scholarly journals Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

2021 ◽  
Author(s):  
Michel Cuenod ◽  
Pascal Steullet ◽  
Jan-Harry Cabungcal ◽  
Daniella Dwir ◽  
Ines Khadimallah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neural Circuit ◽  
Complex Dynamics ◽  
Signal To Noise Ratio ◽  
Therapeutic Approaches ◽  
Feed Forward ◽  
Reverse Translation ◽  
Convergence Point ◽  
And Function

AbstractA growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or “central hub” for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating “vicious circles” centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

scholarly journals Roles of Autophagy in Oxidative Stress

2020 ◽  
Vol 21 (9) ◽  
pp. 3289 ◽  
Author(s):  
Hyeong Rok Yun ◽  
Yong Hwa Jo ◽  
Jieun Kim ◽  
Yoonhwa Shin ◽  
Sung Soo Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Stress Responses ◽  
Basic Mechanism ◽  
Redox Signalling ◽  
Mitochondrial Ros ◽  
Related Stress ◽  
And Function ◽  
Catabolic Process

Autophagy is a catabolic process for unnecessary or dysfunctional cytoplasmic contents by lysosomal degradation pathways. Autophagy is implicated in various biological processes such as programmed cell death, stress responses, elimination of damaged organelles and development. The role of autophagy as a crucial mediator has been clarified and expanded in the pathological response to redox signalling. Autophagy is a major sensor of the redox signalling. Reactive oxygen species (ROS) are highly reactive molecules that are generated as by-products of cellular metabolism, principally by mitochondria. Mitochondrial ROS (mROS) are beneficial or detrimental to cells depending on their concentration and location. mROS function as redox messengers in intracellular signalling at physiologically low level, whereas excessive production of mROS causes oxidative damage to cellular constituents and thus incurs cell death. Hence, the balance of autophagy-related stress adaptation and cell death is important to comprehend redox signalling-related pathogenesis. In this review, we attempt to provide an overview the basic mechanism and function of autophagy in the context of response to oxidative stress and redox signalling in pathology.

Structure and Function of the Plant Alternative Oxidase: Its Putative Role in the Oxygen Defence Mechanism

1997 ◽  
Vol 17 (3) ◽  
pp. 319-333 ◽  
Author(s):  
Anneke M. Wagner ◽  
Anthony L. Moore
Keyword(s):  
Oxidative Stress ◽  
Alternative Oxidase ◽  
Structure And Function ◽  
Current Understanding ◽  
Defence Mechanism ◽  
Putative Role ◽  
And Function

Current understanding of the structure and function of the plant alternative oxidase is reviewed. In particular, the role of the oxidase in the protection of tissues against oxidative stress is developed.

scholarly journals P-glycoprotein (ABCB1) and Oxidative Stress: Focus on Alzheimer’s Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Giulia Sita ◽  
Patrizia Hrelia ◽  
Andrea Tarozzi ◽  
Fabiana Morroni
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Drug ◽  
Amyloid A ◽  
P Glycoprotein ◽  
And Function ◽  
The Brain ◽  
Brain Homeostasis

ATP-binding cassette (ABC) transporters, in particular P-glycoprotein (encoded by ABCB1), are important and selective elements of the blood-brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (Aβ) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer’s disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the Aβtransport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain.

scholarly journals 17β-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B

2017 ◽  
Vol 232 (2) ◽  
pp. 297-308 ◽  
Author(s):  
Bel M Galmés-Pascual ◽  
Antonia Nadal-Casellas ◽  
Marco Bauza-Thorbrügge ◽  
Miquel Sbert-Roig ◽  
Francisco J García-Palmer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Biogenesis ◽  
Oxidative Capacity ◽  
Protective Role ◽  
Rat Tissues ◽  
Peroxisome Proliferator ◽  
Ovx Rats ◽  
17Β Estradiol ◽  
And Function

Sexual dimorphism in mitochondrial biogenesis and function has been described in many rat tissues, with females showing larger and more functional mitochondria. The family of the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) plays a central role in the regulatory network governing mitochondrial biogenesis and function, but little is known about the different contribution of hepatic PGC1A and PGC1B in these processes. The aim of this study was to elucidate the role of 17β-estradiol (E2) in mitochondrial biogenesis and function in liver and assess the contribution of both hepatic PGC1A and PGC1B as mediators of these effects. In ovariectomized (OVX) rats (half of which were treated with E2) estrogen deficiency led to impaired mitochondrial biogenesis and function, increased oxidative stress, and defective lipid metabolism, but was counteracted by E2 treatment. In HepG2 hepatocytes, the role of E2 in enhancing mitochondrial biogenesis and function was confirmed. These effects were unaffected by the knockdown of PGC1A, but were impaired when PGC1B expression was knocked down by specific siRNA. Our results reveal a widespread protective role of E2 in hepatocytes, which is explained by enhanced mitochondrial content and oxidative capacity, lower hepatic lipid accumulation, and a reduction of oxidative stress. We also suggest a novel hepatic protective role of PGC1B as a modulator of E2 effects on mitochondrial biogenesis and function supporting activation of PGC1B as a therapeutic target for hepatic mitochondrial disorders.

Weak signal detection and propagation in diluted feed-forward neural network with recurrent excitation and inhibition

2016 ◽  
Vol 30 (02) ◽  
pp. 1550253 ◽  
Author(s):  
Jiang Wang ◽  
Ruixue Han ◽  
Xilei Wei ◽  
Yingmei Qin ◽  
Haitao Yu ◽  
...  
Keyword(s):  
Neural Circuit ◽  
Signal Propagation ◽  
Weak Signal ◽  
Feed Forward Neural Network ◽  
Feed Forward ◽  
Recurrent Excitation ◽  
Iterated Maps ◽  
Network States ◽  
Circuit Function

Reliable signal propagation across distributed brain areas provides the basis for neural circuit function. Modeling studies on cortical circuits have shown that multilayered feed-forward networks (FFNs), if strongly and/or densely connected, can enable robust signal propagation. However, cortical networks are typically neither densely connected nor have strong synapses. This paper investigates under which conditions spiking activity can be propagated reliably across diluted FFNs. Extending previous works, we model each layer as a recurrent sub-network constituting both excitatory (E) and inhibitory (I) neurons and consider the effect of interactions between local excitation and inhibition on signal propagation. It is shown that elevation of cellular excitation–inhibition (EI) balance in the local sub-networks (layers) softens the requirement for dense/strong anatomical connections and thereby promotes weak signal propagation in weakly connected networks. By means of iterated maps, we show how elevated local excitability state compensates for the decreased gain of synchrony transfer function that is due to sparse long-range connectivity. Finally, we report that modulations of EI balance and background activity provide a mechanism for selectively gating and routing neural signal. Our results highlight the essential role of intrinsic network states in neural computation.

scholarly journals The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.

2006 ◽  
Vol 53 (4) ◽  
pp. 651-662 ◽  
Author(s):  
Laura L Yates ◽  
Dariusz C Górecki
Keyword(s):  
Nuclear Factor Kappab ◽  
Specific Response ◽  
Nuclear Factor ◽  
Therapeutic Approaches ◽  
Altered Regulation ◽  
Nf Kappab ◽  
Novel Therapeutic Strategies ◽  
And Function

The nuclear factor-kappaB (NF-kappaB) transcription factors regulate a plethora of cellular pathways and processes including the immune response, inflammation, proliferation, apoptosis and calcium homeostasis. In addition to the complexity of its physiological roles, the composition and function of this family of proteins is very complicated. While the basic understanding of NF-kappaB signalling is extensive, relatively little is know of the in vivo dynamics of this pathway or what controls the balance between various outcomes. Although we know a large number of NF-kappaB-responsive genes, the contribution of these genes to a specific response is not always clear. Finally, the involvement of NF-kappaB in pathological processes is only now beginning to be unravelled. In addition to cancer and immunodeficiency disorders, altered regulation of NF-kappaB has been associated with several inherited diseases. These findings indicate that modulation of the NF-kappaB pathways may be beneficial. However, our limited knowledge of NF-kappaB signalling hinders therapeutic approaches: in many situations it is not clear whether the enhancement or inhibition of NF-kappaB activity would be beneficial or which pathways to interfere with and what the required level of activation is. Further studies of the role of NF-kappaB are needed as these may result in novel therapeutic strategies for a wide variety of diseases.

The role of Non-coding Genome in Cancer-associated Fibroblasts; state-of-the-art and perspectives in cancer targeted therapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Arezoo Gowhari Shabgah ◽  
Hamed Mohammadi ◽  
Pouya Goleij ◽  
Mahdiyeh Hedayati-Moghadam ◽  
Arash Salmaninejad ◽  
...  
Keyword(s):  
Healing Process ◽  
Wound Healing Process ◽  
Cancer Associated Fibroblasts ◽  
Therapeutic Approaches ◽  
Signaling Center ◽  
Non Coding Rnas ◽  
And Function ◽  
Cancer Targeted Therapy ◽  
Shed Light

: Cancer-associated fibroblasts (CAFs) are senescent fibroblasts in tumor nest, which trigger a signaling center to remodel a desmoplastic tumor niche. CAF’s functions in cancer are closely similar to myofibroblasts during the wound healing process. They can produce cytokine, enzymes, and protein- or RNA-containing exosomes to alter the function of surrounding cells. Non-coding RNAs, including microRNAs and long non-coding RNAs, modulate pathologic mechanisms in cancer. Dysregulation of these RNAs influences the formation and function of CAFs. Furthermore, it has been demonstrated that CAFs, by releasing non-coding RNAs-containing exosomes, affect the tumor cells’ behavior. CAFs also secrete mediators such as chemokines to alter the expression of non-coding RNAs in the tumor microenvironment. This study aimed to discuss the role of non-coding RNAs in CAF development in cancer situations. Additionally, we are going to shed light on the therapeutic approaches to develop the strategies based-on the alteration of non-coding RNAs in cancer.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals Th17 and Treg Cells in Bone Related Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Min Wang ◽  
Tian Tian ◽  
Shuang Yu ◽  
Na He ◽  
Daoxin Ma
Keyword(s):  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Treg Cells ◽  
Bone Diseases ◽  
Reciprocal Relationship ◽  
T Helper ◽  
Therapeutic Approaches ◽  
T Helper 17 ◽  
And Function

Bone-related diseases share the process of immune response that targets bone tissue and bone marrow and then induce adverse effects on structure and function. In recent years, reciprocal relationship between immune cells and bone systems has been uncovered gradually. Regulatory T (Treg) and T helper 17 (Th17) cells are newly identified subsets of CD4+ T cells, and the balance between them is particularly essential for maintaining immune homeostasis. Accumulated data have demonstrated quantitative or functional imbalance between Th17 and Treg in bone related diseases, suggesting that Th17 and Treg cells are involved in these bone diseases. Understanding the molecular mechanisms regulating Th17 and Treg cells will create opportunities for the development of therapeutic approaches. This review will present the role of Th17 and Treg cells in the inflammatory bone diseases and bone marrow malignancies and find the potential therapeutic target for immunotherapy.

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