Water Structure, Osmolytes And Cancer

[LLight]

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency. - PubMed - NCBI

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

It has been increasingly appreciated that patients with primary immunodeficiency syndromes exhibit not only an increased susceptibility to infections, but also paradoxical manifestations of autoimmunity (1, 2). Patients with well-recognized disorders such as common variable immunodeficiency (CVID) are susceptible to bacterial infections but can also present with a wide spectrum of autoimmune manifestations including vitiligo, hemolytic anemia, rheumatoid arthritis, and gastroenteropathy (3). It has been suggested that infections that fail to be cleared in an immunodeficient individual may initiate a compensatory, dysregulated inflammatory response that eventually leads to autoimmunity (4). However, an underlying primary immunodeficiency may be overlooked when patients present with predominant autoimmune manifestations. Alternatively, many patients can present with signs and symptoms suggestive of an immune deficiency, but fail to meet the diagnostic criteria for any known disorder. These observations raise the possibility that
many immunodeficiency syndromes remain to be identified.

Nuclear Factor of Activated T cells 5 (NFAT5), also known as tonicity enhancer binding protein (TonEBP), is a DNA-binding protein that is activated in response to osmotic stress, translocates to the nucleus, and initiates the transcription of downstream targets, including genes required for cell cycle progression and inflammation (9-13). In T lymphocytes, NFAT5 exists as a constitutive dimer and its transcriptional regulatory activity can be induced independently by either T cell receptor stimulation or hyperosmotic stress (14, 15). NFAT5 directly binds to the TNFα promoter in vivo, suggesting a critical role for this transcription factor in mediating inflammation and regulating immune responses (14). T lymphocytes with reduced NFAT5 function exhibit impaired proliferation and survival (16, 17). Importantly, lymphoid tissues have been shown to be hyperosmolar compared to blood, suggesting that the ability of lymphocytes, via induction of NFAT5 and related pathways, to adapt to osmotic stress may be important in the initiation of immune responses (18). However, NFAT5 deficiency has not previously been reported to be associated with human disease.

Here we describe a patient with a diagnosis of AIE who presented with symptoms of autoimmunity. Immunologic evaluation demonstrated defects in innate and adaptive immunity while genetic testing revealed de novo haploinsufficiency of NFAT5. We confirmed that the patient had significantly impaired induction of NFAT5 mRNA and protein in response to osmotic stress. Using both dominant negative and RNA interference approaches in human and murine lymphocytes, we demonstrate that reduced NFAT5 activity disrupted the ability of T cells to produce TNFα and to survive in hyperosmolar conditions. Analysis of colonic tissue from patients with active inflammatory bowel disease, another immune-mediated disease, revealed reduced NFAT5 expression at the mRNA level. Together these results suggest that NFAT5 may play an important role in immune responses and that NFAT5 deficiency may be linked to human autoimmunity.

 

[LLight]

Context-dependent regulation of Th17-associated genes and IFNγ expression by the transcription factor NFAT5. - PubMed - NCBI

Using a model of experimental colitis, we observed that mice lacking NFAT5 in T cells exhibited exacerbated intestinal colitis and enhanced expression of IFNγ in draining lymph nodes and colon. These results show that NFAT5 can modulate different T-cell responses depending on stress conditions and stimulatory context.

Our finding that lack of NFAT5 in T cells could worsen inflammatory processes is in line with the recent characterization of the first human patient identified to date with an NFAT5 haploinsufficiency, who presented with an autoimmune enterocolopathy with symptoms resembling inflammatory bowel disease. T lymphocytes of this patient expressed NFAT5 to about 20% of the level found in healthy individuals and had reduced capability to resist hypertonic stress.

The same study also found that patients with ulcerative colitis and Crohn's disease showed reduced levels of NFAT5 mRNA in intestinal tissue compared with healthy controls.

 

[LLight]

Cleavage of osmosensitive transcriptional factor NFAT5 by Coxsackieviral protease 2A promotes viral replication

"Nuclear factor of activated T cells 5 (NFAT5)/Tonicity enhancer binding protein (TonEBP) is a transcription factor induced by hypertonic stress in the kidney. However, the function of NFAT5 in other organs has rarely been studied, even though it is ubiquitously expressed. Indeed, although NFAT5 was reported to be critical for heart development and function, its role in infectious heart diseases has remained obscure. In this study, we aimed to understand the mechanism by which NFAT5 interferes with infection of Coxsackievirus B3 (CVB3), a major cause of viral myocarditis. Our initial results demonstrated that although the mRNA level of NFAT5 remained constant during CVB3 infection, NFAT5 protein level decreased because the protein was cleaved. Bioinformatic prediction and verification of the predicted site by site-directed mutagenesis experiments determined that the NFAT5 protein was cleaved by CVB3 protease 2A at Glycine 503. Such cleavage led to the inactivation of NFAT5, and the 70-kDa N-terminal cleavage product (p70-NFAT5) exerted a dominant negative effect on the full-length NFAT5 protein. We further showed that elevated expression of NFAT5 to counteract viral protease cleavage, especially overexpression of a non-cleavable mutant of NFAT5, significantly inhibited CVB3 replication. Ectopic expression of NFAT5 resulted in elevated expression of inducible nitric oxide synthase (iNOS), a factor reported to inhibit CVB3 replication. The necessity of iNOS for the anti-CVB3 effect of NFAT5 was supported by the observation that inhibition of iNOS blocked the anti-CVB3 effect of NFAT5. In a murine model of viral myocarditis, we observed that treatment with hypertonic saline or mannitol solution upregulated NFAT5 and iNOS expression, inhibited CVB3 replication and reduced tissue damage in the heart. Taken together, our data demonstrate that the anti-CVB3 activity of NFAT5 is impaired during CVB3 infection due to 2A-mediated cleavage of NFAT5. Thus induction of NFAT5 by hypertonic agents may be a promising strategy for the development of anti-CVB3 therapeutics."​

 

[LLight]

From "La fin des maladies ?" written by Laurent Schwartz, a french researcher working on metabolic treatment of cancer:

"Scientific research published on DMSO confirms its ability to preserve cell vitality, but its mechanism of action is unknown. Worse still, the virtues of this substance do not seem to interest anyone. It was to find out more that I met Marc Henry, professor and researcher at the University of Strasbourg, a specialist in water physics. For him, DMSO is a solvent; it easily crosses skin membranes to circulate in the blood. However, tumor cells are rich in water; they easily fix DMSO, that modifies the activity of water inside the cells. We assume that DMSO helps to block cell division by modifying water activity."

 

[LLight]

Abstract
Polyamines are polycations that interact with negatively charged molecules such as DNA, RNA and proteins. They play multiple roles in cell growth, survival and proliferation. Changes in polyamine levels have been associated with aging and diseases. Their levels decline continuously with age and polyamine (spermidine or high-polyamine diet) supplementation increases life span in model organisms. Polyamines have also been involved in stress resistance. On the other hand, polyamines are increased in cancer cells and are a target for potential chemotherapeutic agents. In this review, we bring together these various results and draw a picture of the state of our knowledge on the roles of polyamines in aging, stress and diseases.

Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell (https://www.sciencedirect.com/science/article/pii/S0022283615003605)

"Intracellular PA levels are tightly regulated in their biosynthesis, catabolism and/ or transport. The enzymes in PA metabolism are controlled via highly specialized and unconventional mechanisms at the level of transcription, translation and protein degradation, involving several feedback loops controlled by PA concentrations. These aforementioned features are highly conserved throughout all kingdoms of life, indicating that the regulation of PA levels is highly critical for the cell."

"Cells are continuously exposed to different types of stress, either by products of their own metabolism or by environmental changes in reactive oxygen species (ROS) levels, pH, osmotic pressure and temperature. Extensive literature has demonstrated that PAs are associated with the response and protection to different types of stress which might involve multiple PA properties. It is usually observed that PA intracellular concentrations change during exposure to stress."

"PAs have known to be associated with cancer for more than 45 years, since Russel and Snyder observed increased ODC activity in tumors [205]. Since then, mounting evidence strongly supports the role of PAs in cancer. For example, PAs have increased abundance in urine and blood of many cancer patients relative to healthy individuals [206], [207]."

"Despite the strong association of PAs with cancer, attempts to use this pathway as a therapeutic target have failed so far. Several drugs targeting different steps in the PA metabolic pathway have been developed, but their efficacy in treating cancer largely falls short of clinical success."

 

[LLight]

Role of Osmolytes in Regulating Immune System. - PubMed - NCBI

"BACKGROUND: The immune system has evolved to protect the host organism from diverse range of pathogenic microbes that are themselves constantly evolving. It is a complex network of cells, humoral factors, chemokines and cytokines. Dysregulation of immune system results in various kinds of immunological disorders. There are several external agents which govern the regulation of immune system. Recent studies have indicated the role of osmolytes in regulation of various immunological processes such as Ag-Ab interaction, Ig assembly, Ag presentation etc.

SCOPE OF REVIEW: In this present review, we have systematically discussed the role of osmolytes involved in regulation of several key immunological processes.

MAJOR CONCLUSION: Osmolytes are involved in the regulation of several key immunological processes such as immunoglobulin assembly and folding, immune cells proliferation, regulation of immune cells function, Ag-Ab interaction, antigen presentation, inflammatory response and protection against photo-immunosuppression. Hence, osmolytes and their transporters might be used as potential drug and drug targets respectively.

GENERAL SIGNIFICANCE: This review is therefore designed to help clinicians in development of osmolyte based therapeutic strategies in the treatment of various immunological disorders. Appropriate future perspectives have also been included."

Sadly, it's not available through Sci-hub.

 

[LLight]

From Urea Research and Cancer : urinefasting:

"Mechanism of Action

The cellular surfaces of malignant tumor cells are known to contain large amounts of glycoproteins and other large molecular surface-active agents. These surfactants on cancer cells have hydrophobic (water-repelling) properties at non-polar sites and hydrophilic (water-attracting) properties at polar sites. This produces a structured water matrix surrounding cancer cells that is substantially different from that surrounding normal cells. Some researchers have theorized that this difference can account for some of the characteristics of malignant tumor growth. Apparently the structured water matrix produces a loss of the cellular contact inhibition that is associated with cancer. This means that cancer cells don't mind crowding together. It also enables cancer cells to excrete and absorb nutrients and other chemicals in an abnormal way.

In 1977 researchers at the University of Illinois Medical Center showed that substances that are capable of disrupting the water matrix of malignant cells will exert anticancer effects. Their investigations of the activity of urea indicated that when urea is administered under proper conditions and in the appropriate concentrations, it disrupts the cellular water matrix and interferes with the processes necessary for continued uncontrolled cellular growth.

The same group of researchers reported that daily injections of a 40-percent urea solution directly into tumor masses and into the area surrounding the growth were successful in regressing and eradicating well-established malignant melanomas in laboratory animals. It has also been shown that additive synergistic effects can be achieved against malignant tumors when urea is used concurrently with localized hyperthermia treatments."

 

[LLight]

From High Salt Inhibits Tumor Growth by Enhancing Anti-tumor Immunity:

"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."

 

[LLight]

Interestingly, abscisic acid, which has been praised by Virginia Livingstone, seems to regulate osmolyte accumulation in plants: Phytohormones Regulate Accumulation of Osmolytes Under Abiotic Stress. - PubMed - NCBI

"The accumulation of osmolytes is further modulated by phytohormones like abscisic acid, brassinosteroids, cytokinins, ethylene, jasmonates, and salicylic acid."
​

Abscisic acid seems to induce thiamine production in plant during abiotic stress: The upregulation of thiamine (vitamin B1) biosynthesis in Arabidopsis thaliana seedlings under salt and osmotic stress conditions is mediated by abscisic acid at the early stages of this stress response

"Conclusions

We here demonstrate for the first time that TDP biosynthesis processes are quickly activated during the early phase (sensing) of the Arabidopsis response to salt and osmotic stress. The produced TDP is incorporated into TDP-dependent enzymes that are upregulated at the same time such as KGDH, PDH, TK, all of which are involved in the main metabolic pathways that respond to stress conditions in plants. ABA seems to be involved in the activation of genes encoding enzymes that function in thiamine and TDP biosynthesis as well as the TDP-dependent KGDH and TK genes. We propose a working model for the contribution of thiamine to the stress sensing and adaptation processes in plants."

 

[LLight]

Also, osmotic stress could induce the expression of the thiamine transporter 1 by activating the Slc19a2 gene (Thiamine transporter 1 - Wikipedia): Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin

"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 (Figure 2B).

This analysis confirmed the sensitivity to Torin1 of the NFAT5-dependent genes Ddit4, Ddit4l, Slc1a3 and the NFAT5-independent Amd1, Bpgm and Slc19a2 (Figure 2B)."

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. - PubMed - NCBI

 

[LLight]

Not everything seems to be known about this derivative of thiamine: Thiamine triphosphate: a ubiquitous molecule in search of a physiological role. - PubMed - NCBI

"A recent study has shown that ThTP exists not only in mammals, but in all major phyla tested: bacteria, fungi, plants, invertebrates and vertebrates."

"A key observation was that in some species cellular ThTP concentrations are not constant. They are generally very low but, under conditions of cellular stress, the intracellular ThTP can increase considerably. This phenomenon was observed in plants during withering (Makarchikov et al. 2003) and in bacteria during amino acid starvation (Lakaye et al. 2004c). The intracellular ThTP concentration is highly regulated in E. coli, strongly depending on physiological conditions: in bacteria growing in aerated rich medium, ThTP is barely detectable, but it quickly accumulates (reaching cellular concentrations ≥ 10 μM) when the bacteria are transferred to minimum medium devoid of amino acids but containing a carbon source such as glucose (Lakaye et al. 2004c). Interestingly, this accumulation is transient, reaching a maximum after 1–2 h, then decreasing eventually to zero. How those regulatory mechanisms respond to the nutritional status remains an open question."

"This led us to propose that ThTP (as well as AThTP) could act as “alarmones” or signals responding to specific conditions of nutritional downshift or metabolic stress (Lakaye et al. 2004c; Gigliobianco et al. 2008, 2010, 2013). The biochemical mechanisms underlying the production of these signals remain to be clarified."

"Now that the mechanisms of ThTP synthesis have been elucidated and that a specific ThTP-hydrolyzing enzyme has been identified, future work should focus on its targets. In this respect, the study of protein phosphorylation by ThTP should be helpful. Organisms such as E. coli and higher plants, in which ThTP appears under very specific stress situations should give interesting insights into the physiological role of this compound."

Not in bacteria, but amino acid deprivation seem to create the same conditions than hyperosmotic stress: Amino acid depletion activates TonEBP and sodium-coupled inositol transport (https://www.physiology.org/doi/full/10.1152/ajpcell.2001.280.6.C1465)

"Transport system A for neutral amino acids, another osmosensitive mechanism, is progressively stimulated if amino acid substrates are not present in the extracellular compartment. Under this condition, as in hypertonicity, cells shrink and mitogen-activated protein kinases are activated."

"We conclude that the incubation in isotonic, amino acid-free saline triggers an osmotic stimulus and elicits TonEBP-dependent responses like hypertonic treatment."

So, thiamine could be involved in the response to osmotic stress and osmolyte accumulation.

 

[LLight]

Reposting this study from another place. There seems to be an interaction between boron (already mentioned in this thread, here Water Structure, Osmolytes And Cancer) and thiamine:

Interactions between dietary boron and thiamine affect lipid metabolism (Interactions between dietary boron and thiamine affect lipid metabolism (Conference) | OSTI.GOV):

"An experiment was designed to test the hypothesis that dietary boron impacts upon the function of various coenzymes involved in energy metabolism. In a 2x7 factorially-arranged experiment, weanling, vitamin D3-deprived rats were fed a ground corn-casein-corn oil based diet supplemented with 0 or 2 mg boron/kg and 50% of the requirement for thiamine (TM), riboflavin (RF), pantothenic acid (PA) or pyridoxine (PX); 0% for folic acid (FA) or nicotinic acid (NA). All vitamins were supplemented in adequate amounts in the control diet. At 8 weeks of age, the TM dietary treatment was the one most affected by supplemental dietary boron (SDB). In rats that were fed 50% TM, SDB increased plasma concentrations of triglyceride (TG) and activity of alanine transaminase (ALT), and the liver to body weight (L/B) ratio. However, in the SDB animals, adequate amounts of TM decreased the means of those variables to near that observed in non-SDB rats fed 50% TM. The findings suggest that an interaction between dietary boron and TM affects lipid metabolism."

Boron seems to use some thiamine in its metabolism (in rats at least). If you are deficient in thiamine, boron could have a negative impact.

 

[LLight]

Osmolality controls the expression of cathelicidin antimicrobial peptide in human macrophages:


NFAT5/TonEBP makes the immune system produce antimicrobial substance, CAMP or also called LL-37.

LL-37 is able to bind to LPS: Evaluation of the ability of LL-37 to neutralise LPS in vitro and ex vivo. - PubMed - NCBI

Dehydration could induce the production of LL-37, which in turn could activate a better immunity against cancer: Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy (https://www.tandfonline.com/doi/full/10.1080/2162402X.2019.1608106)

"CD103+ DCs (CD141+ in humans) have emerged as a fundamentally important subset that excels in cross-presentation, CD8+ T-cell activation and the induction of antitumor immunity."

"Here, we identify a novel role for the antimicrobial host defense peptide LL-37 in directing the expansion and differentiation of DCs in culture toward an “enhanced” CD141+/CD103+-like phenotype with dramatically improved antitumor activity."

 

[LLight]

NFAT5 moves to Fat City

"NFAT5 plays a more diverse functional role, including a hardly appreciated function in blood pressure regulation and in the development of autoimmune diseases. Despite the growing significance of NFAT5 in physiology and diseases, our understanding of how NFAT5 is regulated is limited. Furthermore, how changes in tonicity are converted into functional outputs via NFAT5 remains elusive."

"Hypertonicity activates NFAT5 by increasing its nuclear localization and by transactivating its activity in the early phase and protein abundance in the late phase of activation. The inhibition of NFAT5 by hypotonicity features a decrease in nuclear NFAT5 expression."

"In this issue of J Mol Med, Li et al. demonstrate that NFAT5 can bind to a TGGAAGCGTTC consensus sequence in the gene (CACNA1C) encoding the calcium channel, voltage-dependent, L type, alpha 1C subunit and activates the transcription of the L-type calcium channel (LTCC)."

"The burning question is, “what triggers NFAT5 to initiate regulation of CACNA1C?” CACNA1C, as the authors point out, is clearly important to the heart. Nonetheless CACNA1C has pivotal functions elsewhere. Could it be that this NFAT5 regulation of CACNA1C is important throughout the life of the organism?"

Voltage-gated calcium channels: Novel targets for cancer therapy

"The present bioinformatics analysis confirmed that CACNA1C exhibited low expressions in the majority of types of cancer, including brain, lymphoma, ovarian, bladder, prostate, renal, salivary gland, cervix and colorectal cancers, compared with normal tissue (Table I). In addition, 9 of the 20 types of cancer showed downregulation in which CACNA1C was ranked in the top 5% of genes that had low expression."

 

[LLight]

Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. - PubMed - NCBI:

"A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose-fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease."

Characterization of the expression of Phaseolus vulgaris OCT1, a dehydration-regulated gene that encodes a new type of phloem transporter. - PubMed - NCBI:

"Several physiological data suggest that long distance transport via the phloem is controlled by developmental and environmental conditions (Delrot et al., 2000). For example, in response to cold, water or salt stress, plants accumulate compatible osmolytes to adjust their cellular osmotic potential (Ingram and Bartels, 1996; Bray, 1997). As osmolyte biosynthesis principally occurs in leaves, membrane-associated transporters are likely involved in the delivery of these solutes throughout the plant via the phloem, and also participate in their cellular distribution."

"We recently initiated a project aimed at isolating dehydration-responsive genes in common bean roots (Phaseolus vulgaris L.) using the mRNA differential display RT-PCR strategy. In this paper, we describe the molecular cloning and the expression pattern of PvOCT1, a dehydration-regulated gene that encodes a new type of transporter in plants."

"In the present study, we isolated a full-length cDNA (PvOCT1) whose expression in roots was modulated by water stress. Sequence analyses showed that PvOCT1 encodes a 547 amino acid encompassing 12 putative TMD which presents homology with the animal OCT transporter family (Figure 1). In animals, OCT are known to transport a large variety of cationic monoamines across the plasmalemma, including xenobiotics, neurotransmitters and carnitine. Functional studies have shown that they can act either as polyspecific organic cation transporters that protect cells from xenobiotics through detoxification (Gorboulev et al., 1997; Kekuda et al., 1998), as specific transporters of extraneuronal monoamines (catecholamine) or as specific carnitine/Na+ symporters (Tamai et al., 1998). Carnitine is a small soluble amphiphilic molecule found in animals, plants and fungi. It binds to cytosolic acyl-CoA and the resulting complex is translocated across the mitochondrial inner membrane via a carnitine acyl-transferase, to allow subsequent oxidation of acyl groups in the mitochondria. Interestingly, L-carnitine has been shown to act as an osmoprotectant in Listeria monocytogenes since it is not metabolized and thus cannot function as a source of carbon or nitrogen (Verheul et al., 1995)."

 

[LLight]

Anticancer and Apoptotic Effects of Ectoine and Hydroxyectoine on Non-Small Cell Lung Cancer cells: An in-vitro Investigation (https://www.researchgate.net/public...l_Lung_Cancer_cells_An_in-vitro_Investigation):

"Introduction: Streptomyces manage the osmotic stress by collecting compatible solutes or osmolytes. Ectoine, 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carboxylic acid, and 5-hydroxyectoine are among the most common osmolytes of this bacteria and have an active role in protecting the genetic material of this microorganism as well as providing resistance to environmental pressures. In this research, the antiproliferative and apoptotic effects of ectoine and 5- hydroxyectoine on human non-small cell lung cancer (NSCLC) cell line (QU-DB) are investigated.
Methods: QU-DB cells were treated by five doses of ectoine and hydroxyectoine for 12, 24 and 48 hours, and the cytotoxic properties were evaluated by MTT assay. Then, the DAPI fluorescent staining was carried out for monitoring of the cells’ nuclear morphology. Recognition and quantification of the apoptosis were done; using the Annexin-V-Fluos technique.
Results: It has been verified that both ectoine and hydroxyectoine persuaded apoptosis on QU-DB cells in a dose-dependently manner. Also, no cytotoxicity effects of these compatible solutes were observed on normal cells (HFLF-PI5).
Conclusions: Ectoine and hydroxyectoine are two natural metabolites which induce apoptosis in lung cancer cells. They don’t have any toxic effect on normal cells and can be used as auxiliary drugs or even as a medicine for the treatment of lung cancer after further optimization of the formulations."

 

[Regina]

Anticancer and Apoptotic Effects of Ectoine and Hydroxyectoine on Non-Small Cell Lung Cancer cells: An in-vitro Investigation (https://www.researchgate.net/public...l_Lung_Cancer_cells_An_in-vitro_Investigation):

"Introduction: Streptomyces manage the osmotic stress by collecting compatible solutes or osmolytes. Ectoine, 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carboxylic acid, and 5-hydroxyectoine are among the most common osmolytes of this bacteria and have an active role in protecting the genetic material of this microorganism as well as providing resistance to environmental pressures. In this research, the antiproliferative and apoptotic effects of ectoine and 5- hydroxyectoine on human non-small cell lung cancer (NSCLC) cell line (QU-DB) are investigated.
Methods: QU-DB cells were treated by five doses of ectoine and hydroxyectoine for 12, 24 and 48 hours, and the cytotoxic properties were evaluated by MTT assay. Then, the DAPI fluorescent staining was carried out for monitoring of the cells’ nuclear morphology. Recognition and quantification of the apoptosis were done; using the Annexin-V-Fluos technique.
Results: It has been verified that both ectoine and hydroxyectoine persuaded apoptosis on QU-DB cells in a dose-dependently manner. Also, no cytotoxicity effects of these compatible solutes were observed on normal cells (HFLF-PI5).
Conclusions: Ectoine and hydroxyectoine are two natural metabolites which induce apoptosis in lung cancer cells. They don’t have any toxic effect on normal cells and can be used as auxiliary drugs or even as a medicine for the treatment of lung cancer after further optimization of the formulations."

Idea Labs Ectoine Inhaler????

 

[LLight]

Idea Labs Ectoine Inhaler????

Would be cool. But these substances need to be more studied. Just this study should be too few.

 

[LLight]

Already posted elsewhere but is interesting regarding the topic, because betaine is an osmolyte, whose uptake is carried out by the BGT1 transporter which is upregulated by hyperosmolarity (The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. - PubMed - NCBI, "To withstand the hyperosmolarity, cells trigger osmotic adaptation, involving concentration of a transcriptional factor TonEBP/NFAT5 in the nucleus, and accumulate betaine and other osmolytes.").

Betaine is a positive regulator of mitochondrial respiration. - PubMed - NCBI:

"Betaine (trimethylglycine) obtained from foods and from synthesis through choline metabolism is abundant in liver and kidney [1,2]. It plays an important role in cellular protection against environmental stress, such as high temperature, osmotic imbalance, or high salinity in microorganisms, plants, and animals and by serving as a methyl-group donor in several biochemical pathways."

"In addition, betaine might suppress cancer cell proliferation. After addition of betaine, cell growth of HepG2 human liver cancer cells was inhibited [21] and tumorigenesis was delayed in the liver of rodents [22]. Interestingly, an inverse correlation between dietary intake of betaine and the risk of lung, colon, and breast cancers in humans has been reported [23–25]."

"We show here with the hepatocyte-derived transformed H.2.35 cell line that betaine treatment leads to improved COX activity and mitochondrial and intact cellular respiration. The maximal effectis obtained with betaine concentrations of 2–5 mM. Thus, the anti-oncogenic effect of betaine might in part be explained by reversal of the Warburg effect."

 

[LLight]

Modulation of gene expression profiles by hyperosmolarity and insulin. - PubMed - NCBI:

"The hyperosmotic upregulation of the glycine transporter Glyt (Slc6a9) mRNA reported here (Table 2B, no. 3; Figure 1) fits well into the adaptive response to hyperosmolarity, which involves also an increased expression of the taurine transporter (Taut, Slc6a6) [12] (this paper, Figure 1), and the betaine/γ-aminobutyrate transporter (Slc6a12) (Table 2B, no. 22) mRNAs and a decreased expression of the Bhmt mRNA [15] (this paper, Table 2A, no.145; Figure 1), leading altogether to a cellular accumulation of compatible organic osmolytes."

"Some findings of this study further corroborate the concept that dehydration drives cells into a catabolic, antiproliferative and proapoptotic state. One example is the hyperosmotic upregulation of IGFBP1 expression (Table 2A, no. 40; Figures 1 and 2). A major function of IGFBPs is to bind insulin-like growth factor (IGF)1 and thereby to inhibit IGF1 receptor binding [47]. It seems well conceivable that hyperosmotic upregulation of IGFBP1 expression antagonizes the known mitogenic, antiapoptotic and metabolic effects of IGF1 and thus confers IGF resistance."

"In summary, gene expression profiling identified novel osmoregulated genes with impact on cell volume regulation, hepatobiliary transport, and proliferation. Insulin-induced gene expression changes were differentially affected by hyperosmolarity, indicating that hyperosmotic insulin resistance at the level of gene expression is not a general phenomenon."