Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

Cheng, Chia-Wei; Villani, Valentina; Buono, Roberta; Wei, Min; Kumar, Sanjeeve; Yılmaz, Ömer H.; Cohen, Pinchas; Sneddon, Julie B.; Perin, Laura; Longo, Valter D.

doi:10.1016/j.cell.2017.01.040

Cited by 282 publications

(258 citation statements)

References 64 publications

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“…Our data revealed that Fcn significantly inhibited the mTOR pathway. Additionally, mTOR also plays an important role in controlling intracellular nutrition, and it could be inhibited during the nutrition depletion [31,32]. In the present study, we observed that Fcn caused a decrease in the ATP level, whereas the exogenous supplement of tricarboxylic acid cycle substrates partially antagonized Fcn-induced apoptosis and autophagy.…”

Section: Cellular Physiologysupporting

confidence: 51%

Fangchinoline Induces Apoptosis, Autophagy and Energetic Impairment in Bladder Cancer

Fan¹,

Zhang²,

Ma³

et al. 2017

Cell Physiol Biochem

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Key Words Bladder cancer • Fangchinoline • Autophagy • Apoptosis • ProliferationAbatract Background/Aims: Tetrandrine and Fangchinoline (Fcn) are two natural products that are found in Stephania tetrandra. Tetrandrine is a known anti-bladder cancer compound, but the effects of Fcn on bladder cancer have been previously unclear. In the present study, we focused on the anti-tumor effects of Fcn on bladder cancer. Methods and Results: We treated T24 and 5637 bladder cancer cell lines with Fcn in vitro. We observed that Fcn inhibited the viability of bladder cancer cells in a concentration-dependent manner. The expression of PCNA, a biomarker of proliferation, was down-regulated. Fcn treatment induced both apoptosis and autophagy in bladder cancer cells, as shown by the increased cleavage of caspase-3, an upregulated LC3-II/LC3-I ratio and the down-regulated p62 level. Blocking autophagy with 3-MA (3-Methyladenine) enhanced Fcn-induced apoptosis, indicating that Fcn-induced autophagy was adaptive. Additionally, we observed that Fcn treatment inhibited mTOR and reduced the intracellular ATP levels. The exogenous addition of methyl pyruvate (MP) to compensate metabolic substrates alleviated Fcn-induced apoptosis and autophagy. Conclusions: Our data indicated that Fcn caused an impairment in energy generation, which led to apoptosis and adaptive autophagy in bladder cancer. These results demonstrated that Fcn may be a potential candidate for use in the prevention and treatment of bladder cancer.

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Section: Cellular Physiologysupporting

confidence: 51%

Fangchinoline Induces Apoptosis, Autophagy and Energetic Impairment in Bladder Cancer

Fan¹,

Zhang²,

Ma³

et al. 2017

Cell Physiol Biochem

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“…The mouse version of the FMD is a 4-day regimen based on the human FMD (Wei et al, 2017; Brandhorst et al, 2015) and has been previously detailed (Cheng et al, 2017). Briefly, a combination of flavored broth mixes, extra virgin olive oil (EVOO), essential fatty acids, vegetable powders (containing beet root, carrot root, collard leaf, kale leaf, nettle leaf, spinach leaf, tomato fruit, and mitake mushroom), vitamins, and minerals were thoroughly mixed and bound together with heated hydrogel (ClearH 2 0, Maine) on Day 1 of the diet.…”

Section: Star ★ Methodsmentioning

confidence: 99%

“…FMDs can reduce cancer incidence and aging-associated immunosuppression/immunosenescence, a process aided by hematopoietic stem-cell-based regeneration (Brandhorst et al, 2015; Cheng et al, 2014). Moreover, FMD cycles ameliorate or reverse disease progression in mouse models of multiple sclerosis (MS), and type I, and type II diabetes (Choi et al, 2016; Cheng et al, 2017). Recent studies also showed positive effects of a 24-hour fast on intestinal stem cell function in young and aged mice by a fatty acid oxidation pathway (Mihaylova et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

et al. 2019

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SUMMARY Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These FMD cycles reduced intestinal inflammation, increased stem cell number, stimulated protective gut microbiota, and reversed intestinal pathology caused by DSS, whereas water-only fasting increased regenerative and reduced inflammatory markers without reversing pathology. Transplants of Lactobacillus or fecal microbiota from DSS- and FMD-treated mice reversed DSS-induced colon shortening, reduced inflammation, and increased colonic stem cells. In a clinical trial, three FMD cycles reduced markers associated with systemic inflammation. The effect of FMD cycles on microbiota composition, immune cell profile, intestinal stem cell levels and the reversal of pathology associated with IBD in mice, and the anti-inflammatory effects demonstrated in a clinical trial show promise for FMD cycles to ameliorate IBD-associated inflammation in humans.

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“…Nonetheless, sustained alterations in cardiac metabolism can lead to prolonged activation of mTOR with adverse consequences (reviewed in Sciarretta et al (180)). While unopposed stimulation of the LYNUS ( Ly sosomal Nu trient S ensing complex)-mTOR axis can provoke contractile dysfunction in cardiometabolic disease states (182, 198, 250), accumulating experimental evidence from our lab and others indicates that cyclic activation and inactivation of this pathway during periods of feeding and fasting may restore cellular homeostasis, in a manner that depends on intact autophagy and lysosomal function (72) (13, 119), Indeed, studies from C. elegans to humans support the notion that fasting strategies prolong lifespan, prevent life-threatening illnesses such as cancer, stimulate cellular regeneration and enhance the ability of organisms to endure subsequent stress (25, 39, 76, 88, 229, 240). In addition, markers of aging and senescence also appear to decrease in models of intermittent fasting (25).…”

Section: Introductionmentioning

confidence: 98%

“…Whether dietary strategies can prevent or even reverse cardiometabolic disease has profound implications for public health. In particular, strategies that emphasize fasting, or various regimens of abstinence from food, have emerged as a way to prevent or even reverse cardiometabolic disease (39, 72, 119, 205). …”

Section: Introductionmentioning

confidence: 99%

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

Mani

Javaheri

Diwan

2018

Comprehensive Physiology

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Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.

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Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

Cited by 282 publications

References 64 publications

Fangchinoline Induces Apoptosis, Autophagy and Energetic Impairment in Bladder Cancer

Fangchinoline Induces Apoptosis, Autophagy and Energetic Impairment in Bladder Cancer

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

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