The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
zc_hl
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Hello Melanie,

Thank you.

If you decided to try dry fasting, please always proceed with caution :)

I believe there is not much issues reported in the literature about ramadan but yet, it's not without risk.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Hypertonicity Regulation of Cytochrome P450 CYP3A (https://tspace.library.utoronto.ca/handle/1807/33963):
Immunofluorescent microscopy revealed an increase of nuclear-distributed mouse NFAT5 in cyclic water-deprived animals, consistent with NFAT5 activation. Most importantly, CYP3A4 mRNA levels were noted to be elevated in the liver and kidney (11.8 ± 4.8-fold over water ad lib, n = 14, p = 0.04 and 2.2 ± 0.4-fold, n = 9, p = 0.02, respectively), with concurrent CYP3A protein and activity increase. [...] In summary, increased expression of in vitro and in vivo human CYP3A was achieved using a hypertonic stimulus; concurrent NFAT5 activation and NFAT5 target gene expression were observed. These results suggested a possible binding of activated NFAT5 to CYP3A TonE situated within the intronic region of CYP3A7. It could be further concluded that NFAT5 may be responsible for the hypertonic induction of human CYP3A.
From Wikipedia:
Cytochrome P450 3A4 oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Anthropometric, Hemodynamic, Metabolic, and Renal Responses during 5 Days of Food and Water Deprivation (https://www.karger.com/Article/FullText/357718):
Background: Although there is considerable research in the field of fasting and fluid restriction, little is known about the impact of food and water deprivation (FWD) on body circumferences and vital parameters. Methods: During 5 days of FWD in 10 healthy adults, hemodynamic, metabolic, and renal parameters, such as weight, 5 circumferences at neck, waist, hip, chest at axilla, chest at nipples, and 1 new oblique hip circumference were measured daily. For each circumference, new quotients of daily circumference-to-weight decrease were calculated. The set of employed parameters quantified and monitored dieting persons' compliance and efficacy of the method. Results: The values of blood pressure, heart rate, hemoglobin oxygen saturation, glucose, K+, Na+, Cl-, urea, creatinine, and serum osmolality proved to be stable. The mean creatinine clearance increased up to 167%. The mean daily weight decrease (1,390 ± 60 g) demonstrated the effectiveness of FWD in weight reduction. The daily decrease of all measured circumferences and the values of the corresponding circumference-to-weight decrease quotients reflected considerable volume decrease in all measured body parts per day and kg of weight loss during FWD. Conclusion: The intervention of 5 FWD days in 10 healthy adults was found to be safe, decreased weight and all measured circumferences, and improved renal function considerably.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Cell hydration as the primary factor in carcinogenesis: A unifying concept (https://www.ncbi.nlm.nih.gov/m/pubmed/16271440/):
The paper discusses the unifying concept that cell hydration is the primary factor in the mechanism of carcinogenesis. The concept includes the following hypotheses:

(1) Increased cell hydration causes cancer not only by promoting cell division and oncogene expression, but also by inactivating genes inducing cell differentiation, and by preventing apoptosis. Conversely, factors that reduce cell hydration prevent cancer by inhibiting cell division and oncogene expression, while activating genes inducing cell differentiation, and by promoting apoptosis. The unique ability of cell hydration to have these opposite effects on cell behavior and gene expression can account for its postulated role as the primary factor in both the promotion and prevention of cancer.

(2) A progressive increase in cell hydration, induced by successive mutations and/or epigenetic changes, is the basic mechanism of multi-step carcinogenesis, the degree of malignancy increasing with the degree of cell hydration.

(3) The increased hydration of cancer cells accelerates their respiration rate, thereby enhancing their ability to compete for nutrients with their normal counterparts. This effect may play a major role in promoting tumor growth and in the postulated mechanism of multi-step carcinogenesis.

(4) Increased cell hydration is also proposed as an alternative or additional explanation of the carcinogenetic effect of inflammatory agents and of hormones.

A survey of the literature provides evidence consistent with these hypotheses, but suggestions are included for further investigations to test their validity and their implications. From a clinical perspective, the abnormally high water content of cancer cells permits the use of microwave technology for tumor detection and treatment. Also of considerable therapeutic significance is the increased sensitivity if cancer cells to desiccation, postulated to result from genetic changes induced by increased hydration. This may well be the achilles heel of cancer, and recent investigations indicate that it may be exploited very effectively in the treatment of the disease. In conclusion, I suggest that the need for studies on the molecular biology of cancer to be supplemented by more information on environmental effects on gene expression and on the biochemical and physiological factors that mediate genetic effects at the cellular level. This approach might also be used to assess the validity of the postulated role of cell hydration as a factor of particular significance.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro (https://www.ncbi.nlm.nih.gov/m/pubmed/30417826/)

"Amyloid-β peptide (Aβ) forms plaques in Alzheimer's disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target."

TRPV1 seems to be activated by osmotic stress too: Osmosensitivity of Transient Receptor Potential Vanilloid 1 Is Synergistically Enhanced by Distinct Activating Stimuli Such as Temperature and Protons (https://journals.plos.org/plosone/artic ... ne.0022246)

"Our findings thus indicate that TRPV1 integrates multiple different types of activating stimuli, and that TRPV1 is sensitive to hypertonic stimuli under physiologically relevant conditions."
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Osmotic stress could induce the expression of the thiamine transporter 1 by activating the Slc19a2 gene (https://en.m.wikipedia.org/wiki/Thiamine_transporter_1): Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378878/)

"We validated by RT–qPCR a sample of 14 genes chosen by their robust induction by osmostress in the microarray experiments, and also illustrative of Torin1-sensitive and -insensitive, as well as NFAT5-dependent and -independent genes.

This analysis confirmed the sensitivity to Torin1 of the NFAT5-dependent genes Ddit4, Ddit4l, Slc1a3 and the NFAT5-independent Amd1, Bpgm and Slc19a2."

Interestingly, thiamine seems to be involved in protein folding, a domain in which osmolytes also appear (they help to re-fold misfolded proteins): Thiamin and protein folding. (https://www.ncbi.nlm.nih.gov/m/pubmed/31371089/)
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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From High Salt Inhibits Tumor Growth by Enhancing Anti-tumor Immunity (https://www.frontiersin.org/articles/10 ... 01141/full)

"Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro. Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy."

"It would be of interest for future studies to analyze the role of known molecular high salt targets like p38/MAPK, SGK1 and NFAT5 and if they are also involved in salt exposed MDSCs, as it has been shown for T cell and monocyte/macrophage populations."
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults (https://www.ncbi.nlm.nih.gov/m/pubmed/31617739/):

"Abstract
High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents, and is thought to result from elevated plasma [Na+] sensitizing central sympathetic networks.

PURPOSE: To test the hypothesis that water deprivation (WD)-induced elevations in serum [Na+] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans.

METHODS: In randomized crossover fashion, 35 adults (17F/18M, age: 25±4 years, systolic/diastolic BP: 107±11/60±7 mmHg, body mass index: 23±3 kg•m-2) completed two hydration protocols: a euhydration control condition (CON) and a step-wise reduction in water intake over three days concluding with 16-hours of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants (n=25) underwent ambulatory BP monitoring during day three of each protocol. We calculated average real variability as an index of BPV.

RESULTS: WD increased serum [Na+] (141.0±2.3 vs. 142.1±1.7 mmol/L, p<0.01) and plasma osmolality (288±4 vs. 292±5 mOsm/kg H2O, p<0.01). However, WD did not increase beat-to-beat (1.9±0.4 vs. 1.8±0.4 mmHg, p=0.24) or ambulatory daytime (9.6±2.1 vs. 9.4±3.3 mmHg, p=0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity (p=0.20) and sympathetic vascular transduction were not different after WD (p=0.17 for peak Δ mean BP following spontaneous MSNA bursts).

CONCLUSION: These findings suggest that despite modestly increasing serum [Na+], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults."
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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If we assume that cancer and alzheimer are both metabolic diseases in nature, this book becomes interesting: Cancer and the New Biology of Water (https://www.goodreads.com/book/show/479 ... y-of-water)

"A groundbreaking look at the role of water in living organisms that ultimately brings us closer to answering the riddle of the etiology of, and therapy and treatment for, cancer."
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

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Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation
https://www.mdpi.com/2218-273X/10/1/132
Most of the neurological disorders in the brain are caused by the abnormal buildup of misfolded or aggregated proteins. Osmolytes are low molecular weight organic molecules usually built up in tissues at a quite high amount during stress or any pathological condition. These molecules help in providing stability to the aggregated proteins and protect these proteins from misfolding. Alzheimer’s disease (AD) is the uttermost universal neurological disorder that can be described by the deposition of neurofibrillary tangles, aggregated/misfolded protein produced by the amyloid β-protein (Aβ). Osmolytes provide stability to the folded, functional form of a protein and alter the folding balance away from aggregation and/or degradation of the protein. Moreover, they are identified as chemical chaperones. Brain osmolytes enhance the pace of Aβ aggregation, combine with the nearby water molecules more promptly, and avert the aggregation/misfolding of proteins by providing stability to them. Therefore, osmolytes can be employed as therapeutic targets and may assist in potential drug design for many neurodegenerative and other diseases.
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