Cells

Editorial

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6 pages, 522 KiB

Open AccessEditorial

Pharmacological and Nutraceutical Activation of Rejuvenation, Geroprotection and Cytoprotection: Proofs of Concept

by Gérard Lizard, Mohamed Hammami and Giuseppe Poli

Cells 2022, 11(23), 3786; https://doi.org/10.3390/cells11233786 - 26 Nov 2022

Cited by 1 | Viewed by 1558

Abstract

Aging is a process associated with life [...] Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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Research

Jump to: Editorial, Review

35 pages, 3091 KiB

Open AccessArticle

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

by Aline Yammine, Amira Zarrouk, Thomas Nury, Anne Vejux, Norbert Latruffe, Dominique Vervandier-Fasseur, Mohammad Samadi, John J. Mackrill, Hélène Greige-Gerges, Lizette Auezova and Gérard Lizard

Cells 2020, 9(11), 2346; https://doi.org/10.3390/cells9112346 - 23 Oct 2020

Cited by 53 | Viewed by 5086

Abstract

The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol [...] Read more.

The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 µM; 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125; 6.25 µM), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level; by an attenuation of the increase in the level and activity of catalase; by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1); by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2); and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (ΨΔm) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase α (AMPKα), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal β-oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal β-oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei; cleaved caspase-3; Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles; activation of microtubule associated protein 1 light chain 3–I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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18 pages, 2013 KiB

Open AccessArticle

Genome-Wide Transcriptomic Analysis Identifies Pathways Regulated by Sterculic Acid in Retinal Pigmented Epithelium Cells

by Ana Pariente, Álvaro Pérez-Sala, Rodrigo Ochoa, Rafael Peláez and Ignacio M. Larráyoz

Cells 2020, 9(5), 1187; https://doi.org/10.3390/cells9051187 - 11 May 2020

Cited by 10 | Viewed by 2588

Abstract

In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment of various diseases. Sterculic acid (SA) is a cyclopropene fatty acid with numerous biological activities, generally attributed to [...] Read more.

In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment of various diseases. Sterculic acid (SA) is a cyclopropene fatty acid with numerous biological activities, generally attributed to its Stearoyl-CoA desaturase (SCD) inhibitory properties. Additional effects exerted by SA, independently of SCD inhibition, may be mediating anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD), but the mechanisms involved are poorly understood. In order to provide insights into those mechanisms, genome-wide transcriptomic analyses were carried out in mRPE cells exposed to SA for 24 h. Integrative functional enrichment analysis of genome-wide expression data provided biological insight about the protective mechanisms induced by SA. On the one hand, pivotal genes related to fatty acid biosynthesis, steroid biosynthesis, cell death, actin-cytoskeleton reorganization and extracellular matrix-receptor interaction were significantly downregulated by exposition to SA. On the other hand, genes related to fatty acid degradation and beta-oxidation were significantly upregulated. In conclusion, SA administration to RPE cells regulates crucial pathways related to cell proliferation, inflammation and cell death that may be of interest for the treatment of ocular diseases. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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20 pages, 4576 KiB

Open AccessFeature PaperArticle

Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent

by Alessandra Scagliarini, Aline Mathey, Virginie Aires and Dominique Delmas

Cells 2020, 9(4), 932; https://doi.org/10.3390/cells9040932 - 10 Apr 2020

Cited by 29 | Viewed by 3876

Abstract

In spite of chemotherapy and systematic screening for people at risk, the mortality rate of colorectal cancer (CRC) remains consistently high, with 600,000 deaths per year. This low success rate in the treatment of CRC results from many failures associated with high resistance [...] Read more.

In spite of chemotherapy and systematic screening for people at risk, the mortality rate of colorectal cancer (CRC) remains consistently high, with 600,000 deaths per year. This low success rate in the treatment of CRC results from many failures associated with high resistance and the risk of metastasis. Therefore, in response to these therapeutic failures, new strategies have been under development for several years aimed at increasing the effect of anticancer compounds and/or at reducing their secondary effects on normal cells, thus enabling the host to better withstand chemotherapy. This study highlights that xanthohumol (Xn) concentrations under the IC₅₀ values were able to induce apoptosis and to enhance the DNA-damage response (DDR). We demonstrate for the first time that Xn exerts its anticancer activity in models of colon cancer through activation of the ataxia telangiectasia mutated (ATM) pathway. Subsequently, the ability of Xn to restore DNA damage in CRC cells can sensitize them to anticancer agents such as SN38 (7-ethyl-10-hydroxycamptothecin) used in chemotherapy. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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12 pages, 1123 KiB

Open AccessFeature PaperArticle

Involvement of 27-Hydroxycholesterol in Mitotane Action on Adrenocortical Carcinoma

by Antonina Germano, Daniela Rossin, Valerio Leoni, Noemi Iaia, Laura Saba, Vittoria Basile, Soraya Puglisi, Claudio Caccia, Giuseppe Poli, Fiorella Biasi and Massimo Terzolo

Cells 2020, 9(4), 885; https://doi.org/10.3390/cells9040885 - 4 Apr 2020

Cited by 2 | Viewed by 4587

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of [...] Read more.

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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13 pages, 1883 KiB

Open AccessArticle

Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts

by David Nareznoi, Jenya Konikov-Rozenman, Dmytro Petukhov, Raphael Breuer and Shulamit B. Wallach-Dayan

Cells 2020, 9(2), 411; https://doi.org/10.3390/cells9020411 - 11 Feb 2020

Cited by 10 | Viewed by 3571

Abstract

A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in [...] Read more.

A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL⁺ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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19 pages, 3516 KiB

Open AccessFeature PaperArticle

A New Highlight of Ephedra alata Decne Properties as Potential Adjuvant in Combination with Cisplatin to Induce Cell Death of 4T1 Breast Cancer Cells In Vitro and In Vivo

by Fairouz Sioud, Souheila Amor, Imène ben Toumia, Aida Lahmar, Virginie Aires, Leila Chekir-Ghedira and Dominique Delmas

Cells 2020, 9(2), 362; https://doi.org/10.3390/cells9020362 - 4 Feb 2020

Cited by 33 | Viewed by 4757

Abstract

Despite major advances in the last 10 years, whether in terms of prevention or treatment, the 5 year survival rate remains relatively low for a large number of cancers. These therapeutic failures can be the consequence of several factors associated with the cellular [...] Read more.

Despite major advances in the last 10 years, whether in terms of prevention or treatment, the 5 year survival rate remains relatively low for a large number of cancers. These therapeutic failures can be the consequence of several factors associated with the cellular modifications or with the host by itself, especially for some anticancer drugs such as cisplatin, which induces a nephrotoxicity. In the strategy of research for active molecules capable both of exerting a protective action against the deleterious effects of cisplatin and exerting a chemosensitizing action with regard to cancer cells, we tested the potential effects of Ephedra alata Decne extract (E.A.) rich in polyphenolic compounds towards a 4T1 breast cancer model in vitro and in vivo. We showed that E.A. extract inhibited cell viability of 4T1 breast cancer cells and induced apoptosis in a caspase-dependent manner, which involved intrinsic pathways. Very interestingly, we observed a synergic antiproliferative and pro-apoptotic action with cisplatin. These events were associated with a strong decrease of breast tumor growth in mice treated with an E.A./cisplatin combination and simultaneously with a decrease of hepato- and nephrotoxicities of cisplatin. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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14 pages, 2017 KiB

Open AccessArticle

Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation

by Yasuomi Urano, Mina Takahachi, Ryo Higashiura, Hitomi Fujiwara, Satoru Funamoto, So Imai, Eugene Futai, Michiaki Okuda, Hachiro Sugimoto and Noriko Noguchi

Cells 2020, 9(2), 349; https://doi.org/10.3390/cells9020349 - 3 Feb 2020

Cited by 20 | Viewed by 4110

Abstract

Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, [...] Read more.

Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screening analysis using a curcumin derivative library with the aim of finding derivatives effective in suppressing Aβ production with improved bioavailability of curcumin using CHO cells that stably express human amyloid-β precursor protein and using human neuroblastoma SH-SY5Y cells. We found that the curcumin derivative GT863/PE859, which has been shown to have an inhibitory effect on Aβ and tau aggregation in vivo, was more effective than curcumin itself in reducing Aβ secretion. We further found that GT863 inhibited neither β- nor γ-secretase activity, but did suppress γ-secretase-mediated cleavage in a substrate-dependent manner. We further found that GT863 suppressed N-linked glycosylation, including that of the γ-secretase subunit nicastrin. We also found that mannosidase inhibitors that block the mannose trimming step of N-glycosylation suppressed Aβ production in a similar fashion, as was observed as a result of treatment with GT863. Collectively, these results suggest that GT863 downregulates N-glycosylation, resulting in suppression of Aβ production without affecting secretase activity. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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13 pages, 2545 KiB

Open AccessFeature PaperArticle

Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

by Dmytro Petukhov, Mark Richter-Dayan, Zvi Fridlender, Raphael Breuer and Shulamit B. Wallach-Dayan

Cells 2019, 8(10), 1211; https://doi.org/10.3390/cells8101211 - 7 Oct 2019

Cited by 8 | Viewed by 3384

Abstract

CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive [...] Read more.

CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive by the ataxia-telangiectasia mutated kinase/ATM pathway, and undergo a CD44-mediated epithelial-mesenchymal transdifferentiation (EMT) with migratory capacities in vitro, and in vivo. We assessed apoptosis vs. proliferation of AECs following bleomycin, ATM/P53 signaling pathway in AECs, and CD44 involvement in EMT, cell motility and tissue regeneration in vitro and in vivo. Expression of survival genes, CD44, and ATM/p53 pathway was elevated in AECs surviving bleomycin injury, as were the markers of EMT (downregulation of E-cadherin, upregulation of N-cadherin and vimentin, nuclear translocation of β-catenin). Inhibition of CD44 decreased AECs transdifferentiation. Bleomycin-treated chimeric CD44^KO-mice had decreased EMT markers, ATM, and mesenchymal cells (α-SMA⁺) accumulation in lung, increased surfactant-b, diminished lung mesenchymal cell motility, and increased lung tissue regenerative capacity following bleomycin injury, as indicated by lung collagen content and semiquantitave morphological index scoring. Thus, AECs surviving lung injury are plastic and undergo ATM-mediated, CD44-dependent transdifferentiation, preventing tissue regeneration and promoting fibrosis. Synthetic or natural compounds that downregulate CD44 may improve tissue regeneration following injury. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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Review

Jump to: Editorial, Research

24 pages, 829 KiB

Open AccessReview

Nutraceutical Activity in Osteoarthritis Biology: A Focus on the Nutrigenomic Role

by Stefania D’Adamo, Silvia Cetrullo, Veronica Panichi, Erminia Mariani, Flavio Flamigni and Rosa Maria Borzì

Cells 2020, 9(5), 1232; https://doi.org/10.3390/cells9051232 - 16 May 2020

Cited by 30 | Viewed by 5782

Abstract

Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients’ quality of life because [...] Read more.

Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients’ quality of life because of pain and disability. It is a whole-joint disease sustained by inflammatory and oxidative signaling pathways and marked epigenetic changes responsible for catabolism of the cartilage extracellular matrix. OA usually progresses until its severity requires joint arthroplasty. To delay this progression and to improve symptoms, a wide range of naturally derived compounds have been proposed and are summarized in this review. Preclinical in vitro and in vivo studies have provided proof of principle that many of these nutraceuticals are able to exert pleiotropic and synergistic effects and effectively counteract OA pathogenesis by exerting both anti-inflammatory and antioxidant activities and by tuning major OA-related signaling pathways. The latter are the basis for the nutrigenomic role played by some of these compounds, given the marked changes in the transcriptome, miRNome, and methylome. Ongoing and future clinical trials will hopefully confirm the disease-modifying ability of these bioactive molecules in OA patients. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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21 pages, 3107 KiB

Open AccessFeature PaperReview

Extra Virgin Olive Oil Polyphenols: Modulation of Cellular Pathways Related to Oxidant Species and Inflammation in Aging

by Gabriele Serreli and Monica Deiana

Cells 2020, 9(2), 478; https://doi.org/10.3390/cells9020478 - 19 Feb 2020

Cited by 78 | Viewed by 9398

Abstract

The olive-oil-centered Mediterranean diet has been associated with extended life expectancy and a reduction in the risk of age-related degenerative diseases. Extra virgin olive oil (EVOO) itself has been proposed to promote a “successful aging”, being able to virtually modulate all the features [...] Read more.

The olive-oil-centered Mediterranean diet has been associated with extended life expectancy and a reduction in the risk of age-related degenerative diseases. Extra virgin olive oil (EVOO) itself has been proposed to promote a “successful aging”, being able to virtually modulate all the features of the aging process, because of its great monounsaturated fatty acids content and its minor bioactive compounds, the polyphenols above all. Polyphenols are mostly antioxidant and anti-inflammatory compounds, able to modulate abnormal cellular signaling induced by pro-inflammatory stimuli and oxidative stress, as that related to NF-E2-related factor 2 (Nrf-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which have been identified as important modulators of age-related disorders and aging itself. This review summarizes existing literature about the interaction between EVOO polyphenols and NF-κB and Nrf-2 signaling pathways. Reported studies show the ability of EVOO phenolics, mainly hydroxytyrosol and tyrosol, to activate Nrf-2 signaling, inducing a cellular defense response and to prevent NF-κB activation, thus suppressing the induction of a pro-inflammatory phenotype. Literature data, although not exhaustive, indicate as a whole that EVOO polyphenols may significantly help to modulate the aging process, so tightly connected to oxidative stress and chronic inflammation. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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20 pages, 1857 KiB

Open AccessFeature PaperReview

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

by Rafael Peláez, Ana Pariente, Álvaro Pérez-Sala and Ignacio M. Larráyoz

Cells 2020, 9(1), 140; https://doi.org/10.3390/cells9010140 - 7 Jan 2020

Cited by 39 | Viewed by 7896

Abstract

In many tissues, stearoyl-CoA desaturase 1 (SCD1) catalyzes the biosynthesis of monounsaturated fatty acids (MUFAS), (i.e., palmitoleate and oleate) from their saturated fatty acid (SFA) precursors (i.e., palmitate and stearate), influencing cellular membrane physiology and signaling, leading to broad effects on human physiology. [...] Read more.

In many tissues, stearoyl-CoA desaturase 1 (SCD1) catalyzes the biosynthesis of monounsaturated fatty acids (MUFAS), (i.e., palmitoleate and oleate) from their saturated fatty acid (SFA) precursors (i.e., palmitate and stearate), influencing cellular membrane physiology and signaling, leading to broad effects on human physiology. In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment for various diseases, such as nonalcoholic steatohepatitis, Alzheimer’s disease, cancer, and skin disorders. Sterculic acid (SA) is a cyclopropene fatty acid originally found in the seeds of the plant Sterculia foetida with numerous biological activities. On the one hand, its ability to inhibit stearoyl-CoA desaturase (SCD) allows its use as a coadjuvant of several pathologies where this enzyme has been associated. On the other hand, additional effects independently of its SCD inhibitory properties, involve anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD). This review aims to summarize the mechanisms by which SA exerts its actions and to highlight the emerging areas where this natural compound may be of help for the development of new therapies for human diseases. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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26 pages, 1293 KiB

Open AccessReview

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

by Magdalena Kusaczuk

Cells 2019, 8(12), 1471; https://doi.org/10.3390/cells8121471 - 20 Nov 2019

Cited by 136 | Viewed by 13112

Abstract

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment [...] Read more.

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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