scholarly journals Transcriptomic Studies Suggest a Coincident Role for Apoptosis and Pyroptosis but Not for Autophagic Neuronal Death in TBEV-Infected Human Neuronal/Glial Cells

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2255
Author(s):  
Mazigh Fares ◽  
Kamila Gorna ◽  
Noémie Berry ◽  
Marielle Cochet-Bernoin ◽  
François Piumi ◽  
...  
Keyword(s):  
Human Brain ◽  
Glial Cells ◽  
Neuronal Death ◽  
Molecular Mechanisms ◽  
Apoptotic Pathway ◽  
Critical Feature ◽  
Permanent Disability ◽  
Pathological Model ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.

scholarly journals Retrograde Activation of the Extrinsic Apoptotic Pathway in Spinal-Projecting Neurons after a Complete Spinal Cord Injury in Lampreys

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Antón Barreiro-Iglesias ◽  
Daniel Sobrido-Cameán ◽  
Michael I. Shifman
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Extrinsic Pathway ◽  
Apoptotic Pathway ◽  
Permanent Disability ◽  
Descending Neurons ◽  
Neuronal Soma ◽  
Cord Injury ◽  
Complete Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition that leads to permanent disability because injured axons do not regenerate across the trauma zone to reconnect to their targets. A prerequisite for axonal regeneration will be the prevention of retrograde degeneration that could lead to neuronal death. However, the specific molecular mechanisms of axotomy-induced degeneration of spinal-projecting neurons have not been elucidated yet. In lampreys, SCI induces the apoptotic death of identifiable descending neurons that are “bad regenerators/poor survivors” after SCI. Here, we investigated the apoptotic process activated in identifiable descending neurons of lampreys after SCI. For this, we studied caspase activation by using fluorochrome-labeled inhibitors of caspases, the degeneration of spinal-projecting neurons using Fluro-Jade C staining, and the involvement of the intrinsic apoptotic pathway by means of cytochrome c and Vαdouble immunofluorescence. Our results provide evidence that, after SCI, bad-regenerating spinal cord-projecting neurons slowly degenerate and that the extrinsic pathway of apoptosis is involved in this process. Experiments using the microtubule stabilizer Taxol showed that caspase-8 signaling is retrogradely transported by microtubules from the site of axotomy to the neuronal soma. Preventing the activation of this process could be an important therapeutic approach after SCI in mammals.

scholarly journals Molecular Mechanisms of Neural Circuit Development and Regeneration

2021 ◽  
Vol 22 (9) ◽  
pp. 4593
Author(s):  
Lieve Moons ◽  
Lies De Groef
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Circuit Development

The human brain contains 86 billion neurons [...]

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

Protective effect of vitamin C against the ethanol mediated toxic effects on human brain glial cells

2003 ◽  
Vol 14 (10) ◽  
pp. 606-613 ◽  
Author(s):  
Concepción Sánchez-Moreno ◽  
Manuel Paniagua ◽  
Antonio Madrid ◽  
Antonio Martín
Keyword(s):  
Vitamin C ◽  
Human Brain ◽  
Protective Effect ◽  
Glial Cells ◽  
Toxic Effects

scholarly journals Infection and injury of human astrocytes by tick-borne encephalitis virus

2014 ◽  
Vol 95 (11) ◽  
pp. 2411-2426 ◽  
Author(s):  
Martin Palus ◽  
Tomáš Bílý ◽  
Jana Elsterová ◽  
Helena Langhansová ◽  
Jiří Salát ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Encephalitis Virus ◽  
Ultrastructural Changes ◽  
Interferon Α ◽  
Human Astrocytes ◽  
Tick Borne Encephalitis ◽  
Infected Cells ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection ◽  
Pro Inflammatory Cytokines

Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents the most important flaviviral neural infection in Europe and north-eastern Asia. In the central nervous system (CNS), neurons are the primary target for TBEV infection; however, infection of non-neuronal CNS cells, such as astrocytes, is not well understood. In this study, we investigated the interaction between TBEV and primary human astrocytes. We report for the first time, to the best of our knowledge, that primary human astrocytes are sensitive to TBEV infection, although the infection did not affect their viability. The infection induced a marked increase in the expression of glial fibrillary acidic protein, a marker of astrocyte activation. In addition, expression of matrix metalloproteinase 9 and several key pro-inflammatory cytokines/chemokines (e.g. tumour necrosis factor α, interferon α, interleukin (IL)-1β, IL-6, IL-8, interferon γ-induced protein 10, macrophage inflammatory protein, but not monocyte chemotactic protein 1) was upregulated. Moreover, we present a detailed description of morphological changes in TBEV-infected cells, as investigated using three-dimensional electron tomography. Several novel ultrastructural changes were observed, including the formation of unique tubule-like structures of 17.9 ±0.15 nm diameter with associated viral particles and/or virus-induced vesicles and located in the rough endoplasmic reticulum of the TBEV-infected cells. This is the first demonstration that TBEV infection activates primary human astrocytes. The infected astrocytes might be a potential source of pro-inflammatory cytokines in the TBEV-infected brain, and might contribute to the TBEV-induced neurotoxicity and blood–brain barrier breakdown that occurs during TBE. The neuropathological significance of our observations is also discussed.

scholarly journals Two Cases of Severe Tick-Borne Encephalitis in Rituximab-Treated Patients in Germany: Implications for Diagnosis and Prevention

2017 ◽  
Vol 4 (4) ◽  
Author(s):  
Philipp A Steininger ◽  
Tobias Bobinger ◽  
Wenke Dietrich ◽  
De-Hyung Lee ◽  
Michael Knott ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
B Cell ◽  
Standard Therapy ◽  
Laboratory Diagnosis ◽  
Antibody Responses ◽  
B Cell Malignancies ◽  
Tick Borne Encephalitis ◽  
Preventive Vaccination ◽  
Tick Borne Encephalitis Virus ◽  
Tbev Infection

Abstract Rituximab (RTX) has become a standard therapy for certain B cell malignancies and autoimmune diseases. We report 2 RTX-treated patients who developed severe tick-borne encephalitis virus (TBEV) infection. The inability to generate new antibody responses renders RTX-treated patients susceptible to TBEV, impedes laboratory diagnosis, and necessitates preventive vaccination in endemic areas.

scholarly journals Tick populations from endemic and non-endemic areas in Germany show differential susceptibility to TBEV

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katrin Liebig ◽  
Mathias Boelke ◽  
Domenic Grund ◽  
Sabine Schicht ◽  
Andrea Springer ◽  
...  
Keyword(s):  
Differential Susceptibility ◽  
Feeding Rates ◽  
Infection Rates ◽  
Lower Saxony ◽  
Tick Borne Encephalitis ◽  
The Central Nervous System ◽  
Tick Borne Encephalitis Virus ◽  
In Vitro Feeding ◽  
Tbev Infection

Abstract Tick-borne encephalitis virus (TBEV) is endemic in twenty-seven European countries, transmitted via the bite of an infected tick. TBEV is the causative agent of one of the most important viral diseases of the central nervous system (CNS). In Germany, 890 human cases were registered between the years 2018–2019. The castor bean tick, Ixodes ricinus, is the TBEV vector with the highest importance in Central Europe, including Germany. Despite the nationwide distribution of this tick species, risk areas of TBEV are largely located in Southern Germany. To increase our understanding of TBEV-tick interactions, we collected ticks from different areas within Germany (Haselmühl/Bavaria, Hanover/Lower Saxony) and infected them via an in vitro feeding system. A TBEV isolate was obtained from an endemic focus in Haselmühl. In two experimental series conducted in 2018 and 2019, ticks sampled in Haselmühl (TBEV focus) showed higher artificial feeding rates, as well as higher TBEV infections rates than ticks from the non-endemic area (Hanover). Other than the tick origin, year and month of the infection experiment as well as co-infection with Borrelia spp., had a significant impact on TBEV Haselmühl infection rates. Taken together, these findings suggest that a specific adaptation of the tick populations to their respective TBEV virus isolates or vice versa, leads to higher TBEV infection rates in those ticks. Furthermore, co-infection with other tick-borne pathogens such as Borrelia spp. can lower TBEV infection rates in specific populations.

7-hydroxyfrullanolide, isolated from Sphaeranthus indicus, inhibits colorectal cancer cell growth by p53-dependent and -independent mechanism

2018 ◽  
Vol 40 (6) ◽  
pp. 791-804
Author(s):  
Praveen Pandey ◽  
Deepika Singh ◽  
Mohammad Hasanain ◽  
Raghib Ashraf ◽  
Mayank Maheshwari ◽  
...  
Keyword(s):  
Cell Growth ◽  
Anticancer Activity ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cancer Cell Growth ◽  
Apoptotic Pathway ◽  
Syngeneic Mouse Model ◽  
Sphaeranthus Indicus

Abstract Sphaeranthus indicus Linn. is commonly used in Indian traditional medicine for management of multiple pathological conditions. However, there are limited studies on anticancer activity of this plant and its underlying molecular mechanisms. Here, we isolated an active constituent, 7-hydroxyfrullanolide (7-HF), from the flowers of this plant, which showed promising chemotherapeutic potential. The compound was more effective in inhibiting in vitro proliferation of colon cancers cells through G2/M phase arrest than other cancer cell lines that were used in this study. Consistent with in vitro data, 7-HF caused substantial regression of tumour volume in a syngeneic mouse model of colon cancer. The molecule triggered extrinsic apoptotic pathway, which was evident as upregulation of DR4 and DR5 expression as well as induction of their downstream effector molecules (FADD, Caspase-8). Concurrent activation of intrinsic pathway was demonstrated with loss of ΔΨm to release pro-apoptotic cytochrome c from mitochondria and activation of downstream caspase cascades (Caspase -9, -3). Loss of p53 resulted in decreased sensitivity of cells towards pro-apoptotic effect of 7-HF with increased number of viable cells indicating p53-dependent arrest of cancer cell growth. This notion was further supported with 7-HF-mediated elevation of endogenous p53 level, decreased expression of MDM2 and transcriptional upregulation of p53 target genes in apoptotic pathway. However, 7-HF was equally effective in preventing progression of HCT116 p53+/+ and p53−/− cell derived xenografts in nude mice, which suggests that differences in p53 status may not influence its in vivo efficacy. Taken together, our results support 7-HF as a potential chemotherapeutic agent and provided a new mechanistic insight into its anticancer activity.

scholarly journals WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunqi Zhu ◽  
Xiangmin Tong ◽  
Ying Wang ◽  
Xiaoya Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hematologic Malignancy ◽  
Apoptotic Pathway ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

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