, Yan Wang, Yingnan Wang, Cuiyan Liu and Chunyang Han
Cells 2022, 11(19), 3162; https://doi.org/10.3390/cells11193162 - 09 Oct 2022
Cited by 2 | Viewed by 1993
Abstract
Although the menstrual cycle driven by sex steroid hormones is an uncomplicated physiological process, it is important for female health, fertility and regenerative biology. However, our understanding of this unique type of tissue homeostasis remains unclear. Here, we examined the biological effects of [...] Read more.
Although the menstrual cycle driven by sex steroid hormones is an uncomplicated physiological process, it is important for female health, fertility and regenerative biology. However, our understanding of this unique type of tissue homeostasis remains unclear. Here, we examined the biological effects of mechanical force by evaluating the changing trend of extracellular matrix (ECM) stiffness, and the results suggested that ECM stiffness was reduced and that breaking of mechanotransduction delayed endometrium repair in a mouse model of simulated menses. We constructed an ECM stiffness interference model in vitro to explain the mechanical force conduction mechanism during endometrial regeneration. We discovered that ECM stiffness increased the expression and nuclear transfer of YAP, which improved the creation of a microenvironment, in a manner that induced proliferation and angiogenesis for endometrial repair by activating YAP. In addition, we observed that physiological endometrial hypoxia occurs during the menstrual cycle and that the expression of HIF-1α was increased. Mechanistically, in addition to the classical F-actin/YAP pathway, we also found that the ROS/HIF-1α/YAP axis was involved in the transmission of mechanical signals. This study provides novel insights into the essential menstrual cycle and presents an effective, nonhormonal treatment for menstrual disorders. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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20 pages, 1377 KiB  
Review
STAT3 and Its Targeting Inhibitors in Oral Squamous Cell Carcinoma
by Mingjing Jiang and Bo Li
Cells 2022, 11(19), 3131; https://doi.org/10.3390/cells11193131 - 05 Oct 2022
Cited by 18 | Viewed by 3162
Abstract
Oral squamous cell carcinoma (OSCC) usually originates from the precancerous lesions of oral mucosa and accounts for approximately 90% of oral cancers. Current therapeutic approaches do not yet meet the needs of patients, and the 5-year survival rate of patients with OSCC is [...] Read more.
Oral squamous cell carcinoma (OSCC) usually originates from the precancerous lesions of oral mucosa and accounts for approximately 90% of oral cancers. Current therapeutic approaches do not yet meet the needs of patients, and the 5-year survival rate of patients with OSCC is only 50%. Recent studies have revealed that the signal transducer and activator of transcription 3 (STAT3) plays a key role in the development and progression of OSCC. STAT3 is overexpressed and constitutively activated in OSCC cells, and promotes cancer cell proliferation and anti-apoptosis, migration and invasion, angiogenesis, radiotherapy resistance, and immune escape, as well as stem cell self-renewal and differentiation by regulating the transcription of its downstream target genes. Inhibitors of the STAT3 signaling pathway have shown the promising anticancer effects in vitro and in vivo, and STAT3 is expected to be a molecular target for the treatment of OSCC. In this review, we highlight the oncogenic significance of STAT3 in OSCC with an emphasis on the therapeutic approaches and effective small molecule inhibitors targeting STAT3. Finally, we also propose the potential research directions in the expectation of developing more specific STAT3 inhibitors for OSCC treatment. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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16 pages, 7652 KiB  
Review
Functional Diversity of Neuronal Cell Adhesion and Recognition Molecule L1CAM through Proteolytic Cleavage
by Irina I. Stoyanova and David Lutz
Cells 2022, 11(19), 3085; https://doi.org/10.3390/cells11193085 - 30 Sep 2022
Cited by 7 | Viewed by 2275
Abstract
The neuronal cell adhesion and recognition molecule L1 does not only ‘keep cells together’ by way of homophilic and heterophilic interactions, but can also promote cell motility when cleaved into fragments by several proteases. It has largely been thought that such fragments are [...] Read more.
The neuronal cell adhesion and recognition molecule L1 does not only ‘keep cells together’ by way of homophilic and heterophilic interactions, but can also promote cell motility when cleaved into fragments by several proteases. It has largely been thought that such fragments are signs of degradation. Now, it is clear that proteolysis contributes to the pronounced functional diversity of L1, which we have reviewed in this work. L1 fragments generated at the plasma membrane are released into the extracellular space, whereas other membrane-bound fragments are internalised and enter the nucleus, thus conveying extracellular signals to the cell interior. Post-translational modifications on L1 determine the sequence of cleavage by proteases and the subcellular localisation of the generated fragments. Inside the neuronal cells, L1 fragments interact with various binding partners to facilitate morphogenic events, as well as regenerative processes. The stimulation of L1 proteolysis via injection of L1 peptides or proteases active on L1 or L1 mimetics is a promising tool for therapy of injured nervous systems. The collective findings gathered over the years not only shed light on the great functional diversity of L1 and its fragments, but also provide novel mechanistic insights into the adhesion molecule proteolysis that is active in the developing and diseased nervous system. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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12 pages, 1812 KiB  
Article
Liraglutide Attenuates Glucolipotoxicity-Induced RSC96 Schwann Cells’ Inflammation and Dysfunction
by Edy Kornelius, Sing-Hua Tsou, Ching-Chi Chang, Ying-Jui Ho, Sheng-Chieh Lin, Wei-Liang Chen, Chien-Ning Huang and Chih-Li Lin
Biomolecules 2022, 12(10), 1338; https://doi.org/10.3390/biom12101338 - 21 Sep 2022
Cited by 8 | Viewed by 1869
Abstract
Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve [...] Read more.
Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs’ dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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13 pages, 2905 KiB  
Article
Generation and Functional Characterization of PLAP CAR-T Cells against Cervical Cancer Cells
by Vahid Yekehfallah, Saghar Pahlavanneshan, Ali Sayadmanesh, Zahra Momtahan, Bin Ma and Mohsen Basiri
Biomolecules 2022, 12(9), 1296; https://doi.org/10.3390/biom12091296 - 14 Sep 2022
Cited by 3 | Viewed by 2726
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target and off-tumor cytotoxicity due [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target and off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta- and tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a fully human scFv against PLAP antigen andthen evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by co-culturing PLAP CAR T cells with HeLa and CaSki cells, we analyzed the tumor-killing functions and the secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only proliferated during co-culture with cancer cells but also eliminated them in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and, potentially, other solid tumors. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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19 pages, 8074 KiB  
Article
A Novel lncRNA Mediates the Delayed Tooth Eruption of Cleidocranial Dysplasia
by Yuejiao Xin, Yang Liu, Jie Li, Dandan Liu, Chenying Zhang, Yixiang Wang and Shuguo Zheng
Cells 2022, 11(17), 2729; https://doi.org/10.3390/cells11172729 - 01 Sep 2022
Cited by 5 | Viewed by 1819
Abstract
Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation [...] Read more.
Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation mediated by long non-coding (lnc)RNAs in CCD remain to be elucidated. Here, a novel osteoclast-specific lncRNA (OC-lncRNA) was identified during the osteoclast differentiation of RAW 264.7 cells transfected with a RUNX2 mutation expression cassette. We further confirmed that OC-lncRNA positively regulated osteoclastogenesis and bone resorption. The OC-lncRNA promoted the expression of CXC chemokine receptor type 3 (CXCR3) by competitively binding to microRNA (miR)-221-5p. The CXCR3–CXC-motif chemokine ligand 10 (CXCL10) interaction and nuclear factor-κB constituted a positive feedback that positively regulated osteoclastogenesis and bone resorption. These results demonstrate that OC-lncRNA-mediated osteoclast dysfunction via the OC-lncRNA–miR-221-5p–CXCR3 axis, which is involved in the process of delayed tooth eruption of CCD. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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11 pages, 1864 KiB  
Article
Evidence for the Neuronal Expression and Secretion of Adiponectin
by Azénor Abgrall, Ghislaine Poizat, Marianne Prevost, Laure Riffault, Laura De La Barrera, Rita Hanine, Katarina Djordjevic, Yacir Benomar and Mohammed Taouis
Cells 2022, 11(17), 2725; https://doi.org/10.3390/cells11172725 - 01 Sep 2022
Cited by 4 | Viewed by 1831
Abstract
Peripheral adiponectin acts on the hypothalamus to inhibit energy expenditure and increase food intake through its receptors AdipoR1 and adipoR2. The hypothalamic expression of adiponectin is poorly documented. We hypothesize that whether hypothalamic adiponectin is confirmed, its expression and secretion could be regulated [...] Read more.
Peripheral adiponectin acts on the hypothalamus to inhibit energy expenditure and increase food intake through its receptors AdipoR1 and adipoR2. The hypothalamic expression of adiponectin is poorly documented. We hypothesize that whether hypothalamic adiponectin is confirmed, its expression and secretion could be regulated as peripheral adiponectin. Thus, in the present work, we aim to determine whether adiponectin is expressed in the hypothalamus and in two neuronal cell lines and investigate the potential mechanisms regulating its neuronal expression. Using immunohistochemistry, we show that adiponectin is expressed in the mediobasal hypothalamic neurons of mice. Adiponectin expression is also evidenced in two neuronal cell lines mHypo POMC (an adult mouse hypothalamic cell line) and SH-SY5Y (human neuroblastoma). The neuronal expression of adiponectin is increased in response to rosiglitazone treatment (a PPARγ agonist) and FGF21 and is decreased in insulin-resistant neurons. Furthermore, we show that adiponectin expressed by mHypo POMC neurons is secreted in a culture medium. Adiponectin also diminished the resistin-induced IL6 expression in SIMA9 cells, a microglia cell line. In conclusion, we evidenced the hypothalamic expression of adiponectin and its regulation at the neuronal level. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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25 pages, 5209 KiB  
Article
Overexpression of Terpenoid Biosynthesis Genes Modifies Root Growth and Nodulation in Soybean (Glycine max)
by Mohammed Ali, Long Miao, Fathia A. Soudy, Doaa Bahaa Eldin Darwish, Salma Saleh Alrdahe, Dikhnah Alshehri, Vagner A. Benedito, Million Tadege, Xiaobo Wang and Jian Zhao
Cells 2022, 11(17), 2622; https://doi.org/10.3390/cells11172622 - 23 Aug 2022
Cited by 3 | Viewed by 1951
Abstract
Root nodule formation in many leguminous plants is known to be affected by endogen ous and exogenous factors that affect formation, development, and longevity of nodules in roots. Therefore, it is important to understand the role of the genes which are involved in [...] Read more.
Root nodule formation in many leguminous plants is known to be affected by endogen ous and exogenous factors that affect formation, development, and longevity of nodules in roots. Therefore, it is important to understand the role of the genes which are involved in the regulation of the nodulation signaling pathway. This study aimed to investigate the effect of terpenoids and terpene biosynthesis genes on root nodule formation in Glycine max. The study aimed to clarify not only the impact of over-expressing five terpene synthesis genes isolated from G. max and Salvia guaranitica on soybean nodulation signaling pathway, but also on the strigolactones pathway. The obtained results revealed that the over expression of GmFDPS, GmGGPPS, SgGPS, SgFPPS, and SgLINS genes enhanced the root nodule numbers, fresh weight of nodules, root, and root length. Moreover, the terpene content in the transgenic G. max hairy roots was estimated. The results explored that the monoterpenes, sesquiterpenes and diterpenes were significantly increased in transgenic soybean hairy roots in comparison with the control. Our results indicate the potential effects of terpenoids and terpene synthesis genes on soybean root growth and nodulation. The study provides novel insights for understanding the epistatic relationship between terpenoids, root development, and nodulation in soybean. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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21 pages, 2931 KiB  
Article
Emergent Role of IFITM1/3 towards Splicing Factor (SRSF1) and Antigen-Presenting Molecule (HLA-B) in Cervical Cancer
by Maria Gómez-Herranz, Jakub Faktor, Marcos Yébenes Mayordomo, Magdalena Pilch, Marta Nekulova, Lenka Hernychova, Kathryn L. Ball, Borivoj Vojtesek, Ted R. Hupp and Sachin Kote
Biomolecules 2022, 12(8), 1090; https://doi.org/10.3390/biom12081090 - 08 Aug 2022
Cited by 2 | Viewed by 2415
Abstract
The IFITM restriction factors play a role in cancer cell progression through undefined mechanisms. We investigate new protein–protein interactions for IFITM1/3 in the context of cancer that would shed some light on how IFITM1/3 attenuate the expression of targeted proteins such as HLA-B. [...] Read more.
The IFITM restriction factors play a role in cancer cell progression through undefined mechanisms. We investigate new protein–protein interactions for IFITM1/3 in the context of cancer that would shed some light on how IFITM1/3 attenuate the expression of targeted proteins such as HLA-B. SBP-tagged IFITM1 protein was used to identify an association of IFITM1 protein with the SRSF1 splicing factor and transporter of mRNA to the ribosome. Using in situ proximity ligation assays, we confirmed a predominant cytosolic protein–protein association for SRSF1 and IFITM1/3. Accordingly, IFITM1/3 interacted with HLA-B mRNA in response to IFNγ stimulation using RNA–protein proximity ligation assays. In addition, RT-qPCR assays in IFITM1/IFITM3 null cells and wt-SiHa cells indicated that HLA-B gene expression at the mRNA level does not account for lowered HLA-B protein synthesis in response to IFNγ. Complementary, shotgun RNA sequencing did not show major transcript differences between IFITM1/IFITM3 null cells and wt-SiHa cells. Furthermore, ribosome profiling using sucrose gradient sedimentation identified a reduction in 80S ribosomal fraction an IFITM1/IFITM3 null cells compared to wild type. It was partially reverted by IFITM1/3 complementation. Our data link IFITM1/3 proteins to HLA-B mRNA and SRSF1 and, all together, our results begin to elucidate how IFITM1/3 catalyze the synthesis of target proteins. IFITMs are widely studied for their role in inhibiting viruses, and multiple studies have associated IFITMs with cancer progression. Our study has identified new proteins associated with IFITMs which support their role in mediating protein expression; a pivotal function that is highly relevant for viral infection and cancer progression. Our results suggest that IFITM1/3 affect the expression of targeted proteins; among them, we identified HLA-B. Changes in HLA-B expression could impact the presentation and recognition of oncogenic antigens on the cell surface by cytotoxic T cells and, ultimately, limit tumor cell eradication. In addition, the role of IFITMs in mediating protein abundance is relevant, as it has the potential for regulating the expression of viral and oncogenic proteins. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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14 pages, 4060 KiB  
Article
Chronic AMPK Activation Reduces the Expression and Alters Distribution of Synaptic Proteins in Neuronal SH-SY5Y Cells
by Alex J. T. Yang, Ahmad Mohammad, Evangelia Tsiani, Aleksandar Necakov and Rebecca E. K. MacPherson
Cells 2022, 11(15), 2354; https://doi.org/10.3390/cells11152354 - 31 Jul 2022
Cited by 1 | Viewed by 2173
Abstract
Neuronal growth and synaptic function are dependent on precise protein production and turnover at the synapse. AMPK-activated protein kinase (AMPK) represents a metabolic node involved in energy sensing and in regulating synaptic protein homeostasis. However, there is ambiguity surrounding the role of AMPK [...] Read more.
Neuronal growth and synaptic function are dependent on precise protein production and turnover at the synapse. AMPK-activated protein kinase (AMPK) represents a metabolic node involved in energy sensing and in regulating synaptic protein homeostasis. However, there is ambiguity surrounding the role of AMPK in regulating neuronal growth and health. This study examined the effect of chronic AMPK activation on markers of synaptic function and growth. Retinoic-acid-differentiated SH-SY5Y human neuroblastoma cells were treated with A-769662 (100 nM) or Compound C (30 nM) for 1, 3, or 5 days before AMPK, mTORC1, and markers for synapse function were examined. Cell morphology, neuronal marker content, and location were quantified after 5 days of treatment. AMPK phosphorylation was maintained throughout all 5 days of treatment with A-769662 and resulted in chronic mTORC1 inhibition. Lower total, soma, and neuritic neuronal marker contents were observed following 5 d of AMPK activation. Neurite protein abundance and distribution was lower following 5 days of A-769662 treatment. Our data suggest that chronic AMPK activation impacts synaptic protein content and reduces neurite protein abundance and distribution. These results highlight a distinct role that metabolism plays on markers of synapse health and function. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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17 pages, 6535 KiB  
Article
BzATP Activates Satellite Glial Cells and Increases the Excitability of Dorsal Root Ganglia Neurons In Vivo
by Zhiyong Chen, Chi Zhang, Xiaodan Song, Xiang Cui, Jing Liu, Neil C. Ford, Shaoqiu He, Guangwu Zhu, Xinzhong Dong, Menachem Hanani and Yun Guan
Cells 2022, 11(15), 2280; https://doi.org/10.3390/cells11152280 - 23 Jul 2022
Cited by 8 | Viewed by 2232
Abstract
The purinergic system plays an important role in pain transmission. Recent studies have suggested that activation of P2-purinergic receptors (P2Rs) may be involved in neuron-satellite glial cell (SGC) interactions in the dorsal root ganglia (DRG), but the details remain unclear. In DRG, P2X7R [...] Read more.
The purinergic system plays an important role in pain transmission. Recent studies have suggested that activation of P2-purinergic receptors (P2Rs) may be involved in neuron-satellite glial cell (SGC) interactions in the dorsal root ganglia (DRG), but the details remain unclear. In DRG, P2X7R is selectively expressed in SGCs, which closely surround neurons, and is highly sensitive to 3’-O-(4-Benzoyl) benzoyl-ATP (BzATP). Using calcium imaging in intact mice to survey a large number of DRG neurons and SGCs, we examined how intra-ganglionic purinergic signaling initiated by BzATP affects neuronal activities in vivo. We developed GFAP-GCaMP6s and Pirt-GCaMP6s mice to express the genetically encoded calcium indicator GGCaM6s in SGCs and DRG neurons, respectively. The application of BzATP to the ganglion induced concentration-dependent activation of SGCs in GFAP-GCaMP6s mice. In Pirt-GCaMP6s mice, BzATP initially activated more large-size neurons than small-size ones. Both glial and neuronal responses to BzATP were blocked by A438079, a P2X7R-selective antagonist. Moreover, blockers to pannexin1 channels (probenecid) and P2X3R (A317491) also reduced the actions of BzATP, suggesting that P2X7R stimulation may induce the opening of pannexin1 channels, leading to paracrine ATP release, which could further excite neurons by acting on P2X3Rs. Importantly, BzATP increased the responses of small-size DRG neurons and wide-dynamic range spinal neurons to subsequent peripheral stimuli. Our findings suggest that intra-ganglionic purinergic signaling initiated by P2X7R activation could trigger SGC-neuron interaction in vivo and increase DRG neuron excitability. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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13 pages, 2222 KiB  
Article
Mechanisms for Bile Acids CDCA- and DCA-Stimulated Hepatic Spexin Expression
by Qi Lai, Yanhua Ma, Jin Bai, Min Zhuang, Shaofei Pei, Ni He, Junlin Yin, Baomin Fan, Zhaoxiang Bian, Guangzhi Zeng and Chengyuan Lin
Cells 2022, 11(14), 2159; https://doi.org/10.3390/cells11142159 - 10 Jul 2022
Cited by 5 | Viewed by 2542
Abstract
Spexin (SPX) is a novel peptide involved in glucose and lipid metabolism and suppresses hepatic total bile acid levels by inhibiting hepatic cholesterol 7α-hydroxylase 1 expression. As important mediators for glycolysis/gluconeogenesis and lipid metabolism, the effects of bile acids on SPX expression is [...] Read more.
Spexin (SPX) is a novel peptide involved in glucose and lipid metabolism and suppresses hepatic total bile acid levels by inhibiting hepatic cholesterol 7α-hydroxylase 1 expression. As important mediators for glycolysis/gluconeogenesis and lipid metabolism, the effects of bile acids on SPX expression is yet to be understood. By using SMMC7721 and BEL-7402 cell lines, we screened the effects of bile acids and found that chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) can stimulate SPX gene transcription. Both CDCA and DCA were able to stimulate SPX mRNA expression in the liver but not colon and ileum in mice. In SMMC7721 and BEL-7402 cells, CDCA- and DCA-induced SPX promoter activity was mimicked by bile acid receptor FXR and TGR5 activation and suppressed by FXR and TGR5 silencing. Adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) activators significantly increased SPX promoter activity whereas the inhibitors for AC/CAMP/protein kinase A (PKA) and mitogen-activated protein kinases (MAPK) pathway attenuated CDCA- and DCA-induced SPX transcription. Thus, CDCA and DCA stimulate SPX expression at the hepatic level through FXR and TGR5 mediated AC/cAMP/PKA and MAPK cascades. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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17 pages, 1477 KiB  
Review
Yeast Protein Kinase A Isoforms: A Means of Encoding Specificity in the Response to Diverse Stress Conditions?
by Declan R. Creamer, Simon J. Hubbard, Mark P. Ashe and Chris M. Grant
Biomolecules 2022, 12(7), 958; https://doi.org/10.3390/biom12070958 - 08 Jul 2022
Cited by 6 | Viewed by 3768
Abstract
Eukaryotic cells have developed a complex circuitry of signalling molecules which monitor changes in their intra- and extracellular environments. One of the most widely studied signalling pathways is the highly conserved cyclic AMP (cAMP)/protein kinase A (PKA) pathway, which is a major glucose [...] Read more.
Eukaryotic cells have developed a complex circuitry of signalling molecules which monitor changes in their intra- and extracellular environments. One of the most widely studied signalling pathways is the highly conserved cyclic AMP (cAMP)/protein kinase A (PKA) pathway, which is a major glucose sensing circuit in the yeast Saccharomyces cerevisiae. PKA activity regulates diverse targets in yeast, positively activating the processes that are associated with rapid cell growth (e.g., fermentative metabolism, ribosome biogenesis and cell division) and negatively regulating the processes that are associated with slow growth, such as respiratory growth, carbohydrate storage and entry into stationary phase. As in higher eukaryotes, yeast has evolved complexity at the level of the PKA catalytic subunit, and Saccharomyces cerevisiae expresses three isoforms, denoted Tpk1-3. Despite evidence for isoform differences in multiple biological processes, the molecular basis of PKA signalling specificity remains poorly defined, and many studies continue to assume redundancy with regards to PKA-mediated regulation. PKA has canonically been shown to play a key role in fine-tuning the cellular response to diverse stressors; however, recent studies have now begun to interrogate the requirement for individual PKA catalytic isoforms in coordinating distinct steps in stress response pathways. In this review, we discuss the known non-redundant functions of the Tpk catalytic subunits and the evolving picture of how these isoforms establish specificity in the response to different stress conditions. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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14 pages, 800 KiB  
Review
Role of Pyroptosis in Gynecological Oncology and Its Therapeutic Regulation
by Yi Huang, Ruiyun Li and Yuan Yang
Biomolecules 2022, 12(7), 924; https://doi.org/10.3390/biom12070924 - 01 Jul 2022
Cited by 8 | Viewed by 2512
Abstract
With the continuous advances in molecular biotechnology, many new cell death methods have been discovered. Pyroptosis is a programmed cell death process that differs from apoptosis and autophagy in cell morphology and function. Compared with apoptosis and autophagy, pyroptosis is primarily mediated by [...] Read more.
With the continuous advances in molecular biotechnology, many new cell death methods have been discovered. Pyroptosis is a programmed cell death process that differs from apoptosis and autophagy in cell morphology and function. Compared with apoptosis and autophagy, pyroptosis is primarily mediated by intracellular inflammasome and gasdermin D of the gasdermin protein family and involves the release of numerous inflammatory factors. Pyroptosis has been found to be involved in the occurrence and development of infectious diseases and other diseases involving the nervous system and the cardiovascular system. Recent studies have also reported the occurrence of pyroptosis in tumor cells. Accordingly, exploring its effect on tumors has become one of the research hotspots. Herein, recent research progress on pyroptosis is reviewed, especially its role in the development of gynecological tumors. As the pathogenesis of gynecological tumor is better understood, new targets have been introduced for the prevention and clinical treatment of gynecological tumors. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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11 pages, 5444 KiB  
Article
TRPC6 Inactivation Reduces Albuminuria Induced by Protein Overload in Sprague Dawley Rats
by Eun Young Kim and Stuart E. Dryer
Cells 2022, 11(13), 1985; https://doi.org/10.3390/cells11131985 - 21 Jun 2022
Cited by 3 | Viewed by 1795
Abstract
Canonical transient receptor potential-6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS), and in renal fibrosis following ureteral obstruction in mice. TRPC6 channels also appear to play a role in driving glomerular disease [...] Read more.
Canonical transient receptor potential-6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS), and in renal fibrosis following ureteral obstruction in mice. TRPC6 channels also appear to play a role in driving glomerular disease in aging and in autoimmune glomerulonephritis. In the present study, we examine the role of TRPC6 in the proteinuric state caused by prolonged albumin overload (AO) in Sprague Dawley rats induced by daily injections of exogenous albumin. This was assessed in rats with a global and constitutive inactivation of TRPC6 channels (Trpc6del/del rats) and in wild-type littermates (Trpc6wt/wt rats). AO for 14 and 28 days caused increased urine albumin excretion that was significantly attenuated in Trpc6del/del rats compared to Trpc6wt/wt controls. AO overload did not induce significant glomerulosclerosis or azotemia in either genotype. AO induced mild tubulointerstitial disease characterized by fibrosis, hypercellularity and increased expression of markers of fibrosis and inflammation. Those changes were equally severe in Trpc6wt/wt and Trpc6del/del rats. Immunoblot analysis of renal cortex indicated that AO increased the abundances of TRPC3 and TRPC6, and caused a nearly complete loss of TRPC5 in Trpc6wt/wt rats. The increase in TRPC3 and the loss of TRPC5 occurred to the same extent in Trpc6del/del rats. These data also suggest that TRPC6 plays a role in the normal function of the glomerular filtration barrier. However, whether TRPC6 inactivation protects the tubulointerstitial compartments in Sprague Dawley rats depends on the disease model examined. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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18 pages, 5364 KiB  
Article
Claudin-17 Deficiency in Mice Results in Kidney Injury Due to Electrolyte Imbalance and Oxidative Stress
by Mir S. Adil, Varun Parvathagiri, Arti Verma, Fang Liu, Madhuri Rudraraju, S. Priya Narayanan and Payaningal R. Somanath
Cells 2022, 11(11), 1782; https://doi.org/10.3390/cells11111782 - 29 May 2022
Cited by 2 | Viewed by 2138
Abstract
The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge [...] Read more.
The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17−/− mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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13 pages, 1552 KiB  
Article
Redistribution of TNF Receptor 1 and 2 Expression on Immune Cells in Patients with Bronchial Asthma
by Alina Alshevskaya, Julia Zhukova, Fedor Kireev, Julia Lopatnikova, Irina Evsegneeva, Daria Demina, Vera Nepomniashchikch, Victor Gladkikh, Alexander Karaulov and Sergey Sennikov
Cells 2022, 11(11), 1736; https://doi.org/10.3390/cells11111736 - 24 May 2022
Cited by 6 | Viewed by 1820
Abstract
Background: The co-expression patterns of type 1 and 2 tumor necrosis factor (TNF)-α membrane receptors (TNFR1/TNFR2) are associated with the presence, stage, and activity of allergic diseases. The aim of this study was to assess the expression levels and dynamics of TNFRs on [...] Read more.
Background: The co-expression patterns of type 1 and 2 tumor necrosis factor (TNF)-α membrane receptors (TNFR1/TNFR2) are associated with the presence, stage, and activity of allergic diseases. The aim of this study was to assess the expression levels and dynamics of TNFRs on immune cells and to assess associations between their expression and severity of bronchial asthma (BA). Methods: Patients with severe (n = 8), moderate (n = 10), and mild (n = 4) BA were enrolled. As a comparison group, data from 46 healthy volunteers (HV) were accessed. Co-expression of TNFR1/2 was evaluated as a percentage of cells and the number of receptors of each type per cell. Multivariate logistic regression analysis was used to identify diagnostic biomarkers of BA. Results: More than 90% of the monocytes in patients with mild BA were TNFR1+TNFR2+ but had significantly lower TNFR1 expression density compared with HV (7.82- to 14.08-fold, depending on disease severity). Lower percentages of the TNFR+ B-lymphocytes were observed in combination with significantly lower receptors density in BA compared with HV (2.59- to 11.64-fold for TNFR1 and 1.72- to 3.4-fold for TNFR2, depending on disease severity). The final multivariate model for predicting the presence of BA included the percentage of double-positive CD5+ B-lymphocytes and average number of TNFR1 molecules expressed on cytotoxic naive T-lymphocytes and T-helper cells (R2 = 0.87). Conclusions: The co-expression patterns of TNFRs on immune cells in BA differed significantly compared with HV. The expression differences were associated with disease severity. TNFR1 expression changes were key parameters that discriminated patients with BA from those with HV. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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33 pages, 13787 KiB  
Article
Activation of MT1/MT2 to Protect Testes and Leydig Cells against Cisplatin-Induced Oxidative Stress through the SIRT1/Nrf2 Signaling Pathway
by Junqiang Zhang, Yuan Fang, Dongdong Tang, Xingyu Xu, Xiaoqian Zhu, Shusheng Wu, Hui Yu, Huiru Cheng, Ting Luo, Qunshan Shen, Yang Gao, Cong Ma, Yajing Liu, Zhaolian Wei, Xiaoyu Chen, Fangbiao Tao, Xiaojin He and Yunxia Cao
Cells 2022, 11(10), 1690; https://doi.org/10.3390/cells11101690 - 19 May 2022
Cited by 15 | Viewed by 3150
Abstract
There is growing concern that chemotherapy drugs can damage Leydig cells and inhibit the production of testosterone. Increasing evidence shows that melatonin benefits the reproductive process. This study mainly explores the protective effect and possible molecular mechanism of melatonin regarding cisplatin-induced oxidative stress [...] Read more.
There is growing concern that chemotherapy drugs can damage Leydig cells and inhibit the production of testosterone. Increasing evidence shows that melatonin benefits the reproductive process. This study mainly explores the protective effect and possible molecular mechanism of melatonin regarding cisplatin-induced oxidative stress in testicular tissue and Leydig cells. We found that there were only Leydig and Sertoli cells in the testes of gastrointestinal tumor patients with azoospermia caused by platinum chemotherapeutic drugs. Melatonin (Mel) receptor 1/melatonin receptor 2 (MT1/MT2) was mainly expressed in human and mouse Leydig cells of the testes. We also observed that the melatonin level in the peripheral blood decreased and oxidative stress occurred in mice treated with cisplatin or gastrointestinal tumor patients treated with platinum-based chemotherapeutic drugs. iTRAQ proteomics showed that SIRT1/Nrf2 signaling and MT1 proteins were downregulated in cisplatin-treated mouse testes. The STRING database predicted that MT1 might be able to regulate the SIRT1/Nrf2 signaling pathway. Melatonin reduced oxidative stress and upregulated SIRT1/Nrf2 signaling in cisplatin-treated mouse testes and Leydig cells. Most importantly, after inhibiting MT1/MT2, melatonin could not upregulate SIRT1/Nrf2 signaling in cisplatin-treated Leydig cells. The MT1/MT2 inhibitor aggravated the cisplatin-induced downregulation of SIRT1/Nrf2 signaling and increased the apoptosis of Leydig cells. We believe that melatonin stimulates SIRT1/Nrf2 signaling by activating MT1/MT2 to prevent the cisplatin-induced apoptosis of Leydig cells. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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22 pages, 4019 KiB  
Article
Integrated Analysis of Cancer Tissue and Vitreous Humor from Retinoblastoma Eyes Reveals Unique Tumor-Specific Metabolic and Cellular Pathways in Advanced and Non-Advanced Tumors
by Vishnu Suresh Babu, Ashwin Mallipatna, Deepak SA, Gagan Dudeja, Ramaraj Kannan, Rohit Shetty, Archana Padmanabhan Nair, Seetharamanjaneyulu Gundimeda, Shyam S. Chaurasia, Navin Kumar Verma, Rajamani Lakshminarayanan, Stephane Heymans, Veluchamy A. Barathi, Nilanjan Guha and Arkasubhra Ghosh
Cells 2022, 11(10), 1668; https://doi.org/10.3390/cells11101668 - 18 May 2022
Cited by 7 | Viewed by 2965
Abstract
Retinoblastoma (Rb) is a pediatric intraocular malignancy that is proposed to originate from maturing cone cell precursors in the developing retina. The molecular mechanisms underlying the biological and clinical behaviors are important to understand in order to improve the management of advanced-stage tumors. [...] Read more.
Retinoblastoma (Rb) is a pediatric intraocular malignancy that is proposed to originate from maturing cone cell precursors in the developing retina. The molecular mechanisms underlying the biological and clinical behaviors are important to understand in order to improve the management of advanced-stage tumors. While the genetic causes of Rb are known, an integrated understanding of the gene expression and metabolic processes in tumors of human eyes is deficient. By integrating transcriptomic profiling from tumor tissues and metabolomics from tumorous eye vitreous humor samples (with healthy, age-matched pediatric retinae and vitreous samples as controls), we uncover unique functional associations between genes and metabolites. We found distinct gene expression patterns between clinically advanced and non-advanced Rb. Global metabolomic analysis of the vitreous humor of the same Rb eyes revealed distinctly altered metabolites, indicating how tumor metabolism has diverged from healthy pediatric retina. Several key enzymes that are related to cellular energy production, such as hexokinase 1, were found to be reduced in a manner corresponding to altered metabolites; notably, a reduction in pyruvate levels. Similarly, E2F2 was the most significantly elevated E2F family member in our cohort that is part of the cell cycle regulatory circuit. Ectopic expression of the wild-type RB1 gene in the Rb-null Y79 and WERI-Rb1 cells rescued hexokinase 1 expression, while E2F2 levels were repressed. In an additional set of Rb tumor samples and pediatric healthy controls, we further validated differences in the expression of HK1 and E2F2. Through an integrated omics analysis of the transcriptomics and metabolomics of Rb, we uncovered a significantly altered tumor-specific metabolic circuit that reduces its dependence on glycolytic pathways and is governed by Rb1 and HK1. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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19 pages, 3866 KiB  
Article
The Plasmodium falciparum CCCH Zinc Finger Protein ZNF4 Plays an Important Role in Gametocyte Exflagellation through the Regulation of Male Enriched Transcripts
by Borja Hanhsen, Afia Farrukh, Gabriele Pradel and Che Julius Ngwa
Cells 2022, 11(10), 1666; https://doi.org/10.3390/cells11101666 - 17 May 2022
Cited by 10 | Viewed by 2817
Abstract
CCCH zinc finger proteins (ZFPs) function mainly as RNA-binding proteins (RBPs) and play a central role in the mRNA metabolism. Over twenty seven CCCH-ZFPs are encoded in the genome of the human malaria parasite Plasmodium falciparum, the causative agent of malaria tropica. [...] Read more.
CCCH zinc finger proteins (ZFPs) function mainly as RNA-binding proteins (RBPs) and play a central role in the mRNA metabolism. Over twenty seven CCCH-ZFPs are encoded in the genome of the human malaria parasite Plasmodium falciparum, the causative agent of malaria tropica. However, little is known about their functions. In this study, we characterize one member of the PfCCCH-ZFP named ZNF4. We show that ZNF4 is highly expressed in mature gametocytes, where it predominantly localizes to the cytoplasm. Targeted gene disruption of ZNF4 showed no significant effect in asexual blood stage replication and gametocyte development while male gametocyte exflagellation was significantly impaired, leading to reduced malaria transmission in the mosquito. Comparative transcriptomics between wildtype (WT) and the ZNF4-deficient line (ZNF4-KO) demonstrated the deregulation of about 473 genes (274 upregulated and 199 downregulated) in mature gametocytes. Most of the downregulated genes show peak expression in mature gametocyte with male enriched genes associated to the axonemal dynein complex formation, and cell projection organization is highly affected, pointing to the phenotype in male gametocyte exflagellation. Upregulated genes are associated to ATP synthesis. Our combined data therefore indicate that ZNF4 is a CCCH zinc finger protein which plays an important role in male gametocyte exflagellation through the regulation of male gametocyte-enriched genes. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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12 pages, 2654 KiB  
Article
MAPK Signaling Pathway Is Essential for Female Reproductive Regulation in the Cabbage Beetle, Colaphellus bowringi
by Zijie Huang, Zhong Tian, Yulian Zhao, Fen Zhu, Wen Liu and Xiaoping Wang
Cells 2022, 11(10), 1602; https://doi.org/10.3390/cells11101602 - 10 May 2022
Cited by 11 | Viewed by 2500
Abstract
The mitogen-activated protein kinase (MAPK) signaling pathway is a well-conserved intracellular signal transduction pathway, and has important roles in mammalian reproduction. However, it is unknown whether MAPK also regulates insect reproductive mechanisms. Therefore, we investigated the role of the MAPK signaling pathway in [...] Read more.
The mitogen-activated protein kinase (MAPK) signaling pathway is a well-conserved intracellular signal transduction pathway, and has important roles in mammalian reproduction. However, it is unknown whether MAPK also regulates insect reproductive mechanisms. Therefore, we investigated the role of the MAPK signaling pathway in ovarian growth and oviposition in the cabbage beetle Colaphellus bowringi, an economically important pest of Cruciferous vegetables. As an initial step, 14 genes from the extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK (P38) cascades were knocked down using RNA interference (RNAi). The results revealed that RNAi knockdown of MAPK-ERK kinase (MEK), ERK, Kinase suppressor of RAS 2 (KSR2), and P38 induced ovarian development stagnation, low fecundity, and decreased longevity, which indicate that ERK and P38 signaling pathways are important for female C. bowringi survival and reproduction. The potential regulatory role of ERK and P38 pathways in the female reproductive process was investigated using quantitative real-time PCR. We found that ERK pathway possibly regulated ecdysone biosynthesis and P38 pathway possibly involved in the germline stem cell (GSC) development and differentiation. Our findings demonstrated the importance of the MAPK signaling pathway in the female reproduction of insects, and further enhanced the molecular mechanism of female reproductive regulation in insects. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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42 pages, 13834 KiB  
Article
Multiomics Approach Reveals an Important Role of BNIP3 in Myocardial Remodeling and the Pathogenesis of Heart Failure with Reduced Ejection Fraction
by Antoine H. Chaanine, LeeAnn Higgins, Lothar Lauterboeck, Todd Markowski, Qinglin Yang and Patrice Delafontaine
Cells 2022, 11(9), 1572; https://doi.org/10.3390/cells11091572 - 06 May 2022
Cited by 6 | Viewed by 2634
Abstract
Previous work showed a role of BNIP3 in myocardial remodeling and progression to HFrEF. We utilized a multiomics approach to unravel BNIP3-related molecular mechanisms in the pathogenesis of HFrEF. BNIP3 knockdown in HFrEF improved glycolysis, pyruvate metabolism, branched-chain amino acid catabolism, and oxidative [...] Read more.
Previous work showed a role of BNIP3 in myocardial remodeling and progression to HFrEF. We utilized a multiomics approach to unravel BNIP3-related molecular mechanisms in the pathogenesis of HFrEF. BNIP3 knockdown in HFrEF improved glycolysis, pyruvate metabolism, branched-chain amino acid catabolism, and oxidative phosphorylation, and restored endoplasmic reticulum (ER)–mitochondrial (mt) calcium and ion homeostasis. These effects of BNIP3 on cardiac metabolism were related to its interaction and downregulation, and/or phosphorylation, of specific mt-proteins involved in the aforementioned metabolic pathways, including the MICOS and SLC25A families of carrier proteins. BNIP3 affected ER–mt-calcium and ion homeostasis via its interaction-induced VDAC1 dimerization and modulation of VDAC1 phosphorylation at Ser104 and Ser241, and the downregulation of LETM1. At the ER level, BNIP3 interacted with the enzyme SERCA2a and the PKA signaling complex, leading to the downregulation of SERCA2a and PKA-mediated Ser16 phospholamban phosphorylation. Additionally, BNIP3 attenuated AMPK and PRKCE activity by modulating AMPK phosphorylation at Ser485/491 and Ser377 residues, and PRKCE phosphorylation at Thr521 and Thr710 residues. BNIP3 also interacted with sarcomeric, cytoskeletal, and cellular transcription and translation proteins, and affected their expression and/or phosphorylation. In conclusion, BNIP3 modulates multiple pathobiological processes and constitutes an attractive therapeutic target in HFrEF. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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40 pages, 9190 KiB  
Article
β-Arrestin2 Is Critically Involved in the Differential Regulation of Phosphosignaling Pathways by Thyrotropin-Releasing Hormone and Taltirelin
by Zdenka Drastichova, Radka Trubacova and Jiri Novotny
Cells 2022, 11(9), 1473; https://doi.org/10.3390/cells11091473 - 27 Apr 2022
Cited by 2 | Viewed by 2845
Abstract
In recent years, thyrotropin-releasing hormone (TRH) and its analogs, including taltirelin (TAL), have demonstrated a range of effects on the central nervous system that represent potential therapeutic agents for the treatment of various neurological disorders, including neurodegenerative diseases. However, the molecular mechanisms of [...] Read more.
In recent years, thyrotropin-releasing hormone (TRH) and its analogs, including taltirelin (TAL), have demonstrated a range of effects on the central nervous system that represent potential therapeutic agents for the treatment of various neurological disorders, including neurodegenerative diseases. However, the molecular mechanisms of their actions remain poorly understood. In this study, we investigated phosphosignaling dynamics in pituitary GH1 cells affected by TRH and TAL and the putative role of β-arrestin2 in mediating these effects. Our results revealed widespread alterations in many phosphosignaling pathways involving signal transduction via small GTPases, MAP kinases, Ser/Thr- and Tyr-protein kinases, Wnt/β-catenin, and members of the Hippo pathway. The differential TRH- or TAL-induced phosphorylation of numerous proteins suggests that these ligands exhibit some degree of biased agonism at the TRH receptor. The different phosphorylation patterns induced by TRH or TAL in β-arrestin2-deficient cells suggest that the β-arrestin2 scaffold is a key factor determining phosphorylation events after TRH receptor activation. Our results suggest that compounds that modulate kinase and phosphatase activity can be considered as additional adjuvants to enhance the potential therapeutic value of TRH or TAL. Full article
(This article belongs to the Topic Cell Signaling Pathways)
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