https://www.healthpromoting.com/sites/default/files/FastingMolecularMechanisms.pdf

Fasting: Molecular Mechanisms and Clinical Applications

Nutrient reference values for Australia and New Zealand: Including recommended dietary intakes

■ Abstract Choline is an essential nutrient needed for the structural integrity and signaling functions of cell membranes; for normal cholinergic neurotransmission; for normal muscle function; for lipid transport from liver; and it is the major source of methyl groups in the diet. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain and spinal cord structure and function and influencing risk for neural tube defects and lifelong memory function. Choline is derived not only from the diet, but from de novo synthesis as well. Though many foods contain choline, there is at least a twofold variation in dietary intake in humans. When deprived of dietary choline, most men and postmenopausal women developed signs of organ dysfunction (fatty liver or muscle damage), while less than half of premenopausal women developed such signs. Aside from gender differences, there is significant variation in the dietary requirement for choline that can be explained by very common genetic polymorphisms.

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Choline: Critical Role During Fetal Development and Dietary Requirements in Adults

The Sevenfold Way of PKC Regulation

Short-term starvation (or fasting) protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here, we show that treatment with starvation conditions sensitized yeast cells (Saccharomyces cerevisiae) expressing the oncogene-like RAS2val19 to oxidative stress and 15 of 17 mammalian cancer cell lines to chemotherapeutic agents. Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of different tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, fasting cycles plus chemotherapy drugs—but not either treatment alone—resulted in long-term cancer-free survival. In 4T1 breast cancer cells, short-term starvation resulted in increased phosphorylation of the stress-sensitizing Akt and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage, and apoptosis. These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers.

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Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy

In contrast to the protective effect of chronic caloric restriction on tumor development, we have shown that fasting sustained tumor initiation in rat liver by a noninitiating dose of diethylnitrosamine. Here we investigated whether fasting had a similar favorable effect on initiation in the colorectal mucosa in 80 male F344 rats. Animals fasted for 4 days were given a single s.c. dose of azoxymethane (AOM) (20 mg/kg) on the first day of re-feeding, and rates of kinetic proliferative parameters, and development of the pre-neoplastic lesions such as aberrant crypt foci (ACF), were evaluated. Starvation before AOM treatment enhanced the growth of ACF, as shown by the significantly higher crypt multiplicity of fasted/re-fed rats as compared with fully fed rats (3.97 +/- 0.50 vs. 2.64 +/- 0.20, p < or = 0.025). This difference was associated with perturbations in cell death and cell proliferation. Fasting induced apoptosis and depressed cell division, while re-feeding had opposite effects, resulting in a higher percentage of S-phase cells at the time of AOM injection and 2 days thereafter. Starvation-induced apoptosis may represent the mitogenic stimulus to an increase in the number of cells susceptible to AOM damage, and may favor its fixation, leading to enhanced growth of ACF. Our data therefore suggest that fasting/re-feeding enhances colon cancer.

Fasting/re‐feeding before initiation enhances the growth of aberrant crypt foci induced by azoxymethane in rat colon and rectum

Caloric restriction causes a generalized decrease in growth rate and has been repeatedly associated with an inhibitory effect on cancer development in several systems. In contrast, exposure to complete fasting followed by refeeding is a metabolic condition associated with increased cell turnover in different organs, including the liver. The present study examines whether such condition is able to sustain the induction of initiated hepatocytes following a subnecrogenic dose of diethylnitrosamine (DENA). Male Fisher-344 rats were fasted for 4 days and 1 day after refeeding they were given a single dose of DENA (20 or 200 mg/kg body wt, i.p.). Negative and positive control groups were fed ad libitum and injected with 20 and 200 mg/kg of DENA, respectively. One week later all animals were subjected to the resistant hepatocyte model for the selection of hepatocyte nodules and they were killed 2 weeks thereafter. Results indicated the presence of gamma-glutamyltransferase (GGT) positive foci and nodules (38 +/- 7/cm2) in rats regularly fed and given 200 mg/kg of DENA, while virtually no focal lesions (< 1/cm2) were found in the group receiving 20 mg/kg of DENA and fed throughout the experiment. However, a significant number of GGT positive foci/nodules (14 +/- 7) also developed in rats exposed to fasting and given 20 mg/kg of DENA 24 h after refeeding. No evidence of hepatocellular necrosis was found in the latter group following DENA administration. No effect of fasting was observed when rats received 200 mg/kg of DENA. It is concluded that fasting/refeeding provides conditions which are able to sustain initiation in rat liver by a subnecrogenic dose of a carcinogen. These findings are in contrast with the commonly reported inhibitory effect of chronic food restriction on various stages of carcinogenesis, including initiation.

A subnecrogenic dose of diethylnitrosamine is able to initiate hepatocarcinogenesis in the rat when coupled with fasting/refeeding.

Phosphatidylethanolamine N-Methyltransferase 2 and CTP-Phosphocholine Cytidylyltransferase Expressions Are Related with Protein Kinase C Isozymes in Developmental Liver Growth☆

A subnecrogenic dose of diethylnitrosamine is able to initiate hepatocarcinogenesis in the rat when coupled with fasting/refeeding. Carcinogenesis 17: 289-292, 1996

A sex difference exists in the response of rats to a choline deficient diet and to ethionine intoxication. Female rats are less susceptible than males to the acute effects of choline deficiency, such as fatty liver and impaired secretion of triglycerides into blood plasma, while they are more susceptible to inhibition of liver protein synthesis and triglyceride accumulation by ethionine. These differences have been ascribed to sex differences in the biosynthesis of phosphatidylcholine in the liver of rats. The available data indicate that females are more dependent than males on the stepwise methylation of phosphatidylethanolamine rather than the direct incorporation of preformed choline. Continuous prefeeding with choline for three weeks was able to shift the female pattern of response to choline deficiency and ethionine intoxication towards that observed in males; thus, choline caused accumulation of hepatic triglycerides and a decrease in plasma triglycerides after choline deficiency, while it protected against ethionine induced triglyceride accumulation and protein synthesis inhibition in the liver. These results suggest that choline prefeeding in females makes them more dependent on choline availability and, thus, more susceptible to a choline deficient diet and less sensitive to ethionine intoxication, as are males. No effect of choline was observed in either choline deficient or ethionine intoxicated male rats.

E. Sesca

Papers

Fasting/re‐feeding before initiation enhances the growth of aberrant crypt foci induced by azoxymethane in rat colon and rectum

A subnecrogenic dose of diethylnitrosamine is able to initiate hepatocarcinogenesis in the rat when coupled with fasting/refeeding.

Phosphatidylethanolamine N-Methyltransferase 2 and CTP-Phosphocholine Cytidylyltransferase Expressions Are Related with Protein Kinase C Isozymes in Developmental Liver Growth☆

A subnecrogenic dose of diethylnitrosamine is able to initiate hepatocarcinogenesis in the rat when coupled with fasting/refeeding. Carcinogenesis 17: 289-292, 1996

Sexually differentiated response to choline in choline deficiency and ethionine intoxication.