Due to a multiplicity of causes provoking traumatic brain injury (TBI), TBI is a highly heterogeneous pathology, characterized by high mortality and disability rates. TBI is an acute neurodegenerative event, potentially and unpredictably evolving into sub-chronic and chronic neurodegenerative events, with transient or permanent neurologic, cognitive, and motor deficits, for which no valid standardized therapies are available. A vast body of literature demonstrates that TBI-induced oxidative/nitrosative stress is involved in the development of both acute and chronic neurodegenerative disorders. Cellular defenses against this phenomenon are largely dependent on low molecular weight antioxidants, most of which are consumed with diet or as nutraceutical supplements. A large number of studies have evaluated the efficacy of antioxidant administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. Points of weakness of preclinical studies are represented by the large variability in the TBI model adopted, in the antioxidant tested, in the timing, dosages, and routes of administration used, and in the variety of molecular and/or neurocognitive parameters evaluated. The analysis of the very few clinical studies does not allow strong conclusions to be drawn on the real effectiveness of antioxidant administration to TBI patients. Standardizing TBI models and different experimental conditions, as well as testing the efficacy of administration of a cocktail of antioxidants rather than only one, should be mandatory. According to some promising clinical results, it appears that sports-related concussion is probably the best type of TBI to test the benefits of antioxidant administration.

Antioxidant therapies in traumatic brain injury

Cancer stemness, defined as the self-renewal and tumor-initiation potential of cancer stem cells (CSCs), is a cancer biology property featuring activation of CSC signaling networks. Canonical WNT signaling through Frizzled and LRP5/6 receptors is transmitted to the β-catenin-TCF/LEF-dependent transcription machinery to up-regulate MYC, CCND1, LGR5, SNAI1, IFNG, CCL28, CD274 (PD-L1) and other target genes. Canonical WNT signaling causes expansion of rapidly cycling CSCs and modulates both immune surveillance and immune tolerance. In contrast, noncanonical WNT signaling through Frizzled or the ROR1/2 receptors is transmitted to phospholipase C, Rac1 and RhoA to control transcriptional outputs mediated by NFAT, AP-1 and YAP-TEAD, respectively. Noncanonical WNT signaling supports maintenance of slowly cycling, quiescent or dormant CSCs and promotes epithelial-mesenchymal transition via crosstalk with TGFβ (transforming growth factor-β) signaling cascades, while the TGFβ signaling network induces immune evasion. The WNT signaling network orchestrates the functions of cancer-associated fibroblasts, endothelial cells and immune cells in the tumor microenvironment and fine-tunes stemness in human cancers, such as breast, colorectal, gastric and lung cancers. Here, WNT-related cancer stemness features, including proliferation/dormancy plasticity, epithelial-mesenchymal plasticity and immune-landscape plasticity, will be discussed. Porcupine inhibitors, β-catenin protein-protein interaction inhibitors, β-catenin proteolysis targeting chimeras, ROR1 inhibitors and ROR1-targeted biologics are investigational drugs targeting WNT signaling cascades. Mechanisms of cancer plasticity regulated by the WNT signaling network are promising targets for therapeutic intervention; however, further understanding of context-dependent reprogramming trajectories might be necessary to optimize the clinical benefits of WNT-targeted monotherapy and applied combination therapy for patients with cancer. 

https://portlandpress.com/essaysbiochem/article-pdf/66/4/319/937187/ebc-2022-0016c.pdf

WNT signaling and cancer stemness

Enhanced oxidative stress is a contributing factor in the pathogenesis of several neurodegenerative disorders such as Alzheimer´s disease. Beneficial effects have been demonstrated for medium-chain fatty acids (MCFAs) nutritionally administered as medium-chain triglycerides (MCTs) or coconut oil (CO). The observed effects on cognitive impairment are generally attributed to the hepatic metabolism of MCFAs, where resulting ketone bodies serve as an alternate energy source to compensate for the impaired glucose utilisation in the human brain. Here we show that the saturated MCFA decanoic acid (10:0) reduces the oxidative stress level in two different neuroblastoma cell lines. Phosphatidylcholine (PC) containing decanoic acid (10:0) (PC10:0/10:0) reduced the cellular H2O2 release in comparison to solvent, L-α-Glycerophosphorylcholine and PC containing the long-chain fatty acid (LCFA) arachidic acid (20:0). This effect seems to be at least partially based on an upregulation of catalase activity, independent of alterations in catalase gene expression. Further, PC10:0/10:0 decreased the intracellular oxidative stress level and attenuated the H2O2-induced cell death. It did not affect the level of the ketone body β-hydroxybutyrate (βHB). These results indicate that decanoic acid (10:0) and possibly MCFAs in general directly reduce oxidative stress levels independent of ketone levels and thus may promote neuronal health.

/pdf/the-medium-chain-fatty-acid-decanoic-acid-reduces-oxidative-i0k2vbax19.pdf

The medium-chain fatty acid decanoic acid reduces oxidative stress levels in neuroblastoma cells

Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration.

DHA (docosahexaenoic acid) is perhaps the most pleiotropic molecule in nerve cell biology. This long-chain highly unsaturated fatty acid has evolved to accomplish essential functions ranging from structural components allowing fast events in nerve cell membrane physiology to regulation of neurogenesis and synaptic function. Strikingly, the plethora of DHA effects has to take place within the hostile pro-oxidant environment of the brain parenchyma, which might suggest a molecular suicide. In order to circumvent this paradox, different molecular strategies have evolved during the evolution of brain cells to preserve DHA and to minimize the deleterious effects of its oxidation. In this context, DHA has emerged as a member of the “indirect antioxidants” family, the redox effects of which are not due to direct redox interactions with reactive species, but to modulation of gene expression within thioredoxin and glutathione antioxidant systems and related pathways. Weakening or deregulation of these self-protecting defenses orchestrated by DHA is associated with normal aging but also, more worryingly, with the development of neurodegenerative diseases. In the present review, we elaborate on the essential functions of DHA in the brain, including its role as indirect antioxidant, the selenium connection for proper antioxidant function and their changes during normal aging and in Alzheimer’s disease.

/pdf/dha-and-its-elaborated-modulation-of-antioxidant-defenses-of-49uu7tnj5x.pdf

DHA and Its Elaborated Modulation of Antioxidant Defenses of the Brain: Implications in Aging and AD Neurodegeneration

PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion

In this study, we explored the neuroprotective effects of docosahexaenoic acid (DHA) in traumatic brain injury (TBI) models. In this study, we first confirmed that DHA was neuroprotective against TBI via the NSS test and Morris water maze experiment. Western blot was conducted to identify the expression of Bax, caspase-3, and Bcl-2. And the cell apoptosis of the TBI models was validated by TUNEL staining. Relationships between nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) pathway-related genes and DHA were explored by RT-PCR and Western blot. Rats of the DHA group performed remarkably better than those of the TBI group in both NSS test and water maze experiment. DHA conspicuously promoted the expression of Bcl-2 and diminished that of cleaved caspase-3 and Bax, indicating the anti-apoptotic role of DHA. Superoxide dismutase (SOD) activity and cortical malondialdehyde content, glutathione peroxidase (GPx) activity were renovated in rats receiving DHA treatment, implying that the neuroprotective influence of DHA was derived from lightening the oxidative stress caused by TBI. Moreover, immunofluorescence and Western blot experiments revealed that DHA facilitated the translocation of Nrf2 to the nucleus. DHA administration also notably increased the expression of the downstream factors NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1(HO-1). DHA exerted neuroprotective influence on the TBI models, potentially through activating the Nrf2- ARE pathway.

Docosahexaenoic Acid (DHA) Provides Neuroprotection in Traumatic Brain Injury Models via Activating Nrf2-ARE Signaling.

Introduction The purpose of our study was to explore the effects of edaravone on rats with traumatic brain injury (TBI) and investigate the underlying mechanism. Material and methods All rats were separated randomly into 3 groups as follows: sham group (n = 25), TBI group (n = 25), TBI + edaravone group (n = 25). Edaravone was administered intraperitoneally (i.p.) at a dose of 3 mg/kg at 30 min, 12 h, and 24 h after TBI. The neurological impairment and spatial cognitive function were assessed by the neurologic severity score (NSS) and Morris water maze (MWM), respectively. Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to determine the expression levels of caspase-3, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB). Transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay as well as flow cytometry assay was used to determine the apoptosis rate of cells. Results Edaravone administration significantly attenuated neurological impairment induced by TBI and promoted cognitive function outcome. The expression of BDNF and TrkB was elevated with treatment of edaravone, which was increased after TBI. The expression of apoptosis related proteins such as caspase-3 and Bax-2 was decreased while that of Bcl-2 was enhanced with edaravone administration following TBI. In addition, edaravone treatment reduced TBI-induced cell apoptosis in the hippocampus. Conclusions Our study showed that administration with edaravone was able to inhibit neuronal apoptosis in the hippocampus in a rat TBI model. The neuroprotective function of edaravone may relate to modulation of the BDNF/TrkB signaling pathway.

https://www.archivesofmedicalscience.com/pdf-80978-62245?filename=Edaravone attenuates.pdf

Edaravone attenuates neuronal apoptosis in hippocampus of rat traumatic brain injury model via activation of BDNF/TrkB signaling pathway

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PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion

Docosahexaenoic Acid (DHA) Provides Neuroprotection in Traumatic Brain Injury Models via Activating Nrf2-ARE Signaling.

Edaravone attenuates neuronal apoptosis in hippocampus of rat traumatic brain injury model via activation of BDNF/TrkB signaling pathway