Phytochemical content of black rice extract (polar fraction).
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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She is a former researcher in morphophysiology at the University of Córdoba/Reina Sofia Hospital, Córdoba, Spain.\nShe graduated in Neurology/ Neurosurgery at the Hospital of Restauração, SES, in Brazil and Neuroradiology/Radiodiagnostics at Paris Marie Curie University. She holds a master’s degree in Medicine from the University of Nova Lisboa in Portugal and in Behavioral Sciences and Neuropsychiatry from the University of Pernambuco. She also has a Ph.D. in Biological Sciences from the University of Pernambuco/Paris Diderot University. She is a former Fellow in Interventional Neuroradiology in France at the Ophthalmological Foundation Adolphe de Rothschild, Beaujon Hospital, and Hospices Civils de Strasbourg. She was Praticien Associé in Interventional Neuroradiology at Neurologique Hospital Pierre Wertheimer, University of Lyon Claude Bernard in Lyon, France, and Visiting Professor of the University of Paris Diderot-Neuri Beaujon. She is actually an independent consultant/supervisor in neuroradiology, neuroendovascular, and imaging. She has been also an academic collaborator researcher in the Cardiovascular Department at the University of Leicester. She has experience in innovative research for the development of new technologies and is also an academic editor and reviewer of several scientific publications about neurological diseases.",institutionString:"Paris Diderot University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Paris Diderot University",institutionURL:null,country:{name:"France"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1056",title:"Neurology",slug:"neurology"}],chapters:[{id:"64150",title:"The Cutaneous Biopsy for the Diagnosis of Peripheral Neuropathies: Meissner’s Corpuscles and Merkel’s Cells",slug:"the-cutaneous-biopsy-for-the-diagnosis-of-peripheral-neuropathies-meissner-s-corpuscles-and-merkel-s",totalDownloads:372,totalCrossrefCites:0,authors:[{id:"59892",title:"Prof.",name:"José A.",surname:"Vega",slug:"jose-a.-vega",fullName:"José A. 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Regenerative Medicine aims to restore the loss of function in tissues and organs due to any cause (trauma, stress, aging, or disease) by the replacement of dysfunctional structures with competent cells, tissues, or organs. In order to achieve this goal Regenerative Medicine takes advantage of different forefront methodologies, such the use of stem cells, gene therapy, and tissue engineering among others.
The isolation and derivation of hESCs by Thompson and colleagues in 1998 attracted significant attention in the Regenerative Medicine field [1]. Indeed, regenerative cell transplantation therapies have been expected to treat incurable diseases, such as spinal cord injury [2], neurodegenerative disease [3], heart failure [4,5], diabetes [6], and retinal disease [7].
Nowadays, clinical application of hESCs still shows many concerns regarding the use of human embryos, tissue rejection after transplantation, and tumour formation. However, hESCs possess the dual ability to proliferate indefinitely without phenotypic alterations, and more importantly, to differentiate, theoretically, into all cell types in the human body. These qualities suggest extensive utility of hESCs in applications varying from the definition of differentiation protocols, to the generation of drug screening platforms for disease treatment. Thus, hESCs represent an ideal source for understanding skeletal muscle development and disease, such skeletal muscle.
In 2006 Professor Shinya Yamanaka and colleagues [8] showed for the very first time, that by introducing different transcription factors the epigenetic status of somatic cells could be reverted to pluripotency. In particular, the Japanese team ectopically induced the expression of specific transcription factors related with embryonic stem cells (ESCs) biology, generating in a period of only 30 days, cells that were identical to mouse ESCs (mESCs) in terms of self-renewal capacity, expression of endogenous pluripotency-related factors, and in vivo and in vitro differentiation potential to give rise to cells belonging to the three germ layers of the embryo (ectoderm, mesoderm, endoderm). This discovery was awarded with the Nobel Price of Medicine in 2012 to Professor Shinya Yamanaka.
While, at first, somatic reprogramming was described using mouse embryonic fibroblasts, the Japanese team could show that also a reduced formula of the original “Yamanaka cocktail” could be used to reprogram human somatic cells towards human iPSCs (hiPSCs) [9]. Since 2007 different research groups, including us, have shown that iPSC technology can be applied to reprogram a huge variety of human somatic cells, independently of their embryonic origin [10–13]. Interestingly, during the last years the generation of protocols avoiding the use of lentiviral or retroviral vectors for the expression of Yamanaka factors has involved the definition of novel strategies for hiPSCs generation, including the use of recombinant proteins [14,15], episomal vectors [16], or mRNAs [17,18], among others [13]. Thus, the generation of hiPSCs, especially the generation of patient-derived iPSCs suitable for disease modelling in vitro, opens the door for the potential translation of patient-derived iPSCs into the clinic. Successful replacement or augmentation of the function of damaged cells by patient-derived differentiated stem cells would provide a novel cell-based therapy for skeletal muscle-related diseases.
Satellite cells (SCs), the adult stem cell pool in skeletal muscle, are often compromised in patients with muscle dystrophies (MDs). Over the last decades the understanding of the transcription factors and intrinsic and extrinsic signals that govern SCs or terminally differentiated myogenic cells have represented a good starting point for the definition of protocols for the generation of myogenic cells from PSCs (both from mouse and human ESCs and iPSCs). In the same manner, the generation of patient-derived cell platforms can help us to develop experimental strategies toward generating muscle stem cells, either by differentiating patient-specific iPSCs or by converting patient’s somatic cells towards myogenic cells (transdifferentiation). Overall, the possibility to generate disease-free patient iPSCs can help us to identify which are the mechanisms driving muscle disease, and more importantly, to develop new compounds for treating MDs (Figure 1).
Patient iPSCs represent an unprecedented tool for the generation of in vitro platforms for disease modelling and the definition of protocols for PSCs differentiation. The correction of the genetic defect(s) leading to disease may help to understand the molecular and cellular mechanisms driving disease gestation and progression, and more importantly, to identify novel mechanisms leading to muscle regeneration.
Both mouse and human PSCs are routinely cultivated in the presence of feeder layers. PSCs grow on the feeder layers as colonies (Figure 2). Generally, human and mouse PSCs are enzymatically dissociated with trypsin, acutase, or dispase to obtain a suspension of single cells, which is then transferred for subculture and expansion or differentiation purposes. For mouse PSCs, LIF can substitute for feeder layers. However, since LIF is not effective for human PSCs, in the last years different chemically defined media have been generated in order to sustain human PSCs culture and expansion in feeder-free substrates.
PSCs are typically maintained in mitotically inactivated supportive cells. A) Mouse iPSCs cultured on top of irradiated mouse embryonic fibroblasts grow in tight colonies that are further trypsinized for subculture or differentiation purposes. B) Human iPSCs cultured on top of human irradiated dermal fibroblasts grow as colonies with defined borders.
As an option for culturing human PSCs without feeder cells, Matrigel™ has proven to be a useful alternative enabling the stable culture of human PSCs. Moreover, we have also shown that Matrigel™ allows the generation of hiPSCs without animal-derived feeder cells [19]. Since Matrigel™ was derived from Engelbreth-Holm-Swarm mouse sarcoma cells [20], other types of matrices which do not contain animal-derived agents have been tested and used as feeder-cell substitutes for the successful maintenance and generation of human PSCs; such as CellStart [21,22], recombinant proteins [23–25], and synthetic polymers [26,27].
The culture media used in the early generation of hESCs contained fetal bovine serum [1]. In order to remove unspecific agents that might cause the differentiation of hESCs, knockout serum replacement (KSR) has now been established as a defined material for maintaining hESCs [28] and is also traditionally used for hiPSC generation [9,12,29,30]. In this regard, mTeSR1 medium was developed as a chemically defined medium for maintaining human PSCs [31]. Importantly, in the last years several authors have reported the generation of commercially developed xeno-free media for maintaining hiPSCs, and such media have already been used successfully for iPSCs generation. These media include: TeSR2 [32], NutriStem [33], Essential E8 [24], and StemFit [34].
When factors that sustain PSCs stemness are deprived from the media, PSCs spontaneously differentiate into derivatives of the three embryonic germ layers. This capacity has been profited for more than 30 years in order to direct PSCs to the desired cell product. In this regard, up to day, an infinite number of protocols have been established to promote the development of the cell type of interest.
The following are basic strategies to induce in vitro differentiation of PSCs cells:
Embryoid Bodies’ (EBs) formation: In contrast to monolayer cultures, EBs are spherical structures that allow PSCs culture in suspension (Figure 3). The three-dimensional structure, including the establishment of complex cell-adhesions and paracrine signaling within the EB microenvironment, enables differentiation and morphogenesis. For that reason, the first protocols for muscle differentiation took advantage of EB induction from mESCs, followed by different periods of exposure to specific cell culture media in which serum, mitogenic factors, and essential substrates (such as amino-acids or glutamine) were formulated. In that manner, those first assays proved the feasibility of mESCs to give rise to myogenic cells, setting the bases for the definition of robust protocols for the differentiation of muscle cells from human PSCs. Up to day, most of the protocols for the generation of myogenic cells from PSCs make use of the differentiation of EBs derived from either wild type or transgenic PSCs.
PSCs are capable to differentiate into cells belonging to the three somatic germ layers of the embryo. The generation of EBs from PSCs is a common method for producing different cell lineages for further purposes. A) EBs from mouse iPSCs grown in suspension. B) EBs derived from human iPSCs grown in suspension.
Modification of medium composition: Monolayers of PSCs and also EBs have been traditionally subjected to changes in nutrient composition, (i.e, reduction/increase of serum concentration, addition/removal of a growth factor or addition/removal of cytokines, among others) in order to induce their differentiation towards the desired cell type. These changes are conducted in order to promote changes on gene expression profiles and cell proliferation rates. In this manner, by means of relatively simple methods, PSCs are artificially guided towards the desired cell type. Although these methodologies have proven low efficiency yields for specific cell types (i.e., motorneurons, hepatic cells; among others), they are extremely valuable when combined together with PSCs in which the expression of master factors critical for differentiation are under the control of hormones (i.e., tamoxifen inducible reporters) or antibiotics (i.e., puromycin, or hygromycin, among others). The control of expression of the specific transcription factor of choice (i.e., MyoD1) together with the addition of specific molecules mimicking tissue development [i.e., insulin like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF)] has demonstrated good results when differentiating mouse or human PSCs towards myogenic cells.
Genetic manipulation of PSCs: Forced expression of transcription factors can direct differentiation of PSCs toward specific lineages. In the last years, the generation of platforms for transgene expression in PSCs has emerged as one of the most potent tools for PSCs differentiation. Whereas the first studies took advantage of exogenous gene expression systems (i.e., lentivirus or retrovirus), nowadays the use of integrative vectors are limited, since they incur uncertain risks for potential cell-based therapeutic applications [35]. In this regard, the use of excisable vectors (i.e., transposons; [36,37], or mRNAs [17]) offer an unprecedented opportunity for the derivation of differentiated PSCs suitable for regenerative medicine.
Use of extracellular matrix (ECM) and signaling molecules: Unlike de novo embryonic muscle formation, muscle regeneration in higher vertebrates depends on the injured tissue retaining of an ECM scaffolding that serves as a template for the formation of muscle fibers [38]. In this regard, the interaction between cells and ECM via integrins determines the expression of signaling molecules that affect PSCs differentiation [39]. Of note, when mouse iPSCs have been cultured in the presence of matrigel, myogenesis (this is, proliferation of myoblasts and further fusion into myotubes) has been positively induced [40]. Similar results have been observed when using collagen-based matrix for the differentiation of human iPSCs expressing a Dox-inducible expression cassette of MyoD1 [41]. For the organization and alignment of muscle fibers not only the composition of the ECM but also its anisotropic architecture are essential. To address this, a number of strategies have been developed to organize myotubes: topography-based approaches based on the use of nanofibers, [42], microabrated surfaces [43], and microcontact printing of ECM proteins such as fibronectin [44] and vitronectin [45]. In a complementary approach, biochemical cues have also been introduced to promote cell alignment and differentiation. By using inkjet bioprinting, spatially defined patterns of myogenic and osteogenic cells were derived from primary muscle-derived stem cells (MDSCs) as a response to BMP-2 patterning [46]. The combination of topographical and biochemical signaling has also been explored by coating sub-micron polystyrene fibers with either FGF-2 or BMP-2 to provide spatial control of cell fate and alignment in order to mimic native tissue organization [47]. The vast majority of these works present cells to static microenvironments. Latest trends point out the relevance of presenting cells to spatially and temporally dynamic microenvironments [48]. Surfaces with gradient concentrations of growth factors (BMP-2 and BMP-7) have shown to successfully drive cell differentiation [49,50]. Although not yet a reality, these strategies appear a promising way to direct the differentiation of PSCs [51].
Use of biomatrices mimicking skeletal muscle niche: Tissue engineering approaches have been used to design synthetic and natural 3D scaffold materials to mimic the structural, biochemical, and mechanical properties of the stem cell niche [52,53]. Synthetic and natural scaffolds have been designed to provide support for muscle growth and allow myofibroblasts to rebuild their native ECM. Natural scaffolds based on ECM proteins such as fibrin and collagens have been used to form hydrogels for musculoskeletal tissue engineering [54–56]. Commercially available ECM substitutes such as Matrigel™ hydrogels are also showing promising results in the differentiation of PSCs towards cardiomyocytes [57]. However, current ECM protein-based scaffolds are limited by their immune rejection and scaling up technologies. Synthetic scaffolds, which can be fabricated with ideal architectures at the nanoscale, pore sizes and mechanical properties, represent an advantageous solution to mimic the 3D ECM microenvironment (Figure 4). Technologies such as electrospinning, which allows organizing the polymers into thin sheets of fibrous meshes, are promising in this field [58,59]. Recently, it has been proved the reprogramming of mouse fibroblasts onto cardiomyocyte-like cells on polyethylene glycol (PEG) hydrogels functionalized with laminin and RGD peptides [60]. This opens new perspectives toward the use of custom-engineered synthetic scaffolds in the differentiation of PSCs to muscle cells. Finally, the use of acellularized tissue scaffolds is also being explored in muscle regeneration. They offer a native ECM with the optimal biochemical and mechanical properties for cell culture and preserve the architectural features of the tissue. Their use as a matrix supporting the commitment of cardiac muscle cells has been recently reported, thus showing the potential of this approach [61].
Bio-inert polyethylene glycol (PEG)-based hydrogels have been designed as the scaffold substrate for biomimetic matrices supporting muscle migration in three dimensions. The picture shows PEGDA hydrogel (MW 550 KDa) cross-linked by UV light.
Co-culture with supportive cells (feeder cells): The co-culture of mouse and human PSCs (either as monolayers or EBs) with feeder cells has been traditionally used in order to induce PSCs differentiation [39]. The stromal cell line OP9 [62,63], which is derived from newborn mouse calvaria, supports hematogenesis [64,65]. The preadipose cell line PA6 [66] promotes neural differentiation of mouse and human PSCs [10,11,67]. In this regard, Baghavati [68] showed that the co-culture of mESCs together with primary muscle cells suffice for myogenic differentiation, since donor-derived myofibers generated by co-culturing mouse EBs on top of primary muscle fibers could be occasionally found on the surface of the host muscle.
During the last 30 years successful generation of myogenic precursors from mouse and human PSCs has been achieved by exogenous expression of transcription factors crucial for myogenic differentiation. PSCs are especially amenable for genome editing because they can undergo extensive tissue culture manipulations, such as drug selection and clonal expansion, while still maintaining their pluripotency signature and genome stability. In his regard, different authors have explored the possibility to generate PSCs stable cell lines that express the myogenic transcription factor of interest under the control of specific drugs (i.e., antibiotics). The myogenic transcription factor of interest is normally subcloned into a viral vector, which possesses high infection efficiency when transducing PSCs. Other methods involve the use of non-integrative vectors such as transposons or excisable lentiviral vectors. Following these strategies different authors have shown that PSCs monolayers or PSCs-derived EBs can be converted into myogenic cells (see below).
Already in 1992 Dekel and colleagues showed that, when mESCs were electroporated with MyoD1 cDNA driven by the Βeta-actin promoter, some cells could be converted to skeletal muscle cells [69]. Moreover, authors showed that contracting skeletal muscle fibers could be generated when the transfected cells were allowed to differentiate in vitro, via EBs, in low-mitogen-containing medium. Although those studies failed to develop efficient protocols for the generation of high yields of myogenic cells, they helped to understand that environmental factors should control MyoD expression and its myogenic differentiation function, and more importantly, that MyoD was required for the establishment of the myogenic program but not for its maintenance.
Thus, those first observations served as a starting point for the definition of enriched cell culture media for mESCs differentiation towards myogenic cells, and more importantly, for the generation of fine-tuned systems in order to control the expression of the desired myogenic factor at a precise moment during the onset of differentiation. Alongside this line, Ozasa and colleagues [70] established a mESC line by introducing a MyoD transgene controlled by a Tet-Off system (ZHTc6-MyoD). The possibility to induce MyoD expression during the time course of differentiation, allowed mESCs to differentiate almost exclusively into the myogenic lineage in the absence of doxycycline, and without pre-differentiation into EBs. To start the differentiation process, Ozasa and colleagues removed doxycycline and used a differentiation medium containing 4% fetal bovine serum (FBS). Under those conditions and only after 7 days, primed cells started to fuse into myotubes, and occasionally light muscle contractions were observed. In that study the potential of the generated cells to differentiate into myofibers in vivo was also investigated by intramuscular injections into mdx mice and clusters of dystrophin-positive myofibers were detected in the injected area.
In the same manner, within the last years several studies have demonstrated the possibility to generate myocytes, and even multinuclear myotubes from both hESCs and patient hiPSCs by means of different systems in which the expression of MyoD is driven under the control of soluble factors during the time course of differentiation. In this regard, early in 2012 two different reports indicated that mesodermal [71] or mesenchymal cells [72] could be generated from iPSCs, demonstrating a high potential for myogenic differentiation in response to MyoD over-expression.
Also Rao and colleagues (2012) generated a transgenic Tet-inducible MyoD cassette in which all the transgenic elements were inserted in hESCs making use of lentiviral vectors. In that particular study, authors were able to generate multinucleated myotubes with 90% of efficiency in a period that lasted only 10 days. Later on, Yasuno and colleagues [37] improved a previous protocol [36] for the generation of terminal multinucleated cells from iPSCs derived from patients affected with Carnitine palmitoyltransferase II (CPT II). Their protocol consisted in the transduction of a self-contained Tet-inducible MyoD1 expressing piggyBac vector (Tet-MyoD1 vector) and transposase into hiPSCs by lipofection. This system allowed the indirect monitoring of induced MyoD expression in response to doxycycline by co-expression of a red fluorescent protein (mCherry). Moreover, in that particular setting authors increased the purity of the generated myocytes by culturing the cells in low glucose conditions, a condition that was also reported to increase differentiated cardiomyocytes out of undifferentiated iPSCs based on the substantial biochemical differences in glucose and lactate metabolism between differentiated cells and undifferentiated iPSCs [73].
Very recently, Abujarour and colleagues [41] found that it is possible to derive myotubes from control iPSC and iPSC lines from patients with either Duchenne or Becker muscular dystrophies. In particular, by using a lentiviral system expressing MyoD under the control of a Tet-inducible promoter, and under-optimized culture conditions, the authors achieved an efficient myogenic differentiation setting the bases for the production of scalable sources of normal and dystrophic myoblasts for further use in disease modelling and drug discovery.
MyoD1 has not been the sole transcription factor of choice when differentiating human PSCs towards myogenic cells. Iacovino and colleagues [74] generated an unprecedented system in which it was possible to integrate the gene of interest into the desired cells (mESCs, kidney murine cells and hESCs) by means of a system that authors called inducible cassette exchange (ICE). In that particular setting, authors were able to integrate one single copy of Myf5 into mESCs and hESCs. Overall, Iacovino and colleagues showed that Myf5 expression is sufficient to promote the myogenic commitment of nascent mesoderm thereby establishing a novel and rapid method of differentiating mESCs and hESCs into skeletal muscle tissue.
Taking advantage of Iacovino´s system [74], Darabi and colleagues generated an improved version of ICE system in order to generate mESCs in which Pax7 expression was controlled under the control of doxycycline, and they succeeded in inducing the myogenic program in mouse cultures [75,76]. Later on, the same authors generated inducible Pax7 hESCs and hiPSCs with a doxycycline-inducible lentiviral vector encoding Pax7 (iPax7 and the expression of the Pax 7 transgene was detected by incorporating an IRES-GFP reporter downstream of the Pax7 gene. Next, iPax7 hESCs and hiPSCs were induced to generate EBs and after three days doxycycline was added into the media in order to induce Pax7 expression. Following 4 days of induction, Pax7+GFP+ cells were purified by FACS and expanded in a secondary monolayer culture in a medium containing doxycycline and bFGF. Under those conditions iPax7 hESCs and hiPSCs expressed markers of early muscle differentiation (Pax7 and Pax3), and terminally differentiated when iPax7 hESCs and iPSCs were subjected to differentiation-inducing conditions (culture media with 5% horse serum and withdrawal of doxycycline and bFGF). Finally, Darabi and colleagues demonstrated that transplantation of Pax7-derived myogenic progenitors into dystrophin-deficient mice (mdx) promotes extensive and long-term muscle regeneration accompanied by functional improvement [77].
Although in the last years different authors have shown the possibility to generate myogenic cells from human PSCs by means of the ectopic expression of specific transcription factors, these methods do not reflect normal development, and most importantly, are not suitable for therapeutic purposes or in vitro disease modelling. For this reason, in the last years different groups have investigated the possibility to expose EBs or monolayers of mouse and human PSCs to different culture media mimicking muscle development. In order to monitor and control the myogenic signature of the produced cells, authors have isolated the different potential populations based on the acquisition of surface markers related to myogenic fate (i.e., paraxial mesoderm) by means of FACS. In the same manner, the majority of these studies have relayed in the analysis of the expression of myogenic-related markers by common techniques such as the expression of myogenic-related factors by polymerase chain reaction or immunohistochemistry. In that way, the different protocols evaluate the efficiency of their method quantifying the percentage of cells that are differentiated towards myogenic cells.
Although EBs exposed to undefined differentiation cell culture media spontaneously develop skeletal muscle cells and other cells in vitro, transplantation of EBs without any induction to direct development along a specific pathway leads to a failure of integration into recipient tissues and often forms teratomas in transplanted tissues. Thus, the definition of the specific conditions able to instruct PSCs towards myogenic cells requires establishment of robust conditions able to guide cells through the different stages of muscle differentiation.
In the first moment authors thought that the co-culture of EBs on top of freshly isolated muscle cells could serve as a novel method for myogenic differentiation. Although authors showed that differentiated cells generated by this method developed vascularized and muscle tissue when transplanted in dystrophic mice (mdx mice), still the number of engrafted cells was too low for potential applications in a clinical setting [68]. Later, Zheng and colleagues [78] showed that human EBs (hEBs) from two different hESCs lines cultured in the presence of differentiation media with different percentages of animal serum with or without Epidermal growth factor and 5-azacytidine could give rise to myogenic precursors. Interestingly, in that same work authors demonstrated that when those hESC-derived myogenic precursors were transplanted in NOD-SCID mice they could incorporate into the host muscle efficiently and become part of regenerating muscle fibers; giving rise to myocytes, myotubes, and myofibers, as well as satellite cells.
In the quest for protocols suitable for regenerative purposes, Barberi and colleagues [79,80] developed simple feeder-free-monolayer culture systems in order to generate mesenchymal precursors that could be further differentiated towards myogenic cells from hESCs. In those studies multipotent mesenchymal precursors (MMPs) were purified for the acquisition of CD73 surface marker using FACS technology. First, MMPs were maintained in inactivated foetal serum and in the presence of the mouse skeletal myoblast line C2C12 [79]. Later, Barberi and colleagues could avoid the use of C2C12 cells by using serum-free N2 medium. Moreover, in that work authors further purified skeletal muscle myoblasts by means of a second FACS analysis for the neural cell adhesion molecule (NCAM), a marker of embryonic skeletal muscle. Those changes allowed for the expansion of hESC-derived myoblasts in a serum-free N2 medium in the presence of insulin [80].
Following a similar strategy Sakurai and colleagues [81] differentiated a murine ESC line towards paraxial mesodermal progenitors. Specifically, authors selected paraxial mesodermal progenitors based on the expression of platelet-derived growth factor receptor α (PDGFR-α) and the absence of Flk-1–a lateral mesodermal marker. Later on, the same authors demonstrated that mESCs could be directed toward the paraxial mesodermal lineage by a combination of bone morphogenetic protein (BMP) and Wnt signaling under chemically-defined conditions [82]. Interestingly, the same group developed a protocol for the generation of paraxial mesoderm progenitors from both miPSCs and hiPSCs. Although some differences in growth factor requirement between mESCs and miPSCs cells were observed, the PDGFR-α+ population derived from miPSCs was almost identical to that of mESCs. Importantly, the work of Sakurai and colleagues showed that, under their specific conditions, two different lines of hiPSCs could be differentiated towards PDGFR-α+/KDR- cells. Those progenitors could be further differentiated into osteocytes, chondrocytes, and skeletal muscle cells, demonstrating the suitability of their procedures for the generation of myogenic cells for regenerative purposes.
Notably, other authors have shown the possibility to generate PDGFR-α+ from hESCs [83]. However, those same authors showed few engraftments of transplanted hESCs-derived myogenic cells into injured skeletal muscle. Interestingly, the same authors have recently demonstrated that, by incorporating Wnt3a in culture medium, myogenic commitment is rapidly achieved from hESCs, and more significantly, that those cells can contribute to finally regenerate cardiotoxin-injured skeletal muscle of NOD/SCID mice [84]. In the same line, other authors have demonstrated that the inhibition of GSK3B and treatment with FGF2 could specifically promote skeletal muscle differentiation. In particular, Xu and colleagues [85] have demonstrated that simultaneous inhibition of GSK3B, activation of adenyl cyclase and stimulation with FGF2 during EBs formation could promote the generation of myogenic precursors that terminally differentiate in vitro and act as satellite cells upon transplantation. Also, Borchin and colleagues [86] have shown that human PSCs can be differentiated towards Pax3/Pax7 double positive cells after GSK3B and FGF2 exposure.
The possibility to direct cell differentiation from human PSCs opens the door for the development of massive platforms for the study of muscle differentiation and disease progression. Moreover, the possibility to combine gene-editing strategies allowing for the correction of the genetic disorder leading to muscle disease, together with the generation of myogenic cells from patients’ cells, represents an unprecedented opportunity for the establishment of in vitro systems for the study of MDs.
So far, different groups have demonstrated the suitability of patient iPSCs approaches in order to model MDs. Abujarour and colleagues [41] have derived myotubes from Duchenne Muscular Distrophy (DMD) and Becker Muscular Distrophy (BMD) hiPSCs. In particular, authors showed that myotubes derived from MDM and BMD iPSCs could respond to insulin-like growth factor 1(IGF-1) and wingless-type MMTV integration site family member 7A (Wnt7a) in a similar manner to primary myotubes. These results point out that iPSC derived from MDM and BMD patients have no intrinsic barriers preventing from myogenesis, and thus represent a scalable source of normal and dystrophic myoblast for further use in disease modelling and drug discovery.
Recently, Tedesco and colleagues [71] generated iPSCs from fibroblasts and myoblasts from limb-girdle muscular dystrophy 2D (LGMD2D) patients, developing the first protocol for the derivation of mesoangioblast-like cells from these iPSCs. Moreover, authors expanded and genetically corrected patient iPSC-derived mesoangioblasts in vitro by means of a lentiviral vector for the expression of human α-sarcoglycan in striated muscle cells. When LGMD2D disease free iPSC-derived mesoangioblasts were transplanted into α-sarcoglycan-null immunodeficient mice authors showed that they were capable to generate muscle fibers expressing α-sarcoglycan. Interestingly, when the same experiments were conducted using mouse-derived mesoangioblasts authors showed a functional amelioration of the dystrophic phenotype and restoration of the depleted progenitors in α-sarcoglycan-null immunodeficient mice. Overall, Tedesco and colleagues showed that transplantation of genetically corrected mesoangioblast-like cells derived from iPSCs from LGMD2D patients could represent a novel therapeutic approach for these patients.
In the same line, other authors [36] have generated iPSCs from patients affected by Miyoshi myopathy (MM), a congenital distal myopathy caused by mutations in dysferlin. Specifically, authors demonstrated that the expression of full-length dysferlin could restore the MM associated phenotype in myotubes differentiated from MM-iPSCs. In the same line, Yasuno and colleagues [87] have shown the possibility to generate iPSCs from patients affected by Carnitine palmitoyltransferase II (CPT II) deficiency, an inherited disorder involving B-oxidation of long-chain fatty acids (FAO).
Very recently, Li and colleagues [88] have demonstrated the possibility to correct iPSCs derived from DMD patients by means of three different strategies: exon skipping, frameshifting, and exon knock-in. In their hands, exon knock-in was the most effective approach. The work of Li reveals the suitability of iPSC technology for the generation of iPSC-based approaches for MDs modelling and therapy.
Overall, these recent advances set the bases for the generation of a previously nonexisting tool for the study of MDs. The possibility to generate human models for the study of MDs by means of iPSC technology opens the door for the development of novel therapeutic compounds for MD treatment, and more importantly, to increase our understanding of MDs and muscle development.
Within the last years, our group has participated in the development of protocols for the derivation of patient iPSCs for disease modelling and compound screening. Taking advantage of different basic techniques that are commonly used on a daily basis in any laboratory worldwide, we have generated simple methodologies that allow the generation of patient-specific iPSCs in a period that lasts only 50 days from the moment we get the primary samples from patients (i.e., skin biopsy, lipoaspirates, etc.). In this section, we provide two concise protocols for the derivation of patient iPSCs taking advantage of retroviruses and episomal vectors.
The development of simple methods for the generation of hiPSCs from keratinocytes from plucked hair samples offers an unprecedented scenario for the production of patient-specific iPSCs, making use of a non-invasive procedure when collecting patient samples.
Our protocol is divided into three consecutive steps, which involve: A) Isolation of keratinocytes from plucked hair samples, B) Production of retrovirus, and C) Infection of keratinocytes. The steps are detailed below. As described elsewhere, the same protocol can be applied when reprogramming cord blood stem cells, kidney tubular epithelial cells, and dermal fibroblasts [11,12,30].
Isolation of keratinocytes from plucked hair
A.1 The day before hair isolation coat the required number of 35-mm culture dishes with Matrigel® (Becton Dickinson, S.A. cat. no. 356234) by adding 1 ml of Matrigel® and incubate overnight at 4 ºC.
A.2 The same day of sample recovery, prepare a non-coated 100-mm bacterial plate containing HBSS (Invitrogen cat. no. 14170-088) with 1% (vol/vol) Penicillin/Streptomycin (Invitrogen cat. no. 15140-122).
A.3 After the patient reads and signs the informed consent use tweezers to gently pull the hair out and place it on plates filled with HBSS medium. As recommended by Aasen and colleagues [89] use hair from the occipital part of the head.
A.4 Making use of forceps submerge the hair in HBSS medium. Next, cut off the external part of the hair leaving the bulb and outer root sheath.
A.5 As described by Aasen [89], at this stage two optional methodologies for growing keratinocytes from plucked hair are described: direct outgrowth and enzymatic digestion. In this section, we are going to detail how to get direct outgrowths of keratinocytes from plucked hair. For enzymatic digestion procedure follow Aasen recommendations [89].
A.6 Remove the plate from 4 ºC, aspirate the Matrigel® coating and rinse the plate with 2 ml of hESCs medium: KO-DMEM (Invitrogen, cat. no. 10829-018), 20% KOSR (Invitrogen, cat. no. 10828-028), 10 ng ml-1 bFGF (Peprotech cat. No. 100-18B), 1 mM Glutamax (Invitrogen, cat. no. 35050-038), 100 µM nonessential amino acids (Invitrogen, cat. no. 11140-050), 100 µM 2-mercaptoethanol (Sigma, cat. no. M7522), and 50 U/ml (penicillin and 50 mg/ml streptomicin).
A.7 Place gently the hair obtained from the coated culture plates.
A.8 Add few drops of hESCs medium (0.3 mL) on top of the hair sample in order to keep the hair humid. In the next 3–4 hours, add gently fresh hESCs medium (0.3 mL). The next day carefully check under the microscope that the hair sample is still attached at the bottom of the plate. Refill the plate with more hESCs medium on top of the hair, if necessary.
A.9 Add 1 ml of hESCs medium every following day. After 4 days, outgrowths of typical epithelial keratinocytes are visible.
A.10 After 10–14 days, large colonies of keratinocytes (up to 1 cm of diameter) are visible. At this stage, it is advisable to split the cells for infection or subculture to avoid cells to initiate contact-dependent differentiation.
Production of retrovirus
B.1 Seed out 4.3x106 Phoenix Amphotropic 293 cells in 10 ml of DMEM complete medium which consists in DMEM (Invitrogen, cat. no. 11965-092), 10% FBS (Invitrogen, cat. no. 10270-106), Glutamax 2 mM, Penicillin/Streptomycin (100 U/ml, 100 µg/ml) in 100-mm culture dishes and place in a 37 ºC 5% CO2 incubator.
B.2 Next day, prepare FuGENE:DNA complex according to the manufacturer´s instructions (Roche Applied Science, cat. no. 1181509001). We recommend a ratio of 27 µl FuGENE to 9 µg plasmid DNA for every 10 cm dish. For virus production, we will make use of pMSCV-based plasmids. pMSCV-based retroviral vectors are commercially available for OCT4, SOX2, KLF4, and c-Myc in Addgene (reference numbers are: 20072, 20073, 20074, and 20075 respectively). If the infection efficiency wants to be monitored pMSCV-based retroviral vectors expressing GFP can be used (Addgene plasmid 20672).
B.3 Add the FuGENE:DNA complex solution dropwise onto media (gently). Move the plate carefully in order to distribute the transfection reaction homogenously.
B.4 Place the transfected cells at 37 ºC, with 5% CO2 overnight.
B.5 Next day, change DMEM complete medium gently (10 ml/plate) and incubate the plates overnight at 32 ºC in a 5% CO2 incubator.
B.6 Collect viral supernatants and add fresh complete DMEM medium to the different plates. Take care to avoid cells detaching from the tissue culture plates.
B.7 Every following day, for 2 days, repeat steps B.5 and B.6 in order to collect more viral supernatants.
B.8 Filter the viral supernatant through a 0.45 µm PVDF filter (Millipore® SLHV033NK) to remove any contaminant cells.
B.9 Add 1 µl polybrene (10 mg/ml; Chemicon cat. no. TR-1003-6) for each ml viral supernatant needed (final polybrene concentration of 10 µg/ml).
Infection of keratinocytes derived from plucked hair samples
C.1 Wash obtained keratinocyte colonies growing from a hair in hESCs medium as described in section (A) with PBS (Invitrogen, cat. no. 10010-056) and trypsinize them using 1 ml 0.25% Trypsin/EDTA (Invitrogen, cat. no. 25200-056).
C.2 After 5–8 minutes, when cells are released from the plastic surface resuspend them with 10 ml hESCs medium.
C.3 Centrifuge at 200g for 5 min.
C.4 Resuspend the pellets in 4 ml of hESCs medium.
C.5 Plate cell suspensions in the desired wells of six-well plates (Corning, cat. no. 153516) previously pre-coated with Matrigel® as explained in step A1. Seed 80.000 keratinocytes/well.
C.6 Next day add 1 ml of every single viral suspension obtained as described in steps B6-B9 for OCT4, SOX2, KLF4, and cMYC. Perform viral transduction in the same manner for GFP in order to monitor the efficiency of viral infection.
C.7 Centrifuge plates at 650g for 45 min.
C.8 Replace with 2 ml fresh hESCs medium (within 4–5 hours).
C.9 Next day, repeat steps C.7-C.8 to infect cells a second time.
C.10 Change media daily with hESCs medium.
C.11 After 1–2 weeks large colonies are visible and can be picked mechanically and transferred onto irradiated human fibroblasts feeder layer (iHFF) and cultured as normal iPSCs following specifications detailed before by others [12,29,30].
The possibility to generate iPSCs by means of non-integrative strategies paves the way for the development of clinical grade iPSCs from patients. Here, we detail a specific protocol for the derivation of hiPSCs from mesenchymal stem cells from adipose tissue.
Our protocol makes use of commercial episomal plasmids generated by Okita and colleagues [16]. Our method offers the possibility to generate patient-specific iPSCs in a period that last only 20 to 22 days from the moment the reprogramming experiment starts.
Before nucleofection
A.1 Following the Human MSC Nucleofector® Kit (DPE-1001, Amaxa) recommendations the solution for nucleofection is prepared by adding 0.5 ml of Supplement to 2.25 ml Nucleofector Solution. Human MSC Nucleofector Solution is now ready to use and is stable for 3 months at 4°C.
A.2 Under the culture hood prepare plasmid mixture by mixing 1 μg of each pCLXE episomal based plasmid (i.e., if we want to reprogram three different samples 3 μg of each pCXLE plasmid will be added to the final mixture). Plasmids are commercially available in Addgene: pCXLE-hOCT3/4-shp53-F (Plasmid #27077), pCXLE-hSK (Plasmid #27078), pCXLE-hUL (Plasmid #27080).
A.3 Pre-warm the complete Human MSC Nucleofector Solution to room temperature.
A.4 Pre-warm an aliquot mesenchymal stem cells culture medium [DMEM (Invitrogen, cat. no. 11965-092), 10% FBS (Invitrogen, cat. no. 10270-106), Glutamax 2 mM, Penicillin/Streptomycin (100 U/ml, 100 µg/ml)] at 37 °C in a 50 ml tube (500 μl per sample; 1.5 ml for 3 samples).
A.5 Prepare 6-well plates by filling the appropriate number of wells with 1 ml of culture medium containing mesenchymal stem cells culture medium and pre-incubate plates in a humidified 37 °C/5% CO2 incubator. Prepare 2 wells/sample (i.e., 6 wells for 3 samples)
Nucleofection and iPSCs generation
B.1 Follow Human MSC Nucleofector® Kit recommendations (http://bio.lonza.com/fileadmin/groups/marketing/Downloads/Protocols/Generated/Optimized_Protocol_90.pd).
B.2 After nucleofection transfer the nucleofected cells from the cuvettes using the plastic pipettes provided by the kit to prevent damage and loss of cells distributing the total amount of cell suspensions into 2 wells containing the pre-warmed mesenchymal stem cells culture medium. Incubate the cells in a humidified 37 °C/5% CO2 incubator.
B.3 After 4 days transfer, wash nucleofected samples with PBS (Invitrogen, cat. no.10010-056) and trypsinize them using 1 ml 0.25% Trypsin/EDTA (Invitrogen, cat. no. 25200-056).
B.4 Transfer the nucleofected cells into six-well plates (Corning, cat. no. 153516) containing irradiated murine fibroblasts (iMEF;C57BL/6 MEF 4M IRR; Global Stem) in hESCs medium: KO-DMEM (Invitrogen, cat. no. 10829-018), 20% KOSR (Invitrogen, cat. no. 10828-028), 10 ng ml-1 bFGF (Peprotech cat. No. 100-18B), 1 mM Glutamax (Invitrogen, cat. no. 35050-038), 100 µM nonessential amino acids (Invitrogen, cat. no. 11140-050), 100 µM 2-mercaptoethanol (Sigma, cat. no. M7522), 50 U/ml (penicillin and 50 mg/ml streptomicin). Change hES media every other day.
B.5 After 20 days, large colonies are visible and can be picked mechanically and transferred onto iMEF and cultured as normal iPSCs following specifications detailed before by others [12,29,30].
L.O and E.G were partially supported by La Fundació Privada La Marató de TV3, 121430/31/32. EM and JS were partially supported by funds from the Spanish Ministry of Economy and Competitiveness (Ref PLE 2009-0164) and the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (2014 SGR 1442). This work was also supported by funds from the “Ministerio de Ciencia e Innovación” (grants AGL2010-17324 to E.C., AGL2011-24961 to I.N. and AGL2012-39768 to J.G.) and the Catalonian Government (grant 2009SGR-00402).N.M was partially supported by La Fundació Privada La Marató de TV3, 121430/31/32, the Spanish Ministry of Economy and Competitiveness (Ref PLE 2009-0164) and from the Catalonian Government (2014SGR 1442). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.
Although white rice is consumed as a major staple food worldwide, quite a few countries in Southeast Asia (SEA) also consume pigmented cultivars such as red, black, purple, and brown rice. Rice cultivars that originated in Southeast Asia (SEA) have been classified in the species of Oryza sativa L., which differs from the Oryza glaberrima Steud. species that is cultivated in West Africa. In Thailand, the total area of cultivation has been recorded at 56.3 million Rai (22.3 million acres) with the majority being comprised of white rice cultivars (90%), while pigmented rice is only 0.1% or makes up approximately 62,000 Rai (24,506 acres) [1]. The largest cultivated area is located in the northeast of Thailand (63.10%) followed by the northern region of Thailand (21.93%), the central area (14.5%), and the south (0.47%). India and Indonesia have more cultivated area of pigmented rice than any other SEA countries, although they report a smaller proportion than that of the white rice cultivar. The total cultivated area in India has been recorded at 43.77 million acers (29.4% of the global rice area) with a production of 90 million tons [2]. The world production of rice is estimated at around 680 million tons, which is equivalent to that of wheat [3]. The color intensities of pigmented rice are obtained from the value of lightness, redness, and yellowness and seem to be correlated to the indicators of its bioactive compounds [4, 5, 6].
Recently, pigmented rice varieties have received increased amounts of attention from consumers for their high bioactive compounds that present potential nutraceutical benefits to health. It is also well known that these compounds are primarily located in the outer layer of the rice grain, which is regarded as a rice by-product. The by-products of rice processing are rice germ and bran, along with the rice hulls which protect the rice seeds during growth. These account for 20% of the rice crop. These by-products are frequently used as animal feed in developing countries. However, recently, significant amounts of data have revealed the beneficial nutritional impacts of these by-products on human health. The major bioactive compounds that are found in red, black, purple, and brown rice include gallic, protocatechuic, hydroxybenzoic, and vanillic acid, cyanidin 3-O-glucoside, peonidin-3-O-glucoside, proanthocyanidin, flavanol, catechin and epicatechin, carotenoids, and γ-oryzanol content. Several research findings have reported on the biological modulating effects of pigmented rice seeds and bran phytochemicals, including anti-inflammatory activities [7, 8], anticancer activities that have suppressed tumor growth in mice and several human cancer cell lines [9, 10, 11, 12, 13], the anti-metastasis properties of cancer cell invasion [14, 15, 16], antiaging effects with the reduction of oxidative stress in both in vitro and in vivo models [17, 18], the modulation of serum lipid profiles and the enhancement of mRNA expression levels of fatty acid metabolism-related genes [19], a reduction of platelet hyperactivity and hypertriglyceridemia in dyslipidemic rats [20], and skin antiaging treatments [21, 22, 23, 24].
In this current review, we have focused on the health benefits of pigmented rice and the relevant bioactive compounds. We have tried to present the information in this chapter in a way that is easy to understand, even for readers who are not experts in this field of research. The bioactive compounds found in pigmented rice display significant immersion potential with regard to a range of beneficial health effects and also provide significant informative data that could lead to the expansion in the growing of pigmented cultivated areas in Thailand and other Southeast Asian countries. There is also the prospect of additional practical implications, not only for agriculture expansion but in the food industry as well. Several pigmented rice varieties have been used to create new nutraceuticals, and these seem to hold a promise in terms of potential cosmeceutical utilization in the new global business era.
The rice processing industry is well-developed and produces a number of products from rice kernels or grains (70%) along with a large quantity of rice by-products. These by-products include rice bran (8–9%), rice germ (1–2%), and rice husks (20%). Figures on rice paddy composition are presented in Figure 1. These by-products are frequently used as animal feed in developing countries [25], but the demand for these by-products in terms of their human nutritional impacts has increased due to their potential health benefits. Rice kernels are primarily a good source for the energy intake of carbohydrates and proteins in humans. Rice bran makes up the outer layer of the rice kernel and is mainly comprised of a pericarp, aleurone, sub-aleurone layer, and germ. Rice bran and germ contain appreciable quantities of fiber, vitamins, minerals, unsaturated fatty acids, tocopherols, γ-oryzanol, and tocotrienols, which offer potent antioxidant content along with a range of other potential health benefits [26, 27].
Rice paddy composition.
Several common extraction techniques that are used in the process of rice extraction include the method of solvent extraction, which is a conventional technique used to extract bioactive compounds from pigmented rice, supercritical fluid extraction, and subcritical water extraction. With regard to the conventional technique, a number of organic solvents are commonly used such as acetone, methanol, ethanol, butanol, and water in certain proportions as the extraction solvent [28, 29, 30]. In our study, 50% ethanol was used as an extraction solvent at a proportion of 1:5 grain or bran liquid, and extraction was carried out at room temperature for 3–12 h. The extracts were then concentrated with a rotary evaporator until all ethanol residues were removed and then further partitioned against saturated butanol to obtain the medium polar bioactive compounds of the black rice extract [31] or red rice extract [7, 15, 16]. The bioactive compounds present in these fractions shall be described in a later section. In another study, 60% ethanol containing 0.1% HCL was used as an extraction solvent with a 1:10 feed to liquid proportion, and extraction was carried out for 3–12 h. The extracts were then concentrated and further partitioned against petroleum ether [8]. In another study, the rice bran was extracted with 70% ethanol for 30 min repeated three times and was then further partitioned with ethyl acetate at pH 2–3 [32]. The same method was used to extract soluble phenolic compounds in white rice, brown rice, and germinated brown rice [33].
Supercritical fluid extraction has been widely used for the extraction of functional active compounds from medicinal plants including rice and cereals. This was in common with the use of supercritical carbon dioxide as an extraction solvent in other successful experiments. Kim et al. [34] used the method of supercritical fluid extraction of rice bran oil from pigmented rice, which provided higher yields of polyunsaturated fatty acids than the conventional use of organic solvent extraction. In yet another study, supercritical carbon dioxide extraction was used, and yields of 17.5% oil were achieved from powdered rice bran, and a yield of 37% of γ-oryzanols was also obtained, which was characterized as 85% of the extraction efficiency [35].
Another extraction technique is the subcritical water extraction method that has been developed for the extraction of bioactive compounds from pigmented rice through the use of hot water at temperatures between 100 and 374°C under high pressure to maintain a liquid status. This technique is considered to be very friendly to the environment because no organic solvents are used, and this can potentially alleviate some of the problems associated with the conventional methods [36, 37].
There were differences in the extraction procedure and the varieties of the rice cultivars that were used to detect the amounts of bioactive compounds in different portions of rice such as in the whole grains, kernels, endosperm, husks, rice, and bran. More than 1000 published studies have been reviewed to make up the cited data based on this information. Some data on rice composition have been selectively recorded elsewhere [27].
Phytochemical profiles of black rice are characterized by the presence of anthocyanins, which are a group of reddish to purple flavonoids that exist in black rice and other pigmented cereal grains. The main anthocyanins in black rice were found to be present in quantities more than 95% and were cyanidin 3-O-glucoside (2.8 mg/g) and peonidin-3-O-glucoside (0.5 mg/g) followed by flavones and flavonols (0.5 mg/g) and flavan-3-ols (0.3 mg/g) [38]. The concentrations of total anthocyanins in black rice cultivars significantly varied from one report to another, while much higher concentrations of anthocyanins were detected in Chinese black-purple rice that contained cyanidin 3-O-glucoside (6.3 mg/g) and peonidin 3-O-glucoside (3.6 mg/g) [39]. The variations of the anthocyanin content in the reports on black rice might be due to the use of different cultivars and the variety of differing growing conditions. The anthocyanidins or aglycons, the basic structure of anthocyanins, consist of an aromatic ring (A) that is bonded to a heterocyclic ring (C) that contains oxygen, which is bonded by a carbon–carbon bond to a third aromatic ring (B). When the anthocyanidins are bonded to a sugar moiety in the glycosidic linkage, they are known as anthocyanins. More than 500 different anthocyanins and 23 anthocyanidins have been reported. Anthocyanins exist as mono-, di-, or tri-O-linked glycosides and acyl glycosides of anthocyanidins in plants. The sugar moiety may be substituted by aliphatic, hydroxybenzoic, or hydroxycinnamic acids. The structural characteristics of anthocyanins make them highly reactive toward the reactive oxygen species (ROS) [27]. The basic structure of this is shown in Figure 2. Major flavone and flavonol glycosides present in black rice are taxifolin, quercetin, apigenin, and luteolin, which are comprised of monomeric and oligomeric constituents. The concentrations of the flavone and flavonol contents were significantly higher in black rice than in red, brown, or white rice. This was especially true with regard to taxifolin O-hexoside, quercetin 3-O-glucoside, and quercetin 3-O-rutinoside, which were detected only in black rice [38]. Abdel-Aal et al. [40] also reported that the mean anthocyanin content in black rice (3.276 mg/g) was about 35-fold higher than that of red rice (0.094 mg/g). Additionally, the contents of anthocyanin present in Northern Thai black rice cultivar obtained from Doi Saket, Chiang Mai, were 8.1 mg/g extract, which was considered very high when compared to the anthocyanin content found to be present in the Northern Thai red rice cultivar obtained from Dok Khamtai [31].
General structure of anthocyanins.
The total procyanidin content in black rice has been found to be present in high variations depending on the grain cultivar; however, it is noteworthy to mention that procyanidins are typically observed in red rice but not in black rice varieties [41, 42, 43, 44, 45]. Interestingly, some black cultivars have shown the presence of oligomeric procyanidins with a 2–10 degree of polymerization [38]. Furthermore, black and red rice were found to contain only one flavan-3-ol monomer, catechin. Additionally, a Canadian black rice variety also contained catechins at levels four times higher than epicatechin. Furthermore, the concentration of catechin was much higher in red rice (92 μg/g) than in black rice (20 μg/g) [46]. Other phytochemicals have been detected in black rice including all four derivatives of γ-oryzanol, such as 24-methylenecycloartenol, campesterol, cycloartenol, and β-sitosterol ferulates, along with lower levels of carotenoids. The main carotenoids detected in black rice were xanthophylls, lutein, and zeaxanthin, while lycopene and β-carotene could be detected but were found to be present as a minor component [38]. The value of the carotenoid content in black rice kernels is lower than the carotenoids found to be present in black rice bran. It was reported that values in a range of 33–41 μg/g of carotenoids were found in the bran extracts of four varieties of Thai black rice [47]. A range of phenolic compounds including vanillic acid, protocatechuic acid, chlorogenic acid, ferulic acid, and coumaric acid has been detected in black rice with the dominant phenolic acids being present in red and black rice bran [7, 31]. The contents of phenolic compounds, flavonoids, catechins, anthocyanins, and proanthocyanidins, are summarized in Table 1 as examples of the phytochemicals that were detected in Doi Saket Thai black rice cultivar. The germ and bran extracts of the black and red rice varieties were found to have the greatest phytochemical content with decreasing amounts occurring in the rice hull and even less in the seeds or kernels. Additionally, the expected low levels of these phytochemicals were found in white rice as a consequence of the milling process.
Compound | (mg/g extract) |
---|---|
Total phenolic content | 117.6 ± 14.6 |
Vanillic acid | 4.2 ± 0.4 |
Protocatechuic acid | 2.3 ± 0.1 |
Gallic acid | ND |
Coumaric acid | 0.5 ± 0.2 |
Ferulic acid | 1.4 ± 0.0 |
Chlorogenic acid | 1.7 ± 0.3 |
Total flavonoid content | 42.9 ± 2.1 |
Anthocyanin | 8.1 ± 1.9 |
Catechin | ND |
Proanthocyanidin | ND |
Phytochemical content of black rice extract (polar fraction).
Values are mean ± S.D., ND = not detectable.
Red rice was characterized by a high quantity of oligomeric procyanidins (0.2 mg/g) with more than 60% of total phytochemicals found in the rice seeds. Proanthocyanidins are high molecular weight polymers or complex flavan-3-ol polymers that consist mainly of catechin, epicatechin, gallocatechin, and epigallocatechin units that can also be found in rice germ and bran, particularly in pigmented rice. The degree of polymerization varied, and the reddish colored test was associated with the presence of a class of polymeric compounds of the proanthocyanidins. These could be in the sum class of the oligomer and polymer contents of the total proanthocyanidins present in the red rice bran extract fraction. The degree of polymerization and galloylation can affect their bioactivity and proanthocyanidin profiles differently depending on the food sources [27, 48]. Proanthocyanidins can be classified into several classes depending on the degree of hydroxylation of the constitutive units and the linkages between them. Our research group has reported on the type of proanthocyanidins found in the red rice that was collected from Dok Khamtai cultivar, Northern Thailand, as a type B proanthocyanidin. The monomeric units of proanthocyanidin in the acid hydrolysis of the red rice extract fraction were found to be catechins, epicatechins, gallocatechins, and epigallocatechins [16]. The results revealed that the proanthocyanidin types were procyanidin (catechin and/or epicatechin) and prodelphinidin (gallocatechin and/or epigallocatechin), while the degree of polymerization was recorded at approximately 4. Interestingly, the majority of proanthocyanidins in our red rice extract were of the oligomer with the same degree of polymerization that was found in grape seed extracts [49]. As has been mentioned previously, red rice has a high content of catechins and proanthocyanidins, but some of the black rice cultivars found in France and Canada have revealed the presence of catechins in their black rice cultivars (four times less than the red rice cultivars). It is worth mentioning that many other records have shown that procyanidins have been typically observed in red but not black rice varieties, including in the Northern Thai black rice cultivar obtained from Doi Saket, Chiang Mai [31]. The general structure of proanthocyanidins is shown in (Figure 3).
General structure of proanthocyanidins [16].
The other active compounds were γ-oryzanol and carotenoids at 27%, whereas flavones, flavonols, and anthocyanins were present in a much less quantity at less than 9% [38]. The main carotenoid detected in red rice bran was lutein, while xanthophylls and zeaxanthin were the carotenoids that were found to be present in lesser quantities. A range of phenolic acids including gallic, protocatechuic, hydroxybenzoic, vanillic, and ferulic acids in red, black, and brown rice have been detected as the dominant phenolic acids present in red and black rice bran [50, 51]. The contents of the phenolic compounds, flavonoids, catechins, anthocyanins, and proanthocyanidins, are summarized in Table 2 as an example of the phytochemicals that were detected in Dok Khamtai Thai red jasmine rice cultivar. The contents of these bioactive compounds can be used to determine the antioxidant activities that may then provide health benefits.
Compounds | (mg/g extract) |
---|---|
Total phenolic content | 237.78 ± 17.26 |
Vanillic acid | 1.53 ± 0.19 |
Protocatechuic acid | 0.35 ± 0.03 |
Gallic acid | ND |
Coumaric acid | 0.2 ± 0.01 |
Ferulic acid | 0.56 ± 0.04 |
Chlorogenic acid | ND |
ϒ-Tocotrienol | ND |
ϒ-Oryzanol | 1.75 ± 0.23 |
Anthocyanin | ND |
Catechin | 6.65 ± 0.57 |
Proanthocyanidin | 53.45 ± 3.23 |
Phytochemical content of red rice extract (polar fraction).
Values are mean ± S.D., ND = not detectable.
The rice bran of whole grain brown rice (unpolished) has been acknowledged as a potential source of edible oil. Although rice bran oil is not very popular worldwide, its demand is increasing due to numerous reports on its health benefits. Previously, rice bran obtained from brown rice has received a significant amount of attention from the nutraceutical industry as brown rice bran is recognized as the primary source of oil extraction. On this issue, agro-industrial by-products are gaining special attention from the food processing industry because rice bran oil presents a positive fatty acid profile along with the presence of other phytochemicals like ϒ-oryzanol, tocopherols, and tocotrienols. Basically, rice bran is rich in carbohydrates (34–62%), lipids (15–20%), proteins (11–15%), and dietary crude fiber (7–11%) [52]. The health benefits of rice bran include the strong antioxidant potential of rice bran oil. This is not only a consequence of the presence of significant quantities of linolenic acid (34%), oleic acid (38.4%), and other unsaturated fatty acids but also occurs as a result of the high contents of γ-oryzanol, tocopherols, and tocotrienols that reveal strong oxidative stability along with a range of other health benefits [53, 54].
The protein content present in rice bran of brown rice is characterized as a good source of protein that is nutritionally superior and hypoallergenic in nature. Rice bran is a rich source of essential amino acids such as lysine, which seems to be present in minute quantities in other cereal grains [55, 56]. The proteins in rice bran are highly digestible and can be utilized as an effective food ingredient. Rice bran is rich in dietary fiber, and, consequently, the rice bran by-products of rice processing are now often present in food commodities and functional foods that have been marketed for the ability to add dietary fiber to the diets of consumers and to offer health benefits in terms of daily nutrition. Additionally, brown rice possesses high contents of a variety of nutrients, such as fiber, vitamins, and minerals that are lost during the process of refining and milling in the production of white rice within the rice agro-industry. Notably, brown rice possesses four times as much dietary fiber as white rice [57].
White rice is a major source of energy nourishment for the world’s population, especially in Asian countries. However, the carbohydrate content in white rice accounts for 80% of its makeup, which is considered a higher amount than wheat. Wheat is a popular grain among European countries and contains a lessor proportion of carbohydrates (approximately 50–70%) [58]. For this reason, there are concerns that white rice possesses a high glycemic content and that it may not be a suitable source of carbohydrates for people who have weight problems. It is interesting to note that white rice does not contain anthocyanins and proanthocyanidins, which are the important phytochemicals that are found in black rice and red rice, respectively, particularly in portions of rice germ and bran extracts. While total flavonols and phenolic compounds are observed to be significantly high in pigmented rice, nonpigmented rice such as white rice possesses a minute quantity of flavone/flavanol content [50].
Phytochemicals found in pigmented rice (brown, black, purple, and red rice) are not present in white rice because many valuable phytochemicals, fiber, vitamins, and nutrients are lost during the processes of refining and milling [57]. Since brown rice contains higher dietary fiber and nutrients, previous studies have revealed that when compared to a white rice diet, a brown rice diet was found to significantly reduce weight, body mass index (BMI), and the circumference of the waist and hips, as well as to lower diastole blood pressure and inflammatory biomarkers such as C-reactive proteins (CRP). Arabinoxylan and β-glucan, prebiotics that are found in brown rice, are beneficial for human gut microbiota such as Bifidobacterium and Lactobacillus. They are considered as contributing factors in producing an anti-obesity effect [57, 59]. Moreover, in terms of their antidiabetic effects, brown rice was used as an intervention for preventing type 2 diabetes. This is likely because one of their components, ϒ-oryzanol, plays an important role in controlling high-fat diet-induced ER stress in the hypothalamus, which helps in reducing the preference for fatty foods [60]. ϒ-Oryzanol in brown rice has also been found to prevent the apoptosis of pancreatic β cells and to reduce levels of blood cholesterol [61]. Dietary rice brans that give brown rice its brown color also reveal potent anticancer activities through their antioxidant activity, as well as offering antiproliferation, immune modulation, and mucosal protection [62, 63].
Natural pigmented rice, such as black and red rice, may even offer more health benefits than brown rice. Not only is natural pigmented rice higher in the beneficial antioxidant activities of black and red rice, but it also displays strong anti-inflammatory activities as well as anticancer and anti-metastasis activities. The antiaging properties of the major components found in pigmented rice may be anthocyanins and proanthocyanidins, which have been found to be especially rich in content in the germ and bran extracts of black and red rice, respectively. The details of which will be described in greater detail in the following section.
The antioxidant activities of black and red rice and their crude extracts have been studied, and the results demonstrated that the addition of the pigmented rice could increase antioxidant capacity, both in vivo and in vitro [64, 65, 66]. In a study involving the supplementation of diets with black rice pigment fractions, the diets that attenuated atherosclerotic plaque formation in apolipoprotein E-deficient mice [66] and the anthocyanin-rich extract of the black rice might play an important role in the enhancement of atherosclerotic plaque stabilization [8]. In another study, a mixture of brown and black rice improved the lipid profiles and antioxidant status in rats [67]. Another animal study also demonstrated that black rice bran pigment effectively escalated hepatic antioxidant enzyme activities including superoxide dismutase and glutathione peroxidase in high-cholesterol-fed rats [68]. In addition to the in vivo studies, in a cell culture experiment, superoxide anions and reactive oxygen species were significantly suppressed after black rice extract exposure in HepG2 hepatocellular carcinoma [17]. When the antioxidant activities of pigmented rice were compared with those of nonpigmented rice in several studies [30, 41], the results demonstrated that the extracts from pigmented rice displayed higher antioxidant activity than did the nonpigmented rice. In another study, the radical scavenging activities of the extracts from white, black, and red rice were tested. The highest activity was observed in red rice (2.77 μmol of Trolox or vitamin E equivalents/ml), followed by black (0.92 μmol) and white (0.26 μmol) [41, 42]. Polymeric proanthocyanidins play an important role as radical-scavenging components in red rice. The relationships between the antioxidant activities and the components of pigmented rice were explored [41, 69, 70]. The antioxidant activities correlated well with the content of polyphenols and phytochemicals that contribute to the intense color of the pigmented rice. Interestingly, some studies have shown that the antioxidant activity of black rice may be reduced by up to 53% during cooking [71, 72, 73].
Inflammation is an important mechanism of immune pathogenesis, which is our body’s response to tissue injury, infection, and stress. Importantly, the prolonged production of inflammatory mediators by macrophage can cause damage to the host and can contribute to the pathology of many diseases including inflamm-aging, arthritis, asthma, cancer, diabetes, and atherosclerosis. Macrophage plays a key role in response to an immediate defensive mechanism of our body against attacking foreign agents, especially with a microbial lipopolysaccharide (LPS) [74]. Macrophage is activated and produces many kinds of inflammatory mediators including nitric oxide (NO), prostaglandins, and many cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-α [75]. Many researchers have studied in vitro and in vivo models to elucidate that natural products are able to ameliorate the inflammatory response in LPS-stimulated macrophage.
During the last decade, it has been shown that anthocyanins reduce the risks of cardiovascular diseases and cancers with inflammatory, antioxidant, and chemoprotective properties [15, 76, 77]. Some reports have demonstrated that lipophilic phytochemicals contained in pigmented rice germ and bran, such as γ-oryzanol and vitamin E derivatives, exert anti-inflammatory activities [78, 79]. On the other hand, pigmented rice contains high amounts of medium polar or hydrophilic compounds such as phenolics, bioflavonoids, anthocyanin, and proanthocyanidins that have been reported for their anti-inflammatory properties, in both in vitro and in vivo models [80, 81, 82].
Pigmented rice contains a variety of bioactive compounds with anti-inflammatory properties; however, there have been quite a few reports employing experimental designs that provide direct evidence to support using the extracts of pigmented rice. For the first time, our research group has demonstrated the molecular mechanisms underlying the anti-inflammatory effects. The anthocyanin-rich fraction of black rice extract significantly inhibited LPS that induced many pro-inflammatory mediators in RAW 264.7 macrophage white blood cells [31]. The pro-inflammatory mediators in this study were NO, TNF-α, and IL-6, and they effectively reduced the expression of two important inflammatory enzymes, the inducible NO synthase (iNOS) and the inducible cyclooxygenase-2 (COX-2). These results were regulated by an inhibition of the mitogen-activated protein kinase signaling pathway (MAPK pathway), leading to a decreased nuclear translocation of NF-κB and AP-1, two major transcription factors involved in the inflammation process. In testing the anti-inflammatory properties of anthocyanin and hydroxybenzoic acid, the major components were detected in the black rice extracts based on our extraction protocol, and similar results were obtained. A schematic diagram of the proposed mechanism of the anti-inflammatory properties of black rice anthocyanin is presented in Figure 4. In a study on cyanidin-3-glucoside and protocatechuic acid, no beneficial effects were found against inflammation induced by LPS [73]. Therefore, the anti-inflammatory properties of black rice might require the synergistic action of many phytochemicals, which are rich in anthocyanin and other phenolic compounds that play a role in this process. Interestingly, the same study has demonstrated that the cooking process did not alter the anti-inflammatory potential of black rice. In another study, other researchers reported that cyanidin-3-glucoside displays anti-inflammatory effects [8]. Our group also conducted a study on the anti-inflammatory effects of proanthocyanidin-rich red rice extract via the suppression of the MAPK, AP-1, and NF-κB pathways in RAW 264.7 macrophages that induced inflammation by LPS [7]. It was found that the red rice medium polar fraction that was enriched with polyphenols and proanthocyanidins exerted potent anti-inflammatory activities by inhibiting the production of TNF-α, IL-6, and NO in LPS-activated macrophage, whereas the red rice nonpolar fractions displayed no anti-inflammatory properties. All of the above results indicate that black rice that is rich in anthocyanins and red rice that is rich in proanthocyanidins exhibit therapeutic potential for the treatment of inflammatory diseases.
Schematic diagram of anti-inflammatory properties of black rice anthocyanin.
Cancer is one of the leading causes of morbidity and mortality worldwide. Notably, only 10% at the most of all cancers are due to genetic factors, while 90% are directly or indirectly correlated with an individual’s lifestyle and dietary habits [83]. Many scientific reports have shown that a healthy lifestyle, including a diet rich in natural products, such as herbs, cereals, fruits, and vegetables, can help reduce the risk of cancer [84, 85]. Some of the phytochemicals found in these natural products are secondary metabolites, including phenolic compounds, bioflavonoids, terpenoids, and alkaloids. In this chapter we shall focus more on the presence of phenolic compounds and flavonoids, including anthocyanins and proanthocyanidins, as the major compounds found in pigmented rice, especially in rice germ and bran.
Active components of pigmented rice bran have demonstrated anticancer properties in in vitro cancer cell models, including those involving leukemia, colon, breast, liver, and stomach cancer cells. In a study on the anticancer potential of rice bran against the proliferation of leukemic cell lines, the antioxidant activities of the active compounds found in rice bran were noted for this beneficial effect [10]. Another investigation on the tumor suppression activities of rice bran from different pigmented and nonpigmented rice varieties reported that 70% ethanolic extract of the pigmented rice bran inhibited phorbol ester-induced tumor promotion in a better manner when compared to the nonpigmented rice bran variety [11]. In yet another study, the growth inhibitory effect of rice bran polyphenols, mainly γ-oryzanol and its derivatives, has been reported in human colorectal adenocarcinoma [86]. The anticancer activity of rice bran could be varied considerably in different rice cultivars or varieties in accordance with the different chemical profiles of the active compounds. In addition, the second study had analyzed seven varieties of rice bran for their growth inhibition potential against human colorectal cancer cells and reported on variations in the degree of growth inhibition depending upon the rice bran variety [9]. Some evidences have indicated that cyanidin-3-glucoside and peonidin-3-glucoside obtained from black rice anthocyanin can be combined with doxorubicin to inhibit cancer cell growth, while both anthocyanin compounds could inhibit cancer invasion into other tissues through the downregulation of the degradative enzymes MMP-2 and MMP-9 [14]. Interestingly, Chen et al. [87] compared the relationship of the bioactive compounds with the growth inhibitory effects of pigmented rice bran extracts. The results revealed that the light brown bran had no effect, the purple bran exhibited a minor effect on leukemia and cervical cancer cells, and the red bran exhibited strong inhibitory effects on leukemic, cervical, and stomach cancer cells. High concentrations of protocatechuic acid and anthocyanins in purple bran and proanthocyanidins in red rice bran have been singled out for their growth inhibitory effects against human cancer cells.
Many studies on anticancer properties have been reported in Thai rice cultivars. In an important study, Kum Phayao black rice cultivar was found to be highly cytotoxic to human HepG2 cells when compared with other Northern Thai purple rice cultivars [12]. In yet another study, the alcoholic extracts of black-purple rice grain cultivar Kum Doi Saket demonstrated an antimutagenic activity against aflatoxin B1 in Ames tests [88]. The therapeutic potential of black rice anthocyanin for treating inflammatory diseases that are associated with cancer has been proposed for its mechanism via the inhibition of the MAPK signaling pathway [31]. A very recent study conducted by our research group revealed that the proanthocyanidin-rich fraction isolated from the red rice germ and bran of the Kum Doi Saket cultivar grown in the northern part of Thailand significantly reduced the cell viability of HepG2 cells (IC50 value at 20 μg/ml) [13]. The proanthocyanidin-rich fraction could inhibit cell proliferation and induce cell apoptosis by increasing the apoptotic proteins, such as cleaved PARP-1, cleaved caspase 8, and cleaved caspase-3, and decreasing the anti-apoptotic protein survivin without p53 protein changes. A schematic diagram of this mechanism is presented in Figure 5. In addition, our previous studies have demonstrated that red rice grain extracts with high proanthocyanidin content displayed an anti-metastasis effect on invasive human breast carcinoma cells MDA-MB231 [16] and human fibrosarcoma HT1080 cell lines [15]. In addition, proanthocyanidins in other colored plants, such as grapes and blackberries, have demonstrated anticancer, anti-inflammatory, and antioxidant activities to a similar extent as the proanthocyanidins that are found in red rice germ and bran [7, 8, 9, 13].
Schematic diagram of anticancer properties of red rice proanthocyanidins.
Inflamm-aging, a state of chronic, low-level systemic inflammation, is a widespread feature of human aging and a major risk factor for disabilities and mortality in aging individuals [89, 90]. Inflamm-aging is characterized by an overall increase in plasma levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and subsequently can increase major inflammatory markers such as C-reactive protein (CRP) and serum amyloid A. This generalized pro-inflammatory status potentially triggers the onset of the most important age-related diseases such as cardiovascular diseases, atherosclerosis, metabolic syndrome, type 2 diabetes, obesity, neurodegeneration, sarcopenia, frailty, and cancer [91, 92].
Since the anti-inflammatory effects of phytochemical components in black rice and red rice (anthocyanins and proanthocyanidins) are able to target many inflammatory signaling pathways, such as the MAP kinase and AMP-activated protein kinase (AMPK) and mTOR pathway, the result can also decrease free radical production by their antioxidant activity, inhibiting NF-κB activation and reducing the expression of inflammatory mediators (NO, iNOS, and pro-inflammatory cytokines) [7, 31, 93, 94]. Therefore, this has made natural pigmented rice a promising candidate as an anti-inflamm-aging agent. Some relevant studies have found that a Mediterranean diet (a diet involving high consumption of vegetables, fruits, and whole grains such as pigmented rice, olive oil, and fish, but low in the intake of saturated fats and other animal fats) can modulate the multi-interconnected processes that are involved in inflammatory responses such as free radical production, NF-κB activation, and the expression of inflammatory mediators by balancing between pro- and anti-inflamm-aging activities as well as maintaining healthy gut microbiota homeostasis and epigenetic modulation of oncogenesis through specific microRNAs [95, 96].
Several studies have identified a number of actions of anthocyanins in a phytochemical diet in the context of neuroinflammation and neurodegeneration in aging individuals. It was also recently reported in an experimental model of multiple sclerosis that anthocyanins (100 mg/kg) could effectively suppress the secretion of pro-inflammatory mediators and protect cellular components against oxidative damages that were induced by demyelination [97]. Anthocyanins also protect neuronal cells from prooxidant and pro-inflammatory damage via the modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the inhibition of NF-κB pathways [98]. Moreover, anthocyanins also exhibited a similar degree of anti-inflammatory effects, and these compounds suppressed the expression and secretion of pro-inflammatory mediators in macrophages by inhibiting the nuclear translocation of NF-κB [99].
Red rice extracts that contain high levels of proanthocyanidins were also found to have neuroprotective effects and anti-inflamm-aging effects that are similar to those of anthocyanins. Previous studies have found that in primary hippocampal neuronal cells that had been treated with proanthocyanidins (14 μg/ml) and exposed to LPS, the major neuroprotective effects of proanthocyanidins were involved with a reduction of NF-κB, p38, and JNK [100]. In brief, the consumption of foods rich in polyphenols has been associated with the prevention of chronic diseases. In particular, anthocyanins, proanthocyanidins that act through various mechanisms that modulate the inflammatory signaling pathways, result in a reduction of inflammation that is often seen in aging individuals. A schematic diagram of the proposed mechanism of anti-inflamm-aging properties of black rice and red rice is presented in Figure 6. From the aforementioned results, it has been determined that black rice and red rice with their anti-inflamm-aging properties have a therapeutic potential that would likely need to be further investigated in geriatrics and gerontology fields.
Schematic diagram of anti-inflamm-aging properties of pigment rice.
Many studies have shown that bioactive compounds found in pigmented rice, such as proanthocyanidin, catechin, vanillic acid, and oryzanol, may be useful in the cosmetic and nutraceutical industries as skin antiaging agents. As mentioned in the previous section in this chapter, these bioactive compounds demonstrated antioxidant and anti-inflammatory properties. For the enhancement of the knowledge of skin antiaging properties, the bioactive compounds in the pigmented rice extract have been elucidated in a number of research laboratories. Skin aging is a process characterized by progressive physiological and structural changes in the skin. These changes could be considered as individually intrinsic and extrinsic factors, such as those associated with age, lifestyle, diet, and sunlight. Additionally, certain environmental factors can contribute to skin aging [101]. In the skin aging process, the level of degradative enzymes, such as elastase and collagenase, in skin fibroblasts are elevated, and this can lead to a loss of skin firmness and the appearance of wrinkles [102]. Mature skin in the elderly or those with sun-exposed skin can cause dark spot formations on the skin or result in the over-synthesis of melanin [103]. Hence, natural or herbal products that can exert skin benefits, including scavenging reactive oxygen species (ROS), the suppression of extracellular matrix degradation enzymes, and the inhibition of melanin synthesis, can be applied in skincare products for their beneficial skin anti-aging properties.
As pigmented rice has been reported to possess antioxidant properties, the extracts could be used for skin-anti-aging purposes. In a study by our research group, red rice extract showed anti-photoaging activity by protecting UV-induced collagen and hyaluronic acid degradation in human skin fibroblasts [21]. The red rice extract also inhibited collagenase and MMP-2 activity. In another study our group [22] has elucidated the skin antiaging properties of the main bioactive compounds in red rice extract including proanthocyanidin, catechin, hydroxybenzoic acid, vanillic acid, and oryzanol. The results showed that collagenase and MMP-2 activity were strongly inhibited by proanthocyanidin and catechin, whereas hydroxybenzoic acid, vanillic acid, and oryzanol had no effect. Both proanthocyanidin and catechin significantly induced the synthesis of collagen and hyaluronic acid, which is an important biological target for skin antiaging agents. Proanthocyanidins and γ-oryzanol could reduce the melanin content in B16-F10 melanoma cells. Some studies have proposed the use of red rice callus or stem cells as a source of materials for replenishing the aging body in a series of experiments. The results demonstrated the efficacy of red rice callus in cosmetic products on 28 volunteer subjects aged 30–55 years and proved to promote skin lightening, hydration, and elasticity. On the other hand, a study performed involving five different varieties of Thai pigmented rice demonstrated that all rice crude extracts with 50% ethanol exhibited a weak level of activity on tyrosinase inhibition [23]. This result is similar to our findings which demonstrated that proanthocyanidin and oryzanol could reduce melanin content but had no effect on mushroom tyrosinase activity [22]. However, our results have produced experimental data to support that proanthocyanidin decreased cellular tyrosinase activity leading to a decrease in melanin content. As has been mentioned previously, proanthocyanidin is highly present in red rice germ and bran and is very similar in chemical structure to the oligomers of catechin and epicatechin that are found in grape seeds and red wine. It is noteworthy to cite the findings of a study that found that the oral administration of grape seed extract was effective in lightening UV-induced pigmentation of guinea pig skin by a reduction in the number of 3,4-dihydroxyphenylalanine (DOPA)-positive melanocytes, Ki-67 positive, proliferating cell nuclear antigen (PCNA)-positive melanin-containing cells in the basal epidermal layer of the UV-irradiated skin in grape seed extract-fed guinea pigs. In addition, this study has demonstrated that grape seed extract effectively inhibited mushroom tyrosinase activity and inhibited melanogenesis without inhibiting the growth of culture B16-F10 mouse melanoma cells.
In this chapter, the by-products of rice processing, such as germ and bran, contain a wide range of biologically active compounds that can be recovered and used in a variety of approaches in nutraceuticals. This is in correlation with an increasingly deeper understanding of the predominant bioactive compounds found in pigmented rice, particularly anthocyanin and proanthocyanidin found in black and red rice, respectively. The dietary intervention and other high-value applications in functional food and cosmetic products have been attracting ever-growing attention in recent decades. The need for scientific evidence of pigmented rice bioactive compounds in different cultivars is encouraging for future perspectives within the new global business era of nutraceutical and agriculture expansion.
Most of the studies on the biological properties of black or red rice bioactive compounds have been conducted through an in vitro approach; however, only a few reports have been applied in preclinical or in animal studies. Further investigations will be needed to produce evidence on the efficacy of pigmented rice in terms of the anticancer activities and anti-inflammation properties in sub-chronic cases, especially among the aging members of the society in which sub-chronic inflammation commonly leads to noncommunicable diseases in later life. In addition, scientific studies have determined that the skin antiaging properties of pigmented rice should be useful and available in clinical studies for their efficacy and their further development in skincare products.
This work was supported by Chiang Mai University and The Excellent Center for Research and Development of Natural Products for Health, Chiang Mai University.
The authors declare no conflict of interest.
The authors would like to thank the Faculty of Medicine of Chiang Mai University (Grant No. 096/2560), The Excellent Center for Research and Development of Natural Products for Health, the Agricultural Research Development Agency (ARDA; Public Organization), and the National Research Council of Thailand (NRCT) for their research funding for rice researches in our laboratory. Our research works that have been contributed in this chapter would not have been completed without their financial support. The authors are also grateful for the English proof editing from Mr. Russel Kirk Hollis of the English Department, Faculty of Humanities, Chiang Mai University.
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