Snail modulates JNK-mediated cell death in Drosophila

AbstractCell death plays a pivotal role in animal development and tissue homeostasis. Dysregulation of this process is associated with a wide variety of human diseases, including developmental and immunological disorders, neurodegenerative diseases and tumors. While the fundamental role of JNK pathway in cell death has been extensively studied, its down-stream regulators and the underlying mechanisms remain largely elusive. From a Drosophila genetic screen, we identified Snail (Sna), a Zinc-finger transcription factor, as a novel modulator of ectopic Egr-induced JNK-mediated cell death. In addition, sna is essential for the physiological function of JNK signaling in development. Our genetic epistasis data suggest that Sna acts downstream of JNK to promote cell death. Mechanistically, JNK signaling triggers dFoxO-dependent transcriptional activation of sna. Thus, our findings not only reveal a novel function and the underlying mechanism of Sna in modulating JNK-mediated cell death, but also provide a potential drug target and therapeutic strategies for JNK signaling-related diseases.

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Frazzled/Dcc acts independently of Netrin to promote germline survival during Drosophila oogenesis

Development ◽

10.1242/dev.199762 ◽

2021 ◽

Vol 148 (24) ◽

Author(s):

Samantha A. Russell ◽

Kaitlin M. Laws ◽

Greg J. Bashaw

Keyword(s):

Cell Death ◽

Axon Guidance ◽

Transcriptional Activation ◽

Nutrient Sensing ◽

Activation Domain ◽

Transcriptional Activation Domain ◽

Egg Chambers ◽

Death Effector ◽

Female Germline

ABSTRACT The Netrin receptor Frazzled/Dcc (Fra in Drosophila) functions in diverse tissue contexts to regulate cell migration, axon guidance and cell survival. Fra signals in response to Netrin to regulate the cytoskeleton and also acts independently of Netrin to directly regulate transcription during axon guidance in Drosophila. In other contexts, Dcc acts as a tumor suppressor by directly promoting apoptosis. In this study, we report that Fra is required in the Drosophila female germline for the progression of egg chambers through mid-oogenesis. Loss of Fra in the germline, but not the somatic cells of the ovary, results in the degeneration of egg chambers. Although a failure in nutrient sensing and disruptions in egg chamber polarity can result in degeneration at mid-oogenesis, these factors do not appear to be affected in fra germline mutants. However, similar to the degeneration that occurs in those contexts, the cell death effector Dcp-1 is activated in fra germline mutants. The function of Fra in the female germline is independent of Netrin and requires the transcriptional activation domain of Fra. In contrast to the role of Dcc in promoting cell death, our observations reveal a role for Fra in regulating germline survival by inhibiting apoptosis.

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An Evidence for a Novel Antiviral Mechanism of Teleost Fish: Serum-Derived Exosomes Inhibit Virus Replication Through Incorporating Mx1 Protein

10.20944/preprints202107.0160.v1 ◽

2021 ◽

Author(s):

Changjun Guo ◽

Jian He ◽

Zhi-Min Li ◽

Yuanyuan Wang ◽

Chen nan nan ◽

...

Keyword(s):

Cancer Progression ◽

Teleost Fish ◽

Protein Composition ◽

Underlying Mechanism ◽

Antiviral Effect ◽

Mandarin Fish ◽

Underlying Mechanisms ◽

Antiviral Mechanism ◽

Fish Serum

Exosomes are associated with cancer progression, pregnancy, cardiovascular diseases, central nervous system–related diseases, immune responses and viral pathogenicity. However, study on the role of exosomes in the immune response of teleost fish, especially antiviral immunity, is limited. Herein, serum-derived exosomes from mandarin fish were used to investigate antiviral effect for the exosomes of teleost fish. Exosomes were isolated from mandarin fish serum by ultracentrifugation could internalize into Mandarin fish fry (MFF-1) cells and inhibited Infectious spleen and kidney necrosis virus (ISKNV) infection. To further investigated the underlying mechanisms of exosomes in inhibiting ISKNV infection. The protein composition of serum-derived exosomes was by analysis mass spectrometry and found that myxovirus resistance 1 (Mx1) was incorporated in the exosomes. Furthermore, the scMx1 protein was proved transferred to the recipient cells though the exosomes. Our results found that the serum-derived exosomes from mandarin fish could inhibit ISKNV replication and suggested an underlying mechanism of the serum-derived exosomes antivirus is that serum-derived exosomes incorporation of the Mx1 protein into exosomes and delivery into recipient cells. This study provided an evidence for the important antiviral role of exosomes in the immune system of teleost fish.

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Loss of Notch3 Signaling Enhances Osteogenesis of Mesenchymal Stem Cells from Mandibular Torus

Journal of Dental Research ◽

10.1177/0022034516680349 ◽

2016 ◽

Vol 96 (3) ◽

pp. 347-354 ◽

Cited By ~ 4

Author(s):

X.W. Dou ◽

W. Park ◽

S. Lee ◽

Q.Z. Zhang ◽

L.R. Carrasco ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Osteogenic Differentiation ◽

Transcriptional Activation ◽

Target Genes ◽

Adipogenic Differentiation ◽

Underlying Mechanism ◽

Jaw Bone ◽

Downstream Target

Mandibular torus (MT) is a common intraoral osseous outgrowth located on the lingual surface of the mandible. Histologic features include hyperplastic bone consisting of mature cortical and trabecular bone. Some theories on the etiology of MT have been postulated, such as genetic factors, masticatory hyperfunction, trauma, and continued growth, but the underlying mechanism remains largely unknown. In this study, we investigated the potential role of mesenchymal stem cells (MSCs) derived from human MT in the pathogenesis of bone outgrowth. We demonstrated that MT harbored a distinct subpopulation of MSCs, with enhanced osteogenic and decreased adipogenic differentiation capacities, as compared with their counterparts from normal jaw bone. The increased osteogenic differentiation of mandibular torus MSCs was associated with the suppression of Notch3 signaling and its downstream target genes, Jag1 and Hey1, and a reciprocal increase in the transcriptional activation of ATF4 and NFATc1 genes. Targeted knockdown of Notch3 expression by transient siRNA transfection promoted the expression of osteogenic transcription factors in normal jaw bone MSCs. Our data suggest that the loss of Notch3 signaling may contribute partly to bone outgrowth in MT, as mediated by enhanced MSC-driven osteogenic differentiation in the jaw bone.

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Regulating inflammation associated Ferroptosis-a treatment strategy for Parkinson disease

Current Medicinal Chemistry ◽

10.2174/0929867328666210419125032 ◽

2021 ◽

Vol 28 ◽

Author(s):

Marthandam Asokan Shibu ◽

B. Mahalakshmi ◽

V. Bharath Kumar

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Treatment Strategy ◽

Neurological Disorders ◽

Neurological Diseases ◽

Underlying Mechanism ◽

Acute Injury ◽

Brain Iron ◽

Kidney Tumors

: Ferroptosis plays a critical regulatory role for a new kind of cell death initiating and developing an array of disorders like neurological diseases, acute injury of kidney, tumors and ischemia etc. This selective deposition of iron is one of the pathogenic reasons for PD and although it’s underlying mechanism is still unknown. In this review, the role of neuroinflammation in Parkinson’s disease (PD) leading to neurodegeneration has been discussed in detail. The accumulation of brain iron has been found in many chronic neurological disorders including PD. We have also discussed the unique features of Ferroptosis as compared to other cellular death pathways and it links in aggravating the pathology of PD. Further, the concept of targeting Ferroptosis for PD pathology and inducers and inhibitors, pharmacological drugs and clinical trials for PD candidates in phase IV stage in completed status are detailed in the respective sections.

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Mathematical modelling of the role of GADD45β in the pathogenesis of multiple myeloma

Royal Society Open Science ◽

10.1098/rsos.192152 ◽

2020 ◽

Vol 7 (5) ◽

pp. 192152

Author(s):

Yao Zhang ◽

Changqing Zhen ◽

Qing Yang ◽

Bing Ji

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Bone Cells ◽

Specific Treatment ◽

Underlying Mechanism ◽

High Morbidity ◽

Jnk Pathway ◽

Incurable Disease ◽

Targeted Treatments

Multiple myeloma (MM) is an incurable disease with relatively high morbidity and mortality rates. Great efforts were made to develop nuclear factor-kappa B (NF-κB)-targeted therapies against MM disease. However, these treatments influence MM cells as well as normal cells, inevitably causing serious side effects. Further research showed that NF-κB signalling promotes the survival of MM cells by interacting with JNK signalling through growth arrest and DNA damage-inducible beta (GADD45β), the downstream module of NF-κB signalling. The GADD45β-targeted intervention was suggested to be an effective and MM cell-specific treatment. However, the underlying mechanism through which GADD45β promotes the survival of MM cells is usually ignored in the previous models. A mathematical model of MM is built in this paper to investigate how NF-κB signalling acts along with JNK signalling through GADD45β and MKK7 to promote the survival of MM cells. The model cannot only mimic the variations in bone cells, the bone volume and MM cells with time, but it can also examine how the NF-κB pathway acts with the JNK pathway to promote the development of MM cells. In addition, the model also investigates the efficacies of GADD45β - and NF-κB-targeted treatments, suggesting that GADD45β-targeted therapy is more effective but has no apparent side effects. The simulation results match the experimental observations. It is anticipated that this model could be employed as a useful tool to initially investigate and even explore potential therapies involving the NF-κB and JNK pathways in the future.

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Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22126259 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6259

Author(s):

Amany Tawfik ◽

Nehal M. Elsherbiny ◽

Yusra Zaidi ◽

Pragya Rajpurohit

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Barrier Function ◽

Underlying Mechanism ◽

Age Related Macular Degeneration ◽

Barrier Dysfunction ◽

Age Related ◽

The Central Nervous System ◽

Underlying Mechanisms

Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.

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The Potential Role of Ferroptosis in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201369 ◽

2021 ◽

Vol 80 (3) ◽

pp. 907-925

Author(s):

Guimei Zhang ◽

Yaru Zhang ◽

Yanxin Shen ◽

Yongchun Wang ◽

Meng Zhao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Peroxidation ◽

Cell Death ◽

Iron Metabolism ◽

Apoptotic Cell ◽

Potential Interaction ◽

Underlying Mechanisms ◽

And Oxidative Stress

Alzheimer’s disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%–80%of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis—an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD.

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Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3

Cell Death and Disease ◽

10.1038/s41419-021-04419-8 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Etienne Delangre ◽

Junjun Liu ◽

Stefania Tolu ◽

Kamel Maouche ◽

Mathieu Armanet ◽

...

Keyword(s):

Cell Death ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Β Cells ◽

Β Cell ◽

Protein Levels ◽

Underlying Mechanisms ◽

Apoptotic Effects

AbstractGlucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.

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JNK signaling prevents biliary cyst formation through a CASPASE-8–dependent function of RIPK1 during aging

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007194118 ◽

2021 ◽

Vol 118 (12) ◽

pp. e2007194118

Author(s):

Katrin Müller ◽

Hanna Honcharova-Biletska ◽

Christiane Koppe ◽

Michèle Egger ◽

Lap Kwan Chan ◽

...

Keyword(s):

Cell Death ◽

Cyst Formation ◽

Jnk Pathway ◽

Interacting Protein ◽

Jnk Signaling ◽

Age Related ◽

Polycystic Liver ◽

Jnk Signaling Pathway ◽

Stress Signals ◽

Parenchymal Cells

The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.

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