Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 35
Filter
Add more filters










Publication year range
1.
Int J Food Sci ; 2024: 5596798, 2024.
Article in English | MEDLINE | ID: mdl-38549663

ABSTRACT

Tempe is an Indonesian food product traditionally obtained from soybeans through solid-state fermentation with Rhizopus. A variety of substrates can be processed into tempe in the presence of other microorganisms. In this study, grass pea seeds with the addition of flaxseed oil cake (20% w/w) were either fermented using individual mould strains-Rhizopus oryzae, R. oligosporus, and Mucor indicus-or cofermented with the moulds and Lactiplantibacillus plantarum. In the obtained products, the content of dietary fibre, B group vitamins, and the level of peptides and antioxidant potential in aqueous extracts were measured. Moreover, peptides, angiotensin I convertase inhibitor, and antioxidant activity were determined after in vitro digestion. The effect of digestates on the differentiation of enterocytes was also investigated. Fermentation generally resulted in a decrease in the dietary fibre, especially the insoluble fraction (30-50%). The product obtained with R. oryzae was the best source of riboflavin and thiamine among all tested. The fermentation process promoted the accumulation of water-soluble peptides and antioxidant compounds. After in vitro digestion, the largest amount of antioxidant and antiradical compounds was released from tempe obtained with R. oryzae. However, the enrichment of the products with antioxidants resulting from solid-state fermentation did not simply translate into an improvement in antioxidant potential after digestion. Generally, fermentation carried out in the presence of L. plantarum brought positive effects only in the case of R. oligosporus DSM 1964. Digestion products obtained from R. oryzae tempe had a positive effect on the viability of Caco-2 cells differentiated into enterocytes. Interestingly, a higher activity of differentiation markers (alkaline phosphatase and sucrase-isomaltase) was observed under the influence of digestate of R. oryzae and L. plantarum tempe.

2.
Cell Signal ; 113: 110938, 2024 01.
Article in English | MEDLINE | ID: mdl-37871667

ABSTRACT

PURPOSE: The role of Wnt signaling in oncogenesis and drug resistance is well known. Receptor-interacting protein kinase (RIPK4) contributing to the increased activity of many signaling pathways, including Wnt/ß-catenin, may be an important target for designing new drugs for metastatic melanoma, but its role in melanoma is not fully understood. METHODS: We tested the effect of genetic manipulation of RIPK4 (CRISPR/Cas9) on xenograft growth. In addition, immunohistochemistry was used to detect active ß-catenin, Ki67 and necrosis in xenografts. Wnt signaling pathway activity was examined using Western blot and Top-Flash. The effect of RIPK4 knockout on melanoma cells in vitro stimulated Wnt3A on wound overgrowth, migration and invasion ability was then evaluated. RESULTS: Our study showed that CRISPR/Cas9-mediated RIPK4 knockout (KO) significantly reduced tumor growth in a mouse model of melanoma, particularly of WM266.4 cells. RIPK4 KO tumors exhibited lower percentages of Ki67+ cells as well as reduced necrotic area and decreased levels of active ß-catenin. In addition, we observed that RIPK4 knockout impaired Wnt3A-induced activation of LRP6 and ß-catenin, as manifested by a decrease in the transcriptional activity of ß-catenin in Top-Flash in both tested melanoma cell lines, A375 and WM266.4. Prolonged incubation (48 h) with Wnt3A showed reduced level of MMP9, C-myc, and increased SOX10, proteins whose transcription is also dependent on ß-catenin activity. Moreover, RIPK4 knockout led to the inhibition of scratch overgrowth, migration and invasion of these cells compared to their controls. CONCLUSION: RIPK4 knockdown inhibits melanoma tumor growth and Wnt3A stimulated migration and invasion indicating that RIPK4 might be a potential target for melanoma therapy.


Subject(s)
Melanoma , Wnt Signaling Pathway , Animals , Humans , Mice , beta Catenin/metabolism , Cell Line, Tumor , Cell Proliferation , Down-Regulation , Ki-67 Antigen/genetics , Ki-67 Antigen/metabolism , Melanoma/pathology , Wnt3A Protein/genetics
3.
Int J Mol Sci ; 23(22)2022 Nov 13.
Article in English | MEDLINE | ID: mdl-36430484

ABSTRACT

Hydrogels, based on natural polymers, such as hyaluronic acid, are gaining an increasing popularity because of their biological activity. The antibacterial effect of ozone is widely known and used, but the instability the gas causes, severely limits its application. Ozone entrapment in olive oil by its reaction with an unsaturated bond, allows for the formation of stable, therapeutically active ozone derivatives. In this study, we obtained an innovative hydrogel, based on hyaluronic acid containing micro/nanocapsules of ozonated olive oil. By combination of the biocompatible polymer with a high regenerative capacity and biologically active ingredients, we obtained a hydrogel with regenerative properties and a very weak inhibitory effect against both bacterial commensal skin microbiota and pathogenic Candida-like yeasts. We assessed the stability and rheological properties of the gel, determined the morphology of the composite, using scanning electron microscopy (SEM) and particle size by the dynamic light scattering (DLS) method. We also performed Attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectroscopy. The functional properties, including the antimicrobial potential were assessed by the microbiological analysis and in vitro testing on the HaCat human keratinocyte cell line. The studies proved that the obtained emulsions were rheologically stable, exhibited an antimicrobial effect and did not show cytotoxicity in the HaCat keratinocyte model.


Subject(s)
Anti-Infective Agents , Ozone , Humans , Capsules , Hyaluronic Acid , Olive Oil , Hydrogels/pharmacology , Hydrogels/chemistry , Anti-Bacterial Agents/pharmacology , Polymers/chemistry , Anti-Infective Agents/pharmacology , Ozone/pharmacology
4.
Int J Mol Sci ; 23(22)2022 Nov 16.
Article in English | MEDLINE | ID: mdl-36430628

ABSTRACT

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed throughout the mammalian gut: in epithelial cells, in the villi of enterocytes and in Paneth cells of intestinal crypts, as well as in some immune cells (e.g., lamina propria macrophages, dendritic cells) of the mucosa. This review examines the reciprocal interaction between PPARα activation and intestinal microbiota. We refer to the published data confirming that microbiota products can influence PPARα signaling and, on the other hand, PPARα activation is able to affect microbiota profile, viability, and diversity. PPARα impact on the broad spectrum of events connected to metabolism, signaling (e.g., NO production), immunological tolerance to dietary antigens, immunity and permeability of the gut are also discussed. We believe that the phenomena described here play a prominent role in gut homeostasis. Therefore, in conclusion we propose future directions for research, including the application of synthetic activators and natural endogenous ligands of PPARα (i.e., endocannabinoids) as therapeutics for intestinal pathologies and systemic diseases assumed to be related to gut dysbiosis.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Animals , PPAR alpha , Dysbiosis , Permeability , Mammals
5.
Int J Mol Sci ; 22(19)2021 Sep 29.
Article in English | MEDLINE | ID: mdl-34638886

ABSTRACT

Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various inflammatory reactions. In this review, we focus on its role in the regulation of innate immunity; in particular, we discuss the PPARα interplay with inflammatory transcription factor signaling, pattern-recognition receptor signaling, and the endocannabinoid system. We also present examples of the PPARα-specific immunomodulatory functions during parasitic, bacterial, and viral infections, as well as approach several issues associated with innate immunity processes, such as the production of reactive nitrogen and oxygen species, phagocytosis, and the effector functions of macrophages, innate lymphoid cells, and mast cells. The described phenomena encourage the application of endogenous and pharmacological PPARα agonists to alleviate the disorders of immunological background and the development of new solutions that engage PPARα activation or suppression.


Subject(s)
Energy Metabolism/immunology , Homeostasis/immunology , Immunity, Innate/immunology , Inflammation/immunology , PPAR alpha/immunology , Signal Transduction/immunology , Adaptive Immunity/immunology , Animals , Humans , Macrophages/immunology , PPAR alpha/metabolism
6.
Polymers (Basel) ; 13(14)2021 Jul 15.
Article in English | MEDLINE | ID: mdl-34301083

ABSTRACT

The application of natural polymer matrices as medical device components or food packaging materials has gained a considerable popularity in recent years, this has occurred in response to the increasing plastic pollution hazard. Currently, constant progress is being made in designing two-component or three-component systems that combine natural materials which help to achieve a quality comparable to the purely synthetic counterparts. This study describes a green synthesis preparation of new bionanocomposites consisting of starch/chitosan/graphene oxide (GO), that possess improved biological activities; namely, good tolerability by human cells with concomitant antimicrobial activity. The structural and morphological properties of bionanocomposites were analyzed using the following techniques: dynamic light scattering, scanning and transmission electron microscopy, wettability and free surface energy determination, and Fourier transform infrared spectroscopy. The study confirmed the homogenous distribution of GO layers within the starch/chitosan matrix and their large particle size. The interactions among the components were stronger in thin films. Additionally, differential scanning calorimetry analysis, UV-vis spectroscopy, surface colour measurements, transparency, water content, solubility, and swelling degree of composites were also performed. The mechanical parameters, such as tensile strength and elongation at break (EAB) were measured in order to characterise the functional properties of obtained nanocomposites. The GO additive altered the thermal features of the composites and decreased their brightness. The EAB of composite was improved by the introduction of GO. Importantly, cell-based analyses revealed no toxic effect of the composites on HaCat keratinocytes and HepG2 hepatoma cells, although a pronounced bacteriostatic effect against various strains of pathogenic bacteria was observed. In conclusion, the starch/chitosan/GO nanocomposites reveal numerous useful physicochemical and biological features, which make them a promising alternative for purely synthetic materials.

7.
Molecules ; 26(5)2021 Mar 06.
Article in English | MEDLINE | ID: mdl-33800895

ABSTRACT

The biological activity of apple pectin extracted conventionally or enzymatically using endo-xylanase and endo-cellulase, was tested in vitro. The analyses were performerd in tetraplicates and the statistical significance of the differences were assessed using ANOVA, Tukey post hoc and LSD (the least significant difference) tests. Multivariate regression analysis was applied to determine the structural components that have a crucial importance for antioxidant and antitumor properties of pectins. The pectins extracted by enzymes contained up to four times more ferulic acid and showed twice as great ability to neutralize free radicals and Fe(III) reduction. The antiradical potential positively correlated with phenols, fucose and rhamnose content. In the assays performed on HT-29 human adenocarcinoma and B16F10 melanoma cell cultures, the "green" pectins, contrary to acid isolated ones, exhibited remarkable anti-neoplastic potential while being nontoxic to nontransformed L929 cell line. The pectins in the dose of 1 mg/mL were capable of inhibiting adhesion (max 23.1%), proliferation (max 40.4%), invasion (max 76.9%) and anchorage-independent growth (max 90%) of HT-29 cells (significance level p < 0.001). These pectin preparations were slightly less active towards B16F10 cells. The enzyme-isolated apple pectins may be useful as a functional food additive and an ingredient of the ointment formulas for post-surgical melanoma treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Cellulase/metabolism , Colonic Neoplasms/drug therapy , Endo-1,4-beta Xylanases/metabolism , Malus/chemistry , Melanoma/drug therapy , Pectins/pharmacology , Apoptosis , Cell Proliferation , Colonic Neoplasms/pathology , Humans , Melanoma/pathology , Tumor Cells, Cultured
8.
Int J Food Sci Nutr ; 72(3): 348-356, 2021 May.
Article in English | MEDLINE | ID: mdl-32900230

ABSTRACT

Due to their health-promoting effects green tea catechins have gained a keen interest in recent years in the context of bodyweight reduction treatments and alleviation of inflammatory diseases. This study was designed to evaluate the impact of native and thermally modified catechins (TMC) on the body weight gain, fatty acid profile in subcutaneous adipose tissue and the activity of the enzymes involved in lipid metabolism regulation: AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in apoE-deficient mice maintained on a high-fat diet. We observed that TMC decreased bodyweight gain as compared to the control group. Furthermore, TMC increased AMPK activity and reduced ACC activity in the metabolically important tissues: intestine, liver and subcutaneous adipose tissue and affected adipose tissue fatty acid composition. Native catechins produced less pronounced effects. These results suggest that TMC down-regulate endogenous fatty acid synthesis, which should be taken into account in dietary applications of catechins.


Subject(s)
Adenosine Monophosphate/metabolism , Adenylate Kinase/metabolism , Catechin/pharmacology , Diet, High-Fat/adverse effects , Acetyl-CoA Carboxylase/metabolism , Adipose Tissue/metabolism , Animals , Apolipoproteins E/metabolism , Fatty Acids/metabolism , Lipid Metabolism , Liver/metabolism , Male , Mice , Mice, Knockout, ApoE , Tea/chemistry , Weight Gain
9.
Exp Dermatol ; 29(4): 436-445, 2020 04.
Article in English | MEDLINE | ID: mdl-31957066

ABSTRACT

Development and progression of melanoma can be accelerated by intensification of particular metabolic pathways, such as aerobic glycolysis and avid amino acid catabolism, and is accompanied by aberrant immune responses within the tumor microenvironment. Contrary to other cancer types, melanoma reveals some unique tissue-specific features, such as melanogenesis, which is intertwined with metabolism. Nuclear peroxisome proliferator-activated receptors (PPARs) take part in regulation of systemic and cellular metabolism, inflammation and melanogenesis. They appear as a focal regulatory point for these three distinct processes by occupying the intersection among AMP-dependent protein kinase (AMPK), mammalian target of rapamycin (mTOR) and PPAR gamma coactivator 1-alpha (PGC-1α) signalling pathways. When deregulated, they may accelerate melanoma malignant growth. Presenting the contribution of PPARα and PPARγ in melanoma biology, we attempt to ask how two contrasting metabolic states: obesity and fasting, can change progression of the disease and possible outcome of the treatment. This short essay is aimed to provoke a discussion about some practical implications for melanoma prevention and treatment, especially: how metabolic manipulation may be exploited to overcome immunosuppression and support immune checkpoint blockade efficacy.


Subject(s)
Melanocytes/metabolism , Melanoma/metabolism , PPAR alpha/metabolism , Skin Neoplasms/metabolism , 3-Hydroxybutyric Acid/chemistry , Acetoacetates/chemistry , Animals , Arginine , Cell Nucleus/metabolism , Humans , Immune System , Immunotherapy/methods , Inflammation , Models, Theoretical , Obesity/metabolism , PPAR gamma/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Tumor Microenvironment
10.
Methods Mol Biol ; 1576: 135-144, 2019.
Article in English | MEDLINE | ID: mdl-27787775

ABSTRACT

The intestinal epithelium isolated from chicken embryos in last 3 days of development can be used to establish the 3D culture of intestinal organoids. When fragments of epithelial tissue released by incubation with EGTA (2.5 mM, 2 h) are embedded in Matrigel matrix on cell culture inserts the formation of empty spheres covered by epithelial cells is observed in first 24 h of culture. The growth and survival of organoids are supported by the addition of R-spondin 1, Noggin, and prostaglandin E2 to the culture medium. The organoids are accompanied by myofibroblasts which become visible in the next 2 days of culture. The intestinal enteroids (free of myofibroblasts) can be obtained from adult chicken intestine.


Subject(s)
Cell Culture Techniques/methods , Cell Differentiation , Epithelial Cells/cytology , Intestines/cytology , Myofibroblasts/cytology , Organoids/cytology , Tissue Engineering/methods , Animals , Cells, Cultured , Chick Embryo , Chickens
11.
Methods Mol Biol ; 1576: 355, 2019.
Article in English | MEDLINE | ID: mdl-30430443

ABSTRACT

In Figure 4 Section A, the upper right corner should read "3d", whereas it was incorrectly printed as "4d."

12.
Protoplasma ; 256(2): 575-581, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30327884

ABSTRACT

The method of organoid culture has become a tool widely used in gastrointestinal research, but so far, the migration of organoids derived from gut epithelium and formed in 3D Matrigel matrix has not been reported and studied. The intestinal epithelial tissue derived from 19-day-old chicken embryo was cultured in Matrigel and the dynamic properties of the forming organoids were analyzed by time-lapse image analysis. It was observed that about one in ten organoids actively moved through the matrix, at a speed of 10-20 µm/h. Moreover, rotation was observed in the majority of organoids that did not migrate long distances. The fusion events took place between organoids, which collided during the movement or growth. In our previous paper, we showed that the presence of Toll-like receptor 4 ligand, Escherichia coli lipopolysaccharide (LPS, 1 µg/ml), increased the mean organoid diameter. Here, we confirm this result and demonstrate that the Rho-associated protein kinase (ROCK) inhibitor Y-27632 (10 µM) did not completely abolish organoid migration, but prevented the fusion events, in both LPS-treated and untreated cultures. In consequence, in the presence of Y-27632, the differences between cultures incubated with and without LPS were not visible. We conclude that migration and fusion of organoids may influence their morphology and suggest that these phenomena should be taken into account during the design of experimental settings.


Subject(s)
Intestinal Mucosa/physiopathology , Organoids/physiopathology , Animals , Cell Differentiation , Chick Embryo , Chickens
13.
Cytotechnology ; 70(3): 1085-1095, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29372467

ABSTRACT

Recently organoids have become widely used in vitro models of many tissue and organs. These type of structures, originated from embryonic or adult mammalian intestines, are called "mini guts". They organize spontaneously when intestinal crypts or stem cells are embedded in the extracellular matrix proteins preparation scaffold (Matrigel). This approach has some disadvantages, as Matrigel is undefined (the concentrations of growth factors and other biologically active components in it may vary from batch to batch), difficult to handle and expensive. Here we show that the organoids derived from chicken embryo intestine are formed in a hanging drop without embedding, providing an attractive alternative for currently used protocols. Using this technique we obtained compact structures composed of contiguous organoids, which were generally similar to chicken organoids cultured in Matrigel in terms of morphology and expression of intestinal epithelial markers. Due to the simplicity, high reproducibility and throughput capacity of hanging drop technique our model may be applied in various studies concerning the gut biology.

14.
J Am Coll Nutr ; 36(7): 579-585, 2017.
Article in English | MEDLINE | ID: mdl-28895793

ABSTRACT

OBJECTIVE: We investigated whether antioxidants may enhance bioavailability of lipids and carbohydrates and therefore increase the risk of obesity development. METHODS: We tested how supplementation with antioxidants (0.01% butylated hydroxytoluene [BHT], α-tocopherol, and green tea catechins) of a diet containing butter and wheat bread affects bioavailability of fats and carbohydrates. The absorption of the in vitro digested diet was estimated in the intestinal epithelia model of the Caco-2 cells cultured in Transwell chambers. RESULTS: In the case of the antioxidant-supplemented diets, we observed increased bioavailability of glucose, cholesterol, and lipids, as well as elevated secretion of the main chylomicron protein apoB-48 to the basal compartment. Importantly, we did not detect any rise in the concentrations of lipid peroxidation products (malondialdehyde, MDA) in the control samples prepared without antioxidants. CONCLUSIONS: Addition of antioxidants (in particular BHT) to the diet increases bioavailability of lipids and carbohydrates, which consequently may increase the risk of obesity development. The dose of antioxidants is a factor of fundamental importance, particularly for catechins: low doses increase absorption of lipids, whereas high doses exert the opposite effect.


Subject(s)
Antioxidants/pharmacology , Butylated Hydroxytoluene/pharmacology , Catechin/pharmacology , Dietary Carbohydrates/pharmacokinetics , Dietary Fats/pharmacokinetics , Food Preservatives/pharmacology , alpha-Tocopherol/pharmacology , Apolipoprotein B-48/metabolism , Biological Availability , Caco-2 Cells , Cholesterol/pharmacokinetics , Chylomicrons , Dietary Carbohydrates/administration & dosage , Dietary Fats/administration & dosage , Glucose/pharmacokinetics , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Lipid Peroxidation/drug effects , Malondialdehyde/blood , Models, Biological , Tea/chemistry
15.
Article in English | MEDLINE | ID: mdl-28750869

ABSTRACT

The intestinal epithelial cells reside in close proximity to myofibroblasts and microbiota, which are supposed to have an impact on intestinal stem cells fate and to influence processes of tissue maturation and regeneration. Mechanism underlying these phenomena and their diversity among vertebrates can be studied in 3D organoid cultures. We investigated the growth of chicken embryo intestinal epithelial organoids in Matrigel with and without Toll-like receptors (TLRs) stimulation. The organoid cultures contained also some myofibroblasts with potential to promote intestinal stem cell survival. Organoid cells, expressing TLR4, TLR2 type 1 and TLR2 type 2 were incubated with their agonists (lipopolysaccharide - LPS and Pam3CSK4) or co-cultured with Lactobacillus acidophilus bacteria (LA-5). Pam3CSK4 and LA-5 promoted organoid growth, which was demonstrated by comparing the morphological parameters (mean number and area of organoids). The profile of prostaglandins (PG), known to promote intestinal regeneration, in supernatants from organoid and fibroblast cultures were evaluated. Both PGE2 and PGD2 were detected. As compared to unstimulated controls, supernatants from the Pam3CSK4-stimulated organoids contained twice as much of PGE2 and PGD2. The changes in production of prostaglandins and the support of epithelial cell growth by myofibroblasts are factors potentially responsible for stimulatory effect of TLR2 activation.


Subject(s)
Intestinal Mucosa/embryology , Lactobacillus acidophilus/physiology , Lipopeptides/pharmacology , Organoids/embryology , Probiotics , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/immunology , Animals , Chick Embryo , Coculture Techniques , Dinoprostone/biosynthesis , Epithelial Cells/physiology , Intestinal Mucosa/microbiology , Myofibroblasts/physiology , Organ Culture Techniques , Organoids/physiology , Prostaglandin D2/biosynthesis , Signal Transduction , Toll-Like Receptor 4/immunology
16.
Arch Dermatol Res ; 309(3): 141-157, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28084540

ABSTRACT

Recent studies revealed the cooperation between peroxisome proliferator-activated receptor gamma (PPARγ) and α-MSH signaling, which results in enhanced melanogenesis in melanocytes and melanoma cells. However, the agonists of PPARα, such as fenofibrate, exert depigmenting effect. Therefore, we aimed to check how the PPARα expression level affects the antimelanogenic activity of fenofibrate and whether PPARα modulates melanogenesis independently of its agonist. To answer these questions, we used three B16 F10-derived cell lines, which varied in the PPARα expression level and were developed by stable transfection with plasmids driving shRNA-based PPARα silencing or overexpression of PPARα-emerald GFP fusion protein. Melanin contents were assessed with electron paramagnetic resonance spectroscopy along with color component image analysis-a novel approach to pigment content characteristics in melanoma cells. B16 F10 wt and Ctrl shRNA lines showed intermediate pigmentation, whereas the pigmentation of the B16 F10-derived cell lines was inversely correlated with the PPARα expression level. We observed that cells overexpressing PPARα were almost amelanotic and cells with reduced PPARα protein level were heavily melanized. Furthermore, fenofibrate down-regulated the melanogenic apparatus (MITF, tyrosinase, and tyrosinase-related proteins) in the cells with the regular PPARα expression level resulting in their visibly lower total melanin content in all the cell lines. From these observations, we conclude that fenofibrate works as a strong depigmenting agent, which acts independently of PPARα, but in an additive fashion. Our results also indicate that alterations in PGC-1a acetylation and expression level might contribute to the regulation of melanogenesis by PPARα and fenofibrate.


Subject(s)
Fenofibrate/pharmacology , Hypolipidemic Agents/pharmacology , Melanins/metabolism , Melanoma, Experimental/metabolism , PPAR alpha/metabolism , Pigmentation/drug effects , Skin Lightening Preparations/pharmacology , Acetylation , Animals , Cell Line, Tumor , Cell Proliferation , Melanocytes/metabolism , Mice , Microphthalmia-Associated Transcription Factor/biosynthesis , Monophenol Monooxygenase/biosynthesis , PPAR alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Pigmentation/physiology , RNA Interference , RNA, Small Interfering/genetics
17.
Int J Mol Sci ; 17(12)2016 Dec 13.
Article in English | MEDLINE | ID: mdl-27983603

ABSTRACT

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.


Subject(s)
Ketone Bodies/metabolism , PPAR alpha/metabolism , Animals , Brain/drug effects , Brain/metabolism , Humans , Neoplasms/metabolism , Neoplasms/pathology , Neuroprotective Agents/pharmacology , Signal Transduction/drug effects
18.
Mitochondrion ; 30: 24-34, 2016 09.
Article in English | MEDLINE | ID: mdl-27288721

ABSTRACT

Mitochondria are the source of damage-associated molecular patterns (DAMPs). DAMPs modulate responses to stress and trauma in animals, influencing the onset of many diseases. Dietary phytochemicals, which target various cellular molecules, are potential modulators of immunological status. In this review the existence of the possible impact of some plant-derived compounds with proven anti-cancer and anti-inflammatory properties (isothiocyanates and curcumin) on DAMPs recognition is highlighted. Special consideration is given to the mtDNA recognizing Toll-like receptor 9 and formyl peptide receptors. In the context of the phytochemicals action, the role of these receptors in epithelial homeostasis is also discussed.


Subject(s)
Anti-Inflammatory Agents/metabolism , Antineoplastic Agents/metabolism , Mitochondria/chemistry , Mitochondria/pathology , Phytochemicals/metabolism , Animals , DNA, Mitochondrial/metabolism , Epithelial Cells/physiology , Homeostasis , Humans , Signal Transduction , Toll-Like Receptor 9/metabolism
19.
Article in English | MEDLINE | ID: mdl-26869992

ABSTRACT

Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.

20.
Mol Cell Biol ; 35(1): 182-98, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25332241

ABSTRACT

Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid ß-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.


Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Fenofibrate/pharmacology , Glioblastoma/drug therapy , Glioblastoma/pathology , Adenosine Triphosphate/metabolism , Animals , Antineoplastic Agents/pharmacology , Astrocytes/cytology , Brain Neoplasms/metabolism , Cell Death , Cell Line, Tumor , Electron Transport , Female , Glioblastoma/metabolism , Glycolysis , Humans , Membrane Potential, Mitochondrial , Mice , Mice, Nude , Mitochondria/metabolism , Neoplasm Transplantation , Oxygen/metabolism , Oxygen Consumption , PPAR alpha/metabolism , Signal Transduction
SELECTION OF CITATIONS
SEARCH DETAIL
...