Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.

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Ketogenic Diet in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20163892 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3892 ◽

Cited By ~ 24

Author(s):

Marta Rusek ◽

Ryszard Pluta ◽

Marzena Ułamek-Kozioł ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ketogenic Diet ◽

Neurodegenerative Disorder ◽

Ketone Bodies ◽

Amyloid Β ◽

The Body ◽

Aging Brain ◽

Effective Prevention ◽

Low Carbohydrate Diet

At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy for Alzheimer’s disease.

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Novel CRM-1 Inhibitors for Therapy In Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2734.2734 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2734-2734

Author(s):

Kejie Zhang ◽

Lan V Pham ◽

Liang Zhang ◽

Archito T. Tamayo ◽

Zhishuo Ou ◽

...

Keyword(s):

B Cells ◽

Western Blot ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Parp Cleavage ◽

Mantle Cell ◽

Dose Dependent

Abstract Abstract 2734 Chromosomal Region Maintenance 1 (CRM1) overexpression has been associated with cancer progression and mortality in several human cancers, suggesting that activation of nuclear export may play a role in human neoplasia and may serve as a novel target for the treatment of cancers. This overexpression of CRM1 may be related to the export of most tumor suppressor and growth regulatory proteins out of the nucleus, thereby functionally inactivating them. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that is not yet curable. The objective of our study was to investigate the status of CRM1 in MCL, both in MCL cell lines and primary MCL cells, in comparison to normal B cells, and to evaluate the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, and to elucidate the mechanism of CRM1 inhibitor-mediated MCL cell apoptosis. We used 8 established MCL cell lines and primary cells from 4 patients with relapsed/refractory MCL. KPT185 and KPT276 are novel, highly selective, drug-like small molecular CRM1 inhibitors. Western Blot analysis showed that CRM1 was expressed in both the cytoplasm and nuclei of 8 MCL cell lines. CRM1 was mainly detected in nuclei of normal resting B cells; In contrast, CRM1 was primarily detected in the cytoplasm of freshly isolated primary MCL cells from patients with relapsed/refractory MCL. In 3H-thymidine incorporation assays, inhibition of CRM1 by KPT185 resulted in a significant dose-dependent growth inhibition of 8 MCL cells, with IC50 values range between 10 nM to 120 nM. The blastoid-variant MCL cell lines (Z-138 and Rec-1) were significantly more sensitive to KPT185 than the non-blastoid variant MCL cell lines. Flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that KPT185 induced MCL cells apoptosis in both time- and dose-dependent manners, but had no effect on cell cycle arrest. MCL cells treated with KPT185 for 12 hours showed caspase 3 activation and PARP cleavage. As shown in Western blot and confocal microscopy, blocking CRM1 activity by KPT185 in MCL cells up-regulated the protein expression of p53, a known CRM1-mediated export protein, and also induced CRM1 translocation to the nucleus and decreased CRM1 expression. In severe combined immunodeficient (SCID) mice bearing palpable Z-138 tumors, treatment with KPT-276 (similar structure to KPT-185 but improved animal pharmacokinetics), 50mg/kg or 150 mg/kg PO QDx5 each week, or cyclophosphamide 100 mg/kg on days 1–3, was initiated. Tumor growth was significantly inhibited (>75%) in all of treatment groups compared with vehicle control. Neutropenia and other cytotoxic-agent specific effects have not been observed in treated animals. In conclusion, CRM1 inhibitors inhibited growth of MCL cells in vitro and in vivo, and induced apoptosis of MCL cells via inhibition of CRM1 expression and blockage of its translocation with functional nuclear proteins. Our data suggest that novel CRM1 inhibitors provide a potential therapy for patients with relapsed/refractory MCL. Disclosures: No relevant conflicts of interest to declare.

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The Ketogenic Diet Increases In Vivo Glutathione Levels in Patients with Epilepsy

Metabolites ◽

10.3390/metabo10120504 ◽

2020 ◽

Vol 10 (12) ◽

pp. 504

Author(s):

Antonio Napolitano ◽

Daniela Longo ◽

Martina Lucignani ◽

Luca Pasquini ◽

Maria Camilla Rossi-Espagnet ◽

...

Keyword(s):

Blood Serum ◽

Ketogenic Diet ◽

Animal Studies ◽

Ketone Bodies ◽

Neuroprotective Effect ◽

Intractable Epilepsy ◽

Epileptic Seizures ◽

Resonance Spectroscopy ◽

Low Carbohydrate Diet

The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with t-test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.

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Regulation of Histone Deacetylase in Waldenström Macroglobulinemia

Blood ◽

10.1182/blood.v112.11.2617.2617 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2617-2617

Author(s):

Xiaoying Jia ◽

Aldo M. Roccaro ◽

Abdel Kareem Azab ◽

Hai T. Ngo ◽

Antonio Sacco ◽

...

Keyword(s):

Bone Marrow ◽

Western Blot ◽

Histone Deacetylase ◽

Cell Lines ◽

Parp Cleavage ◽

Low Grade ◽

Dependent Manner ◽

Apoptotic Pathways ◽

Dose Dependent

Abstract Background: Waldenström’s Macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Histone deacetylase (HDAC) inhibitors represent promising new treatment strategy in B cell malignancies. We therefore investigated the in vitro effect of the novel hydroxamic acid derivative HDAC inhibitor LBH589 in WM. Methods: WM cell lines (BCWM1 and WSU-WM) and IgM secreting low-grade lymphoma cell lines (MEC1, RL) were used. Bone marrow primary CD19+ cells and bone marrow stromal cells (BMSC) were obtained from patients with WM after informed consent. Cytotoxicity and DNA synthesis were measured by MTS assay and thymidine uptake assay. Cell signaling and apoptotic pathways were determined by Western Blot and immunofluorescence. Results: LBH589 induced a significant decrease of proliferation and triggered cytotoxicity in all cell lines tested and primary CD19+ WM cells (IC50 of 20–40nM), even in the presence of BMSC, IL-6 and IGF-1, which induce resistance to conventional therapies. Importantly, LBH589 did not induce cytotoxicity in healthy donor peripheral blood mononuclear cells. LBH589 induced both intrinsic and extrinsic apoptotic pathways, with caspase-9, caspase-8, caspase-3, and PARP cleavage in a dose-dependent manner. We also demonstrated significant upregulation of the proapoptotic transcription factor p53 and down-regulation of the anti-apoptotic proteins BclxL, Mcl-1 and c-myc. We then demonstrated that LBH589 induced apoptosis in WM cells in a caspase-independent manner through induction of autophagy, as shown by upregulation of LC3B and Rab7 expression. We further determined the mechanism of action of LBH589 in WM, investigating the effect of LBH589 on histone acetylation and NF-kB pathways. We found that LBH589 induced a dose-dependent increase in histone H3-H4 acetylation; and inhibited both canonical and non-canonical pathways of NF-κB, as shown by western blot and immunofluorescence. In addition, LBH589 augmented rituximab, fludarabine, bortezomib, and perifosine-induced cyotoxicity in WM cells. Conclusion: LBH589 has significant antitumor activity in WM in vitro, providing the framework for clinical trials evaluating LBH589 as a new therapeutic agent in patients with WM.

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Loss of hematopoietic stem cell self-renewal after bone marrow transplantation

Blood ◽

10.1182/blood.v74.2.872.872 ◽

1989 ◽

Vol 74 (2) ◽

pp. 872-875 ◽

Cited By ~ 47

Author(s):

P Mauch ◽

S Hellman

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Cell Dose ◽

Dose Dependent Decrease ◽

Dose Dependent

Abstract The quality of long-term hematopoietic engraftment after bone marrow transplantation (BMT) has not been well characterized. Clinical autologous BMT involves removal of less than 5% of the total content of the recipient marrow followed by ablation of the remaining marrow and reinfusion. To study long-term consequences of transplanting limited numbers of BM stem cells further, we evaluated the hematopoietic reserve in recipient animals after transplantation of varying quantities of BM. Recipient animals demonstrated a donor BM cell dose- dependent decrease in stem cell content and self-renewal capacity that was not reflected in peripheral blood (PB) counts or BM cellularity. This decrease was observed after initial BM recovery and did not change with time after transplantation, demonstrating a permanent loss in BM self-renewal capacity. In addition, animals alive at 3 months, a time selected to allow BM recovery, also demonstrated a donor BM cell dose- dependent decrease in survival at 1 year. These results emphasize the importance of optimizing stem cell number in BMT.

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Single Agent and Combinatorial Efficacy of First-in-Class Small Molecule ONC201 in Acute Leukemia and Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.2759.2759 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2759-2759 ◽

Cited By ~ 1

Author(s):

Varun V Prabhu ◽

Amriti Lulla ◽

Christina L Kline ◽

Peter J Van den Heuvel ◽

Mala K. Talekar ◽

...

Keyword(s):

Western Blot ◽

Cell Viability ◽

Cell Lines ◽

Blot Analysis ◽

Western Blot Analysis ◽

Single Agent ◽

Employment Equity ◽

Equity Ownership ◽

Dose Dependent Decrease ◽

Dose Dependent

Abstract ONC201 is the founding member of the imipridone class of anti-cancer small molecules that possess a unique core chemical structure. ONC201 is currently being evaluated in several Phase I/II clinical trials for advanced cancers. In the current study, we evaluated the single agent and combinatorial efficacy of ONC201 in preclinical models of acute leukemia and multiple myeloma (MM). In acute leukemia, we evaluated ONC201 anti-cancer effects in acute myeloid leukemia (AML) (Kasumi-1, HL60) and acute lymphoblastic leukemia (ALL) (Reh, Jurkat and MOLT-4) cell lines. We observed a time- and dose-dependent decrease in cell viability for every cell line in the panel (EC50 1-5 µM). Vincristine-resistant cells HL60/VCR were also sensitive to single agent ONC201 with EC50 values on par with corresponding vincristine-sensitive parental cells. Dose- and time-dependent induction of apoptosis was noted in Western blot analysis of caspase-3 cleavage in AML cell lines treated with 2.5 µM or 5 µM of ONC201 for 48 hr. Western Blot analysis further demonstrated inhibition of Akt and Foxo3a phosphorylation in Kasumi-1 cells, in line with the previously reported late-stage signaling effects of ONC201 in solid tumor cells (Allen et al, 2013). Sub-G1 analysis indicated that ONC201 induces apoptosis in ALL cells and a pan-caspase inhibitor reduced ONC201-mediated apoptosis. Western blot analysis revealed ONC201-mediated apoptosis involves PARP cleavage and caspase-9 activation in ALL cells. Anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xl were downregulated while the pro-apoptotic Bcl-2 family member Bim is upregulated in response to ONC201 treatment in ALL cells. ONC201 also downregulates the inhibitor of apoptosis (IAP) family proteins cIAP1 and cIAP2 in ALL cells. We observed inhibition of Akt phosphorylation upon ONC201 treatment of ALL cells. Fresh AML patient cells were also found to be sensitive to ONC201 in cell viability and caspase 3/7 activity assays at 5µM. We observed that independent clones of cancer cells with acquired resistance to ONC201 were more sensitive to cytarabine compared to parental ONC201-sensitive cancer cells. In addition, ONC201 demonstrated synergistic reduction in cell viability in combination with cytarabine in AML cell lines. Determination of combination indices (CI) revealed synergy at several concentrations (CI 0.336-0.75 in CMK cells). Also, ONC201 combined additively with midostaurin in CMK cells and vincristine in HL60/VCR cells. Thus, ONC201 is a promising combinatorial partner for AML therapies based on these preclinical sensitization results. In accordance with ONC201-mediated activation of the integrated stress response that B cells are highly sensitive to (Kline et al and Ishizawa et al, 2016), MM was identified as one of the most ONC201-sensitive tumor types in the Genomics of Drug Sensitivity in Cancer collection of cell lines. Three human MM cell lines were used for validation (KMS18, MM.1S and RPMI-8226), which revealed a time- and dose-dependent decrease in cell viability (EC50 1-2.5 µM). Bortezomib-resistant cells MM.1S 33X were sensitive to ONC201 as a single agent with EC50 values comparable to bortezomib-sensitive parental cells. We observed an average of 10-fold induction of ONC201-mediated apoptosis using Sub-G1 analyses in MM cells at 5 µM, 48 hrs post-treatment. Rescue of ONC201-mediated apoptosis was demonstrated using the pan-caspase inhibitor (Z-VAD-FMK). In addition, Western blot analysis in MM cells indicated a dose-dependent decrease in the anti-apoptotic protein XIAP which is a key mediator of apoptosis inhibition and is reported to be highly up-regulated in MM cells. Furthermore, ONC201 demonstrated synergistic reduction in cell viability at various concentrations in combination with either ixazomib or dexamethasone, which are used in the clinical treatment of MM, in RPMI8226 cells (CI 0.228-0.75). Also, ONC201 combined additively with bortezomib in RPMI8226 and MM.1S 33X cells. In summary, these preclinical studies support the ongoing ONC201 single agent trials in acute leukemias and MM. Our findings suggest that ONC201 may be an important therapeutic option for patients with hematological malignancies who have developed resistance to approved therapies. Additionally, our results point to specific standard-of-care therapies that may be combined with ONC201 to exert durable responses without adding to the burden of toxicity. Disclosures Prabhu: Oncoceutics: Employment. Tarapore:Oncoceutics: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Allen:Oncoceutics: Employment, Equity Ownership. El-Deiry:Oncoceutics: Equity Ownership.

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Loss of hematopoietic stem cell self-renewal after bone marrow transplantation

Blood ◽

10.1182/blood.v74.2.872.bloodjournal742872 ◽

1989 ◽

Vol 74 (2) ◽

pp. 872-875 ◽

Cited By ~ 1

Author(s):

P Mauch ◽

S Hellman

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Cell Dose ◽

Dose Dependent Decrease ◽

Dose Dependent

The quality of long-term hematopoietic engraftment after bone marrow transplantation (BMT) has not been well characterized. Clinical autologous BMT involves removal of less than 5% of the total content of the recipient marrow followed by ablation of the remaining marrow and reinfusion. To study long-term consequences of transplanting limited numbers of BM stem cells further, we evaluated the hematopoietic reserve in recipient animals after transplantation of varying quantities of BM. Recipient animals demonstrated a donor BM cell dose- dependent decrease in stem cell content and self-renewal capacity that was not reflected in peripheral blood (PB) counts or BM cellularity. This decrease was observed after initial BM recovery and did not change with time after transplantation, demonstrating a permanent loss in BM self-renewal capacity. In addition, animals alive at 3 months, a time selected to allow BM recovery, also demonstrated a donor BM cell dose- dependent decrease in survival at 1 year. These results emphasize the importance of optimizing stem cell number in BMT.

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Effect of Selenium Fertilization and Methyl Jasmonate Treatment on Glucosinolate Accumulation in Broccoli Florets

Journal of the American Society for Horticultural Science ◽

10.21273/jashs.136.4.239 ◽

2011 ◽

Vol 136 (4) ◽

pp. 239-246 ◽

Cited By ~ 35

Author(s):

Hyoung Seok Kim ◽

John A. Juvik

Keyword(s):

Methyl Jasmonate ◽

Combined Treatment ◽

Cultivar Selection ◽

Meja Treatment ◽

High Concentrations ◽

Dose Dependent Decrease ◽

Risk Of Cancer ◽

Genotype Response ◽

Dose Dependent ◽

Sulfur Containing

Broccoli (Brassica oleracea ssp. italica) is a rich source of glucosinolates (GSs), phytochemicals that are hydrolyzed into isothiocyanates with known human anticarcinogenic bioactivity. Increasing dietary intake of the element selenium (Se) can also reduce the risk of cancer. Previous research reported that Se fertilization at high concentrations reduces the concentration of GSs in brassicaceous plants. This research was conducted to determine the effect of Se fertilization on accumulation of different types of GSs in broccoli floret tissues in five genotypes. Methyl jasmonate (MeJA), an elicitor known to stimulate biosynthesis of indolyl GSs, was used to analyze changes in biosynthetic capability of indolyl GSs in broccoli floret tissue under Se-enriched conditions. Five broccoli genotypes were subjected to root fertilization with low and high levels of Na2SeO4 solutions (0.17 and 5.2 mm), MeJA sprays to aerial portions of the plants (250 μM), and the combined treatment of 5.2 mm Se with 250 μM MeJA, respectively. The effect of Se fertilization on GS accumulation varied among genotypes and the level of Se fertilization. Variation in the level of Se fertilization resulted in a dose-dependent decrease in glucoraphanin concentrations with no significant effect on indolyl GS accumulation in broccoli florets across the five genotypes. MeJA treatment increased indolyl and aromatic GS accumulation in floret tissues. MeJA-mediated increases in these GSs were inhibited in the high Se fertilization treatment, but the increase in neoglucobrassicin concentrations was less affected than other GSs in florets across the five genotypes. An experiment conducted with 6-week-old broccoli plants under the high Se treatment demonstrated greater accumulation of Se with depressed accumulation of sulfur and complete inhibition of MeJA-mediated indolyl GS accumulation compared with those changes in florets of mature broccoli plants. These results suggest that GS accumulation under Se fertilization may be influenced by not only the level of Se fertilization, but also the differences in sizes of available pools of resources (sulfur and sulfur-containing amino acids) required for GS biosynthesis and accumulation in broccoli plants. Partitioning of the variance indicated that the existence of substantial variability in GS concentrations was primarily attributed to differences in genotype response across different treatments. Results suggest that cultivar selection and breeding of broccoli can be used to develop broccoli germplasm with enhanced capacity for Se uptake and stability of GS biosynthesis with varying Se fertilization.

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Neuroprotection by the Ketogenic Diet: Evidence and Controversies

Frontiers in Nutrition ◽

10.3389/fnut.2021.782657 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sarah M. Gough ◽

Alicia Casella ◽

Kristen Jasmin Ortega ◽

Abigail S. Hackam

Keyword(s):

Multiple Sclerosis ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ketogenic Diet ◽

Molecular Mechanisms ◽

Ketone Bodies ◽

Current Evidence ◽

Pediatric Epilepsy ◽

Low Carbohydrate Diet ◽

Cord Injury

The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.

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Classic ketogenic diet (and its modifications) - the therapy for epileptiform conditions caused by some defects of carbohydrate and fat metabolism. Part I. Ketogenic diet mechanisms of action

Психическое здоровье ◽

10.25557/2074-014x.2018.01.66-83 ◽

2018 ◽

pp. 66-83

Author(s):

В.К. Поздеев

Keyword(s):

Fatty Acids ◽

Ketogenic Diet ◽

Ketone Bodies ◽

Fat Metabolism ◽

Minimal Amount ◽

Peripheral Tissues ◽

Glut 1 ◽

Low Carbohydrate Diet ◽

Mitochondrial Fatty Acid ◽

Kidney Insufficiency

Кетогенная диета (КД) - это низкоуглеводная диета с высоким содержанием жиров и умеренным содержанием белков с включением витаминных комплексов, микро-, макроэлементов, особенно, кальция в сочетании с витамином D. У здорового человека при традиционном взвешенном питании углеводы, поступающие с пищей, перерабатываются в глюкозу, которая обеспечивает энергетическое питание и функционирование ЦНС. Посредством КД в рационе присутствует малое количество углеводов, поэтому печень компенсаторно, стремясь обеспечить организм энергетическим питанием, начинает интенсивно преобразовывать жир в жирные кислоты, затем в кетоновые тела - ацетоацетат, b-оксибутират, ацетон (кетогенез) в качестве альтернативы глюкозе. В результате, формируется состояние кетоза - повышенного уровня кетоновых тел в крови - и затем их утилизация в митохондриях периферических тканей и ЦНС (кетолизис). Одновременно происходит глубокое перепрограммирование метаболических процессов с терапевтическими (при эпилепсии и многих нейродегенеративных заболеваниях), или негативными последствиями при дефектах метаболизма жиров, функции печени и почек. КД изначально применялась (часто, с высоким терапевтическим эффектом) для лечения эпилептиформных состояний, вызванных дефектами энергетического метаболизма, у детей; затем у взрослых - ее облегченные модификации посредством умеренного повышения в рационе углеводов, белков, среднецепочечных жирных кислот. КД предусматривает (в соответствии с ростом и возрастом) достаточное количество калорий для поддержания нормальной массы тела, необходимое количество белков и минимальное количество углеводов для роста, регенерации организма. КД-терапия успешно используется при дефекте транспорта глюкозы (транспортера GLUT-1) в ЦНС, дефиците пируватдегидрогеназы; оказывает положительное действие при ожирении, диабете 2-го типа, болезнях Паркинсона и Альцгеймера, боковом амиотрофическом склерозе, рассеянном склерозе, инсультах, травмах и злокачествеенных опухолях головного мозга. Классическая КД противопоказана при нарушениях кетогенеза и кетолизиса, нарушениях функции печени и почек, недостаточности карнитин-пальмитоилтрансферазы I (транспортера жирных кислот в митохондрии), но ее модификации эффективны при некоторых дефектах обмена жиров. Ketogenic diet (KD) is a low carbohydrate diet that contains high amounts of fats and moderate amounts of proteins and includes vitamins, micro- and macroelements (particularly, calcium in combination with vitamin D). In a healthy human on traditional balanced diet, carbohydrates from food are being converted to glucose that provides energy for the central nervous system (CNS). KD contains little carbohydrates, therefore liver, to provide organism with energy, compensatory converts fat into fatty acids and then into ketone bodies acetoacetate, b-hydroxybutyrate, acetone as an alternative to glucose (ketogenesis). This results in ketosis - increased levels of ketone bodies in blood followed by their utilization in mitochondria of peripheral tissues and CNS (ketolysis). Simultaneously, a deep reprogramming of metabolic processes occurs resulting in therapeutic (in epilepsy and many neurodegenerative diseases) or negative (when fat metabolism defects or liver and kidney insufficiency are present) consequences. KD was initially used (frequently with therapeutic benefit) for the treatment of epileptiform conditions caused by defects in energy metabolism in children and later in adults (using lightened modifications with modestly increased levels of carbohydrates, proteins and medium-chain fatty acids). KD provides sufficient number of calories (matching patient’s height and age) to maintain normal body weight, necessary amount of protein and minimal amount of carbohydrates for organism growth and regeneration. KD is used successfully in patients with CNS glucose transport defects (GLUT-1), pyruvate dehydrogenase deficit, it provides benefits in obesity, type 2 diabetes, Parkinson’s and Alzheimer’s disease, lateral amyotrophic sclerosis, multiple sclerosis, stroke, traumas and brain malignancies, Classic KD is contraindicated in ketogenesis and ketolysis defects, liver insufficiency, kidney insufficiency, carnitine palmitoyltransferase I (mitochondrial fatty acid transporter) deficiency but its modifications are effective in some fat metabolism defects.

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