\r\n\t \r\n\tRecently in 2019, International Council on Systems Engineering (INCOSE) has released the latest version of the “Guidelines for the Utilization of ISO/IEC/IEEE 15288 in the Context of System of Systems (SoS) Engineering” to industry for review and comments. The document was developed under the Partner Standards Development Organization cooperation agreement between ISO and IEEE, as it was approved by Council Resolution 49/2007. This document provides guidance for the utilization of ISO/IEC/IEEE 15288 in the context of SoS in many domains, including healthcare, transportation, energy, defense, corporations, cities, and governments. This document treats an SoS as a system whose elements are managerially and/or operationally independent systems, and which together usually produce results that cannot be achieved by the individual systems alone. This INCOSE guide book perceives that SoS engineering demands a balance between linear procedural procedures for systematic activity and holistic nonlinear procedures due to additional complexity from SoS perspectives. \r\n\tThe objective of this book is to provide a comprehensive reference on Systems-of-Systems Engineering, Modeling, Simulation and Analysis (MS&A) for engineers and researchers in both system engineering and advanced mathematical modeling fields. \r\n\tThe book is organized in two parts, namely Part I and Part II. Part I presents an overview of SOS, SOS Engineering, SOS Enterprise Architecture (SOSEA) and SOS Enterprise (SOSE) Concept of Operations (CONOPS). Part II discusses SOSE MS&A approaches for assessing SOS Enterprise CONOPS (SOSE-CONOPS) and characterizing SOSE performance behavior. Part II focuses on advanced mathematical application concepts to address future complex space SOS challenges that require interdisciplinary research involving game theory, probability and statistics, non-linear programming and mathematical modeling components.
\r\n
\r\n\tPart I should include topics related to the following areas: \r\n\t- SOS and SOS Engineering Introduction \r\n\t- Taxonomy of SOS \r\n\t- SOS Enterprise (SOSE), SOSE CONOPS, Architecture Frameworks and Decision Support Tools
\r\n
\r\n\tPart II should address the following research areas: \r\n\t- SOS Modeling, Simulation & Analysis (SOS M&SA) Methods \r\n\t- SOS Enterprise Architecture Design Frameworks and Decision Support Tools \r\n\t- SOS Enterprise CONOPS Assessment Frameworks and Decision Support Tools.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"677fbbd5fc2550e8be540f40c0969a62",bookSignature:"Dr. Tien Manh Nguyen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7772.jpg",keywords:"Autonomy of Constituents, Operational Independence, Taxonomy, Acquisition Classification, SOS Enterprise Architecture Design, Decision Support Tools, State Modeling, SOS Simulation Methods, DOD Architecture Framework, Enterprise System Engineering, SOS Enterprise CONOPS, Satellite Operations (SATOPS)",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 31st 2019",dateEndSecondStepPublish:"November 21st 2019",dateEndThirdStepPublish:"January 20th 2020",dateEndFourthStepPublish:"April 9th 2020",dateEndFifthStepPublish:"June 8th 2020",remainingDaysToSecondStep:"15 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,editors:[{id:"210657",title:"Dr.",name:"Tien",middleName:"Manh",surname:"Nguyen",slug:"tien-nguyen",fullName:"Tien Nguyen",profilePictureURL:"https://mts.intechopen.com/storage/users/210657/images/system/210657.jpg",biography:"Dr. Tien M. Nguyen received his M.A. in Mathematics, and his Ph.D. in Applied Mathematics from the Claremont Graduate University; M.S.E.E. in Communication Systems Theory from University of California San Diego; and B.S.E. in Electronics and M.S.E. in Electromagnetic Field Theory from California State University Fullerton (CSUF). He also completed all course requirements and passed the comprehensive exam for his M.S.E.E. in Digital Signal Processing from California State University Long Beach. Dr. Nguyen is an expert in Satellite Operations (SATOPS), Satellite Communications (SATCOMs), advanced mathematical modeling for complex systems-of-systems, sensing and communication networks.\nCurrently, he serves as Adjunct Research Professor at CSUF, Mathematics Dept. Concurrently, he is also with the Aerospace Corporation, serving as a Sr. P.E. in Space System Group Program Office, Space System Architect Division, Global Partnerships Subdivision. He has more than 13-years of service at Aerospace, and prior to his current position; he has served as Sr. Engineering Specialist, Sr. Project Lead, Section Manager, Associate Director, Interim Director, and Principal Technical Staff (the highest technical level at the corporation). At Aerospace, he invented HPA linearizer, GMSK synchronizers and developed advanced optimization techniques using game theory for achieving affordable and low-risk acquisition strategy. Prior to CSUF, he had also held a Research Assistant Professor at the Catholic University of America in concurrent with The Aerospace Corporation positions. \nHe was a Engineering Fellow from Raytheon, where he had 10-year of services at Raytheon, serving as Program Area Chief Engineer, Program Chief Engineer, PI, Technical Director, Program Manager, Lead Architect and Lead System Engineer for many advanced programs and pursuits related to sensing and communication networks. At Raytheon, he invented radar-communication technology and gun barrel detector using millimeter-wave. Previous to Raytheon and Aerospace Corporation, Dr. Nguyen was with NASA/JPL for more than 11-years, where he served as the NASA delegate to the international Consultative Committee for Space Data System (CCSDS). Many of his works on RF and Modulation were adopted as the CCSDS standards for USB waveforms and space RF systems. At JPL he invented QPSK phase ambiguity resolver and developed innovative optimization technique for simultaneous range-command-telemetry operation. He built the first laser lab and automated manufacturing lab when he was with ITT Technical Services in the early ’80s. \nHe has published more than 250 technical reports and papers. His work has appeared in NASA TechBrief, textbook, Open Access Book, SIAM Publication, CCSDS Blue Book, and Wiley & Sons Encyclopedia of Electrical and Electronics Engineering. He was selected as a Vietnamese-American Role Model by KCSI-TV, Channel 18 in 2002, and Recognition Honoree at 50-Year Celebration of CSUF in 2007. He received numerous Raytheon, Aerospace and NASA awards, and Air Force commendations. He holds 16 patents. 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1. Introduction
Tumors have developed different strategies to evade immune recognition by cytotoxic T lymphocytes (CTLs) as well as natural killer (NK) cells. This is caused by alterations of the tumor itself, changes of the tumor microenvironment (TME), reduced frequency, and impaired function of diverse immune subpopulations. The processes leading to immune evasion of tumors are diverse and could be associated with structural alterations and/or deregulation of genes/proteins from tumor cells, but also from different immune cells important for recognition and killing of tumor cells or in the induction of immune suppression. The identification of microRNAs (miRNAs), involved in the RNA interference (RNAi)-based control of these immune modulatory molecules, clarified the complexity of the mechanisms conditioning tumor immune escape. This review is focused on the identification and characterization of immune modulatory miRNAs (im-miRNAs) in tumors, thereby altering the antitumoral immune response by miRNAi-mediated RNAi.
2. The MHC class I antigen processing and presentation machinery (APM)
The major histocompatibility complex class I (MHC) molecules present an array of peptide epitopes for surveillance by CD8+ T cells. These peptides are classically derived from proteins synthesized in the cytosol. Upon proteasomal degradation of ubiquitinated proteins, the yielded peptides are then transported into the endoplasmic reticulum (ER) via the heterodimeric peptide transporter associated with antigen processing (TAP). The peptide transport into the ER is ATP dependent and sequence specific. The TAP heterodimer associates in ER with a number of other proteins to form the peptide loading complex (PLC). These include the chaperone tapasin, which recruits MHC class I heavy chain (HC)/β2-microglobulin (β2-m) dimers and calreticulin. The peptides are either trimmed by ER-resident aminopeptidases or directly loaded onto MHC class I molecules [1]. Upon peptide loading, the PLC dissociates from the trimer consisting of the MHC class I HC, β2-m, and peptide is then transported via the trans Golgi to the cell surface and exposed to CD8+ CTLs [1].
3. Immune stimulatory and immune inhibitory molecules and immune response
An effective T-cell response requires two signals. The first is mediated by the interaction with MHC class I antigens on the antigen-presenting cells (APC), and the second is mediated by the interaction of B7 family members on APC with CD28 or CTLA4 on T cells. The prototypes of B7 family members are B7-1 (CD80) and B7-2 (CD86). During the last years, the B7 family was growing consisting of B7-H1 (PDL-1), B7-H2, B7-H3, B7-H4, and B7-H6 molecules [2, 3]. While B7-H1 and B7-H4 represent coinhibitory molecules, B7-H2 was identified as costimulatory molecule, which is mainly expressed on B cells, monocytes and dendritic cells (DC): B7-H2 binds to the receptor ICOS, which results in activation of T cells through phosphatidylinositol-3-kinase-dependent signal transduction pathways and in the induction of Th2 cell-mediated immune response, proliferation, and cytokine production [4]. The role of B7-H3 is currently controversially discussed and depends on the cell types analyzed, demonstrating either costimulatory or coinhibitory activity. Regarding B7-H4, its expression is primarily restricted to activated T cells, B cells, monocytes, and DCs [5, 6]. B7-H4 is not detected in the majority of normal tissues and cells but is overexpressed in a variety of tumor tissues. B7-H6 has been identified as ligand for the NK cell receptor NKp30 and is detectable on surface or in the cytosol of tumor cells and as soluble factor in the peritoneal fluid [7], while it is not expressed on healthy cells. The interaction of B7-H6 with NKp30 is involved in NK cell responses [8]. It is noteworthy that many other coinhibitory molecules have also been identified and their role on immune responses is currently under investigation [2, 3].
4. Features of the interferon-γ-mediated signal transduction
Interferons (IFN) are a group of pleiotropic cytokines that play a key role in the intercellular communication during innate and adaptive immune responses, in particular in the host defense against viral and bacterial infections and neoplastic transformation [9]. The IFN family could be classified into type I and type II IFNs, which differ in their activity regarding immune modulation [10].
IFN-γ belongs to the type II IFN and is a central regulator of immune responses by controlling and modulating the expression of targets essential for cell-cell communication and cellular interactions. It is secreted by activated T cells, NK cells, and macrophages and induced by DC and monocytes stimulated with bacterial cell wall components [11]. IFN-γ exerts its activity by binding to its heterodimeric receptor consisting of IFN-γ-R1 and IFN-γ-R2 subunits [12, 13]. This results in the dimerization of the receptor subunits followed by activation (transphosphorylation) of the receptor-associated tyrosine kinases JAK1 and JAK2 belonging to the Janus kinase (JAK) family and phosphorylation and dimerization of the JAK-associated STAT1 transcription factor. The activated STAT1 is translocated into the nucleus and recruited to the IFN-γ-activated sequence (GAS) element of the promoters of the STAT1 target genes leading to their transcriptional activation.
IFN-γ-regulated genes can be classified into primary and secondary responsive genes. Primary responsive genes are induced early due to the binding of STAT dimers to the GAS element in the promoter region of target genes, like IRF1, CXCL9, and CXCL10 [14]. IRF1 binds to IFN-stimulated response elements (ISRE) and modulates gene induction of the secondary responsive genes. IFN-γ induced the transcription of MHC class I and class II antigens and of many APM components and at high concentrations could lead to a caspase-dependent apoptosis. In addition, IFN-γ is involved in amplifying toll-like receptor (TLR) signaling by increasing or inhibiting the transcription of TLRs, chemokines, and cytokines [15, 16]. Furthermore, IFN-γ promotes the induction of SOCs proteins (suppressor of cytokine signaling), which inhibit IFN-γ signaling by a negative feedback loop, resulting in the inactivation of JAK1 and JAK2 [17]. Moreover, IFN-γ signaling is controlled by inhibiting JAK1, JAK2, and IFN-γ-R1 via dephosphorylation mediated by SH2-domain-containing protein tyrosine phosphatase 2 [18], by proteasomal degradation of JAK1 and JAK2 [18] and by inhibition of STAT1, which is mediated by the protein inhibitor of activated STAT1 [19].
5. Distinct levels of tumor immune escape
Tumors have developed different strategies to escape immune surveillance, which could occur at the level of immune cells, tumor micromilieu, and the tumor itself (Figure 1). The frequency, activity, and function of CD8+ and CD4+ T lymphocytes, DC, NK cells, and B cells are often downregulated in peripheral blood of tumor patients, while the number of immune-suppressive myeloid-derived suppressor cells (MDSC), NKT cells, and regulatory T cells (Treg) is upregulated [20-23].
Figure 1.
Tumor immune escape mechanisms containing (A) loss of tumor antigen expression; (B) variations in tumor antigen processing; (C) defects in the peptide transporter TAP, chaperone tapasin, and protease ERAP1; (D) defects in expression of MHC class I heavy chain and β2-microglobulin; (E) release of anti-inflammatory cytokines; (F) downregulation of IFN-γ-R1, JAK1, JAK2, STAT1, and STAT2; (G) altered phosphorylation states of STAT1; (H) impaired upregulation of IFN-γ regulated genes (MHC class I, APM); (I) upregulated expression of HLA-G; (J) altered methylation pattern of IRF; (K) overexpression of SOCS1; and (L) protection from T-cell-mediated apoptosis.
The tumor microenvironment (TME) consists of various cellular and soluble factors and is of clinical relevance since its composition significantly correlates with the tumor patients’ outcome. These include different cellular components, such as fibroblasts, blood vessels, immune cells, stroma cells, extracellular matrix, and soluble factors such as immune-suppressive cytokines, like interleukin (IL)-10, transforming growth factor (TGF)-β, metabolites, arginase and prostaglandin, hypoxia, and pH, which negatively interfere with the antitumoral immune responses.
In tumors, an aggressive and deregulated growth of neoplastic transformed cells, which overexpress proangiogenic factors, such as the vascular endothelial growth factor (VEGF), leads to the development of organized blood vessels. These blood vessels are fundamentally different from the normal vasculature. Tumor-associated fibroblasts (TAF) represent the major constituents of the tumor stroma and produce growth factors, including the VEGF and inhibitory cytokines that activate extracellular matrix thereby contributing to the tumor growth.
Furthermore, cancer is often driven by inflammation mediated by monocytes and tumor-associated macrophages (TAM), which belong to the innate immune cells. Macrophages could be classified in type 1 and 2 macrophages. While M1 macrophages express a series of proinflammatory cytokines, chemokines and effector molecules, the M2 macrophages express a wide array of anti-inflammatory molecules, including IL-10, IL-35, TGF-β, and adenosine. TAMs are mainly of the M2 phenotype and secrete different cytokines, chemokines and proteases, which promote tumor angiogenesis, growth, metastasis as well as immune suppression.
In addition to TAM and TAF, MDSC represent a heterogeneous population derived from myeloid progenitors [20]. They can promote tumor growth by enhancing angiogenesis or suppression of innate and adaptive immune responses. Regarding the innate immune cells, MDSCs suppress NK cell cytotoxicity, promote M2 macrophage differentiation, and modulate the priming activity of mature DC [24]. Moreover, MDSCs suppress T-cell responses by induction of apoptosis, secretion of immune modulatory factors, modulation of amino acid metabolism, restriction of T-cell homing, and induction of Treg [25-28]. Tregs suppress the activity of immune cells and maintain immune tolerance to self-antigens. They express CD4, CD25 and FoxP3 [22]. The elevated numbers of Tregs in cancer is due to their efficient migration into the tumor sites [29], local expansion in the tumor environment[29], and de novo generation within the tumor [30].
5.1. Alterations of the tumors
Immune escape mechanisms include loss or downregulation of HLA class I antigens and/or components of the antigen processing machinery (APM), upregulation of nonclassical HLA-G and HLA-E antigens, and coinhibitory molecules, including PDL-1, as well as alterations of signaling transduction cascades, including in particular the IFN signaling pathway [31]. The frequency of these different mechanisms highly varied between tumor (sub)types and is often correlated with a worse prognosis and reduced survival of tumor patients.
5.1.1. MHC class I abnormalities
The classical MHC class I pathway and the APM components are involved in eradication of developing tumors [32]. Since CD8+ CTLs recognize and eliminate cells presenting tumor antigens via HLA class I molecules, loss of HLA class I expression results in evasion of CTL-mediated cell death [33]. Abnormalities of HLA class I antigens are often due to downregulation of various components of the MHC class I APM, in particular of TAP, tapasin, β2-m, and MHC class I HC. Structural alterations of these components are rare, while MHC class I defects are mainly due to deregulation of the different components, which could be controlled at the transcriptional, epigenetic (methylation, acetylation), posttranscriptional (e.g., microRNAs, protein degradation), or posttranslational (phosphorylation) level.
HLA-G has been demonstrated as a nonclassical HLA class I antigen, which is in general only expressed on immune privileged organs, but also on many tumors of distinct origin [34]. The overexpression of HLA-G or secretion of soluble HLA-G are directly associated with tumor progression and reduced patients’ survival. It suppresses antitumoral immune responses by binding to receptors of various immune populations, thereby inhibiting the sensitivity to CTL- and NK cell-mediated lysis in particular [34]. In contrast, tumor cells with deficient expression of classical HLA class I molecules are eradicated by NK cells.
5.1.2. Check points as important regulators of immune response
During carcinogenesis, members of the B7-family play a key regulatory role of both stimulatory and inhibitory T-cell responses, which depends on the available B7 ligand and receptor on the respective target and immune cells [35, 36]. Interestingly, B7-H1 and B7-H4 were often overexpressed on tumors leading to impaired immune recognition. By interaction with these coinhibitory molecules, the intensity of the T-cell responses is reduced by raising the threshold of activation, halting proliferation, enhancing apoptosis, and inhibiting the differentiation of effector cells [37].
5.1.3. Role of IFN-γ in cancer immunogenicity
Abnormalities of MHC class I expression on tumor cells due to the downregulation or loss of APM component expression are common mechanisms, by which tumor cells can escape from anti-tumor-specific immunity [38, 39]. In addition, tumor cells are often not susceptible to treatment with IFN-γ, which could be due to structural alterations or deregulation of constituents of the IFN signal pathway. Several studies confirmed that defects in the IFN-γ receptor signaling cascade could be occur at multiple steps of this pathway, including lack of the expression of the IFN-γ-R1, abnormal forms of JAK2, lack of expression of JAK1 [40], altered phosphorylation, repressed STAT1 expression, and overexpression of SOCS1. The latter results in an increased negative feedback regulation of the IFN-γ signal cascade. The defects in the IFN-γ receptor signaling cascade caused impaired expression of IFN-γ regulated genes.
Previous studies demonstrated that IFN-γ responsive genes are frequently downregulated in tumor cells due to impaired IRF1 expression as well as defective transcriptional and posttranscriptional regulation of components involved in the IFN-γ signal transduction pathway. The loss of the IFN-γ-mediated upregulation of TAP in a renal cell carcinoma is associated with the lack of IRF1 and STAT1 binding activities as well as JAK1, JAK2, and STAT1 phosphorylation [41]. This impaired IFN-γ-mediated phosphorylation could not be restored by JAK1 and/or JAK2 gene transfer. Furthermore, an impaired STAT1-phosphorylation associated with the loss of IFN-γ-mediated MHC class I upregulation was also reported in melanoma and colorectal carcinoma cells [42].
IFN-γ treatment is able to restore the expression of many genes belonging to the MHC class I APM [43, 44]. As a consequence, anti-tumor-specific immune responses can be induced, suggesting that IFN-γ acts as key regulator of immunogenicity [45]. Its antitumoral activity includes also the induction of apoptosis and inhibition of cell proliferation by STAT1 activation, which induces expression of cell cycle inhibitor, CDKN1A [46]. In addition, the IFN-γ-mediated upregulation of MHC class I antigens could be due to DNA demethylation of MHC class I APM genes, suggesting that IFN-γ acts as an epigenetic modifier of APM components [47]. Therefore, IFN-γ is a major player in the regulatory network combating tumor cell proliferation and tumor survival.
6. Features of miRNAs
miRNAs are small noncoding ~22 nucleotide long regulatory RNAs encoded in the human genome, which control the posttranscriptional gene expression by binding to the 3′-untranslated region (UTR) of mRNA of target genes, thereby affecting their stability and/or their translation [48]. An individual miRNA could target numerous cellular mRNAs, while single miRNA can be regulated by several proteins [49, 50]. miRNAs have emerged as key players in the posttranscriptional control of gene expression and based on their prediction appear to be directly involved in the expression of at least 50% of all protein-coding genes in mammals [51].
A strong relationship between miRNAs and human cancer has been developed during the past years. High throughput analysis allows the comparison of miRNA expression pattern in normal and tumor tissues demonstrating global changes within the miRNA expression in different malignancies. Interestingly, the miRNA genes were frequently located at fragile sites and cancer-associated chromosomal regions. The deregulation of the biogenesis and expression of miRNAs is involved in the initiation as well as progression of tumors, metastasis formation, and therapy resistance [52]. Furthermore, miRNAs can participate in reprogramming components of the tissue tumor microenvironment (TME) in order to promote tumorgenicity [53]. In the following sections, miRNAs are described as powerful RNAi inducing regulators of immune modulatory genes involved in escape from immune surveillance. Moreover, this review highlights some miRNAs and their roles in immune escape and discusses these miRNAs as putative targets for (immune) therapy (Figure 2).
Figure 2.
Scale of miRNAs targeting immune pathways in cancer exhibit an imbalance of tumor-suppressive miRNAs, which occur more frequent than oncogenic miRNAs as per knowledge from today. Oncogenic miRNA are highly expressed in cancer, while tumor-suppressive miRNAs possess a reduced expression.
6.1. Antigen processing and presentation machinery and miRNAs
Recent studies showed identified miRNAs able to affect the expression of APM components. Microarray analysis of miRNA-9 overexpressing nasopharyngeal carcinoma cells demonstrated that miRNA-9 controls the expression of components of the classical MHC class I pathway. miRNA-9 targets many IFN-induced genes and MHC class I APM molecules, such as the proteasome subunits PSMB8 and PSMB10, TAP1, β2-m, HLA-B, HLA-C, and the nonclassical HLA-F and HLA-H antigens [54]. However, the binding of miRNA-9 to the 3′-UTR of these molecules has not yet been shown. miRNA-9 is involved in the cellular differentiation [55] and aberrantly expressed in many cancer types breast cancer[56], colon cancer [57], nasopharyngeal carcinoma [58], and melanoma [59], suggesting that the decreased miRNA-9 expression is associated with tumor suppressor activity. In contrast, miRNA-9 expression is increased in brain cancer [60] and in Hodgkin’s lymphoma [61], implying an oncomir potential. Furthermore, miRNA-9 has been shown to regulate the proliferation [56, 60-62] epithelial-mesenchymal transition (EMT), invasion and metastasis [62-64], apoptosis [56], tumor angiogenesis [63-64], and evasion of immune surveillance in many cancer types [54]. Although the function of miRNA-9 in the classical MHC class I pathway has still to be characterized in extent, miRNA-9-mediated regulation of APM deficiencies might be at least partially responsible for the T cell-mediated immune escape.
Besides miRNA-9, the ER stress-induced miRNA-346 modulates the expression of APM components and IFN-induced genes as shown by miRNA arrays. Functional studies revealed that TAP1 is a direct target of miRNA-346 using overexpression and RNAi knockdown experiments with miRNA mimic and miRNA inhibitors. The ER stress-mediated MHC class I-associated antigen presentation decrease might be explained by increased miRNA-346 expression [65], although the function of miRNA-346 in cancer has not yet been fully analyzed.
The inflammation and overexpression of miRNA-451 are associated with the carcinogenesis of lung cancer. A decrease in the proliferation, invasion, and metastatic potential of lung cancer cells was detected after the overexpression of miRNA-451. In addition, the proteasome subunit PSMB8 has been identified as a direct target of miRNA-451 using both bioinformatics and dual luciferase reporter assays. This was confirmed by miRNA-451-overexpressing lung cancer cells, demonstrating a reduced PSMB8 protein expression. These data suggest that miRNA-451 inhibits the development and metastasis of lung cancer [66].
There are variations that exist in the 3′-UTR of HLA-C, which modulate the miRNA-binding capacity and consequently the HLA-C surface expression. miR-148a has been shown to bind to the HLA-C 3′-UTR. Next to cancer, the miRNA-148a expression is associated with the control of HIV [67-70]. Furthermore, miRNA-181a is upregulated in Hepatitis B virus infected cells and has a binding site in the 3′-UTR of the HLA-A gene, which might be a target of miRNA-181a [71]. Moreover, viral DNA or RNA can encode miRNAs, e.g., miRNA-US4-1 from the human cytomegalovirus, which targets the aminopeptidase ERAP1, thereby blocking CTL response [72].
6.2. Control of HLA-G and MHC-related proteins by miRNAs
Recently, a number of HLA-G-specific miRNAs have been identified, which belong to the miRNA-148 family consisting of three members, miRNA-148a, miRNA-148b, and miRNA-152. These miRNAs have been shown to act as tumor suppressors in many tumors, including prostate, ovarian, endometrial, and colorectal cancer [69, 73, 74]. In addition, other miRNAs such as miRNA-133, miRNA-548, and miRNA-628 have been identified to inhibit HLA-G expression. The HLA-C-regulating miRNAs are involved in inducing T and/or NK cell responses and have a tumor-suppressive capacity. Moreover, some of the HLA-G-regulated miRNAs are inversely expressed when compared to HLA-G in tumor lesions and are associated with disease progression [74].
The cytotoxicity of NK cells is determined by activating and inactivating signals. The ligands of the activating NK cell receptor NKG2D are the major histocompatibility complex class I-related molecules (MIC) A and B and the human cytomegalovirus UL16-binding proteins (ULBP) [73]. The expression of MICA and MICB is controlled by several oncogenic miRNAs, like miRNA-10b, miRNA-17-5p, miRNA-20a, miRNA-25, miRNA-93, and miRNA-106b, which increase the proliferative, invasive, and angiogenic potential of tumors [73, 75-83] and affect the NK cell cytotoxicity. The tumor-suppressive miRNA-302c, miRNA-376a, and miRNA-433-3p showed a reduced expression in cancer and target the 3′-UTR of MIC [73, 84-87]. Furthermore, the expression of ULBP is regulated by many tumor-suppressive miRNAs, e.g., miRNA-34a/c, miRNA-140-5p, miRNA-302c, miRNA-409-3p, and miRNA-433-p, and by the oncogenic miRNA-650 [73, 83, 85, 87].
6.3. Control of B7 family members by miRNA
The expression of B7 family members is subject to the regulatory control of miRNAs: B7-H1 could act as a costimulatory molecule, which is expressed on B cells, T cells, macrophages, and DCs [88], and acts as a ligand for PDL-1. miRNA-513 targets B7-H1 and inhibits its expression by translational repression [89]. In this context, Tamura and coworkers identified an association between low expression of B7-H2 and the escape from immune surveillance indicating that B7-H2 has a potential role in tumorigenesis. B7-H2 [90] is a direct target of miRNA-24, which inhibits B7-H3 expression and therefore is involved in cancer immune evasion. B7-H3 is an immune regulatory molecule, which is often overexpressed in different cancers and associated with metastasis and poor prognosis [91, 92]. Its expression could be posttranscriptionally regulated by miRNA-29c. The miRNA-29c-mediated downregulation of B7-H3 expression was found in breast cancer and acts therefore as tumor-suppressive miRNA [93]. Furthermore, another B7-H3-regulating miRNA, miRNA-187, has been identified in clear renal cell carcinoma, and its expression is downregulated in this disease [94]. The coinhibitor B7-H4 functions as a negative mediator of immune responses. So far, no information exists about the role of miRNAs in the regulation of B7-H4 expression. In addition, miRNAs binding to the 3′-UTR of B7-H6 have not yet been identified.
6.4. Control of the IFN-γ pathway by miRNAs
The regulation of IFN-γ signaling includes negative as well as positive regulators, such as kinases and phosphatases as well as transcription factors. A main regulatory role of IFN-γ signaling is attributed to miRNAs, affecting genes involved in proliferation, differentiation, signal transduction, immune response, and carcinogenesis [50, 95].
IFN-γ can modulate the expression levels of miRNAs and to regulate miRNAs at the level of miRNA biogenesis [96], whereas miRNAs can inhibit IFN expression directly or indirectly. In addition, studies have confirmed that miRNAs are able to target components of the IFN-γ signaling pathway and components of the JAK/STAT-pathway can regulate miRNAs simultaneously. The latter has been described by controlling miRNA expression via transcription factors, such as c-myc, the hypoxia-induced factor (HIF), and STATs [97]. The contribution and regulatory role of miRNAs in IFN-γ signaling is still under investigation and an emerging research area. Here, to highlight the regulatory function of miRNAs in the IFN-γ signaling pathway, the functional role of miRNA-155 has been described in more detail.
miRNA-155 proceeding from the non-protein-coding transcript of the BIC gene RNA is required for the normal function of B, T, and DC [98. 99], and its expression is increased during B cell, T cell, macrophage, and DC activation [100]. miRNA-155 has been shown to regulate IFN-γ production in NK cells, while its disruption or knockdown suppressed IFN-γ induction of NK cells [101]. Additional studies reported that miRNA-155 also downregulates IFN-γ-R expression [102]. Furthermore, STAT1 upregulates miRNA-155, which in turn downregulates SOCS1, a negative inhibitor of JAK1 [103]. These findings illustrate that a single miRNA can regulate several target mRNAs of the IFN cascade and miRNAs can be regulated by a number of targets.
miRNA regulating components of IFN-γ signaling pathway mainly act as tumor-suppressive miRNAs. An antiproliferative effect of miRNA-375, which affects JAK2 protein expression, has been recently described [104, 105]. Furthermore, miRNA-135a expression was downregulated in gastric cancer cell lines, while its overexpression results in inhibition of gastric cancer cell proliferation by targeting JAK2 [106]. Thus, miRNA-135a may function as tumor suppressor by regulating JAK2 expression in gastric cancer cells [107]. Several studies confirmed other miRNAs targeting JAK2, including miRNA-216a, which is known to inhibit cell growth and promote apoptosis of pancreatic cancer cells by regulating JAK2/STAT3 signaling pathway [108, 109], as well as miRNA-101, which promotes apoptosis of breast cancer cells by targeting JAK2 [110]. Similar results were found for STAT1 and miRNA-145 [111]. miRNA-145 is reported to be downregulated in several cancers [112, 113] and has STAT1 as direct target [111]. Moreover, STAT1 is able to upregulate miRNA-29 family members in melanoma cells, which inhibit melanoma cell proliferation by downregulating CDK6 [114].
Further studies confirmed that miRNA-223 and miRNA-150 are equally involved in IFN-γ signaling, but their role in cancer cells is still controversially discussed. Both miRNA-150 and miRNA-223 could exert oncogenic or tumor-suppressive activity. In hepatocellular carcinoma, acute myeloid leukemia (AML) [115] and gastric mucosa-associated lymphoid tissue lymphoma miRNA-223 expression is repressed [116], while an upregulation of miRNA-223 has been recently described in T-cell acute lymphocytic leukemia (T-ALL) [117]. In this context, Moles and coworkers [118] demonstrated that both miRNA-223 and miRNA-150 target STAT1 3′-UTR and reduce STAT1 expression, which in turn results in reduced expression of IFN-γ-regulated genes. The expression of miRNA-150 is upregulated in CD19+ B cells from chronic lymphocytic leukemia [119, 120], while in chronic myeloid leukemia [121, 122], ALL [123] and mantel cell carcinoma miRNA-150 is downregulated. Moreover, miRNA-150 is upregulated in adult T-cell leukemia/lymphoma cells. This discrepant expression pattern of miRNA-223 and miRNA-150 suggests that both miRNAs could act as oncogenic as well as tumor suppressor miRNAs, which are dependent on the cellular context.
6.5. Role of miRNAs in immune cell function
Cancer cells upregulate and downregulate different miRNAs in immune cells to limit the antitumor response. It is well known that tumor cells reprogram the myeloid compartment to evade the immune system and promote tumorigenesis. This might be partially mediated by alterations in the miRNA expression pattern. The miRNA-155 modulates the immune response mediated by T cells, NK cells, B cells, and antigen presenting cells, such as macrophages and DC [124]. Furthermore, miRNA-155 expression has been found to be downregulated in TAMs [125], but also in hepatocellular carcinoma. The restoration of miRNA-155 in macrophages leads to enhanced T-cell function by targeting the suppressor of cytokine signaling. Other miRNAs, like miRNA-142-3p, miRNA-125b, and miRNA-19a-3p, are often downregulated in TAMs, thereby limiting the tumor infiltration of macrophages and reducing the therapeutic effect of adoptive transfer. The restoration of miRNA-125b in macrophages enhances antitumor response by targeting the IFN-regulatory factor 4, which promotes the M2 macrophage phenotype [126].
Recently, miRNAs have been identified to play a role in MDSC that regulate immune suppression within the tumor microenvironment. miRNA array analysis identified a number of deregulated miRNAs, e.g., miRNA-494, which suppresses the antitumor CD8+ T-cell responses due to response to TGF-β. miRNA-494 targets PTEN in MDSC, which is responsible for the enhanced immune suppression of CD8+ T cells [127]. Furthermore, a number of other miRNAs are downregulated in MDSC [128], which promote the differentiation of myeloid cells and regulate immune-suppressive signaling pathways.
In addition, miRNAs have been demonstrated in tumor-infiltrating lymphocytes. The suppression of T-cell activity is due to different mechanisms, including the dysregulation of miRNA expression. In CD4+ T cells from tumor bearing mice and tumor patients, the expression of miRNA-17-92 family members was reduced, while T cells derived from miRNA-17-9 transgenic mice demonstrated a superior type 1 phenotype [129]. Furthermore, the expression of miRNA-155 was shown to promote antitumor responses. miRNA-155 in combination with miRNA-146a could upregulate the IFN-γ production of T cells. Furthermore, cancer cells could regulate miRNAs in T cells in order to modulate antitumor T-cell responses. In order to escape immune surveillance, cancer cells alter the expression of transcription factors, surface receptors, soluble chemokines/cytokines, and miRNAs to support the immune system. The downregulation of miRNA-124 increases Treg infiltration and reduces cytokines production through an altered expression of STAT3, which represents a target of miRNA-124. In contrast, tumor-secreted miRNA-214 induces Treg. Regarding NK cells, the TGF-β-inducible miRNA-183 affects NK cell activity [130]. Thus, the regulation of miRNAs within the cancer cell alters the TME through manipulation.
7. Conclusion and future perspectives
Taken together, during the past years, the posttranscriptional control of gene expression by miRNAs has gained relevance as key regulator in a wide variety of physiological and pathophysiological processes due to the role of miRNA-mediated RNAi not only in differentiation, proliferation, apoptosis, immune responses but also in viral and bacterial infections as well as neoplastic transformation (Table 1). A deregulated expression of miRNAs has been often found in tumors of distinct origin, which have been classified into oncogenic or tumor-suppressive miRNAs known to play an essential role in cancer initiation and progression. Therefore, these miRNAs could act as potential biomarkers and therapeutic targets in cancer. In silico prediction analysis further proposed that many miRNAs could target different immune modulatory molecules expressed either on tumor cells or on different immune cell subpopulations.
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Table 1.
Identified miRNAs involved in the tumor immune escape and their tumor–associated function. Controversially discussed miRNAs are found as tumor suppressors in some cancer types, while exhibiting oncogenic properties in other cancer types. n.d., no data.
As summarized, an emerging relevance of miRNAs in mounting the tumor immune escape by altering the communication between cancer cells, immune cells, and other components of the TME has been demonstrated. This leads to another level of complexity due to the involvement of miRNAs in the interaction between cancer cells and immune cells. These miRNAs might not only provide new insights into tumor growth and progression as well as antitumoral immune responses but also represent promising therapeutic targets for (immune) therapy. To date, many cancer-deregulated miRNAs have been identified in particular in cancer cells and also in components of the TMA. However, their role in modulating the antitumor immune responses has not yet been characterized in detail. Although the majority of the miRNA alterations detected are dedicated to cancer cells, there is already evidence that miRNAs of infiltrating immune cells also particularly influence tumorgenicity. The identification of further im-miRNAs as well as their functional characterization might lead to a plethora of novel candidate biomarkers for monitoring of immune responses, which might be also potentially used for targeted RNAi therapy.
8. Abbreviations
APC, antigen presenting cell; APM, antigen processing machinery; β2-m, β2-microglobulin; CDKN, cyclin-dependent kinase inhibitor; CTL, cytotoxic T lymphocyte; CXCL, chemokine (CXC motif) ligand; DC, dendritic cell; GAS, IFN-γ-activated sequence; HC, heavy chain; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; ISRE, IFN-stimulated response element; im-miRNA, immune modulatory miRNA; JAK, janus kinase; LMP, low molecular mass polypeptide; MAPK, MAP kinase; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; MIC, major histocompatibility complex class I-related molecule; miRNA, microRNA; NK, natural killer cell; PD, programmed death; PDL, PD ligand; PLC, peptide loading complex; STAT, signal transducer and activator of transcription; SOCS, suppressor of cytokine signaling; TAF, tumor-associated fibroblast; TAM, tumor-associated macrophage; TAP, transporter associated with antigen processing; TGF, transforming growth factor; TLR, toll-like receptor; TME, tumor microenvironment; Treg, regulatory T cell; ULBP, human cytomegalovirus UL16-binding protein; UTR, untranslated region; and VEGF, vascular endothelial growth factor.
Acknowledgments
We would like to thank Sylvi Magdeburg for excellent secretarial help. This work was supported by a grant from the DFG SE585/22-1, GRK1591, GIF (I 1187-69), and Cancer Research Aid (110703).
\n',keywords:"APM, IFN, immune escape, microRNA, tumor microenvironment",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/49613.pdf",chapterXML:"https://mts.intechopen.com/source/xml/49613.xml",downloadPdfUrl:"/chapter/pdf-download/49613",previewPdfUrl:"/chapter/pdf-preview/49613",totalDownloads:1287,totalViews:400,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"May 12th 2015",dateReviewed:"October 20th 2015",datePrePublished:null,datePublished:"April 6th 2016",readingETA:"0",abstract:"Tumors could evade the control of CD8+ T and/or NK cell-mediated surveillance by distinct immune escape strategies. These include the aberrant expression of HLA class I antigens, coinhibitory or costimulatory molecules, and components of the interferon (IFN) signal transduction pathway. In addition, alterations of the tumor microenvironment could interfere with a proper antitumoral immune response by downregulating or inhibiting the frequency and/or activity of immune effector cells and professional antigen presenting cells. Based on the identification as major mediators of the posttranscriptional silencing of gene expression, microRNAs (miRNAs) have been suggested to play a key role in many biological processes known to be involved in neoplastic transformation. Indeed, miRNA expression is frequently deregulated in many cancer types and could have tumor-suppressive as well as oncogenic potential. This review focused on the characterization of miRNAs, which are involved in the control of the immune surveillance or immune escape of tumors and their use as potential diagnostic and prognostic biomarkers as well as therapeutic targets. Moreover, miRNAs can have dual activities by affecting the neoplastic and immunogenic phenotype of tumors.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/49613",risUrl:"/chapter/ris/49613",book:{slug:"rna-interference"},signatures:"Barbara Seliger, Anne Meinhardt and Doerte Falke",authors:[{id:"176780",title:"Prof.",name:"Barbara",middleName:null,surname:"Seliger",fullName:"Barbara Seliger",slug:"barbara-seliger",email:"barbara.seliger@uk-halle.de",position:null,institution:{name:"Martin Luther University Halle-Wittenberg",institutionURL:null,country:{name:"Germany"}}},{id:"178207",title:"MSc.",name:"Anne",middleName:null,surname:"Meinhardt",fullName:"Anne Meinhardt",slug:"anne-meinhardt",email:"anne.meinhardt@uk-halle.de",position:null,institution:null},{id:"178208",title:"MSc.",name:"Doerte",middleName:null,surname:"Falke",fullName:"Doerte Falke",slug:"doerte-falke",email:"doerte.falke@uk-halle.de",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The MHC class I antigen processing and presentation machinery (APM)",level:"1"},{id:"sec_3",title:"3. Immune stimulatory and immune inhibitory molecules and immune response",level:"1"},{id:"sec_4",title:"4. Features of the interferon-γ-mediated signal transduction",level:"1"},{id:"sec_5",title:"5. Distinct levels of tumor immune escape",level:"1"},{id:"sec_5_2",title:"5.1. Alterations of the tumors",level:"2"},{id:"sec_5_3",title:"5.1.1. MHC class I abnormalities",level:"3"},{id:"sec_6_3",title:"5.1.2. Check points as important regulators of immune response",level:"3"},{id:"sec_7_3",title:"5.1.3. Role of IFN-γ in cancer immunogenicity",level:"3"},{id:"sec_10",title:"6. Features of miRNAs",level:"1"},{id:"sec_10_2",title:"6.1. Antigen processing and presentation machinery and miRNAs",level:"2"},{id:"sec_11_2",title:"6.2. Control of HLA-G and MHC-related proteins by miRNAs",level:"2"},{id:"sec_12_2",title:"6.3. Control of B7 family members by miRNA",level:"2"},{id:"sec_13_2",title:"6.4. Control of the IFN-γ pathway by miRNAs",level:"2"},{id:"sec_14_2",title:"6.5. Role of miRNAs in immune cell function",level:"2"},{id:"sec_16",title:"7. Conclusion and future perspectives",level:"1"},{id:"sec_17",title:"8. Abbreviations",level:"1"},{id:"sec_18",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol. 2013;31:443. DOI: 10.1146/annurev-immunol-032712-095910.'},{id:"B2",body:'Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34(11):556. DOI: 10.1016/j.it.2013.07.003.'},{id:"B3",body:'Maj T, Wei S, Welling T, Zou W. T cells and costimulation in cancer. Cancer J. 2013;19(6):473. DOI: 10.1097/PPO.0000000000000002.'},{id:"B4",body:'Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L. 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DOI: 10.1186/1476-4598-10-41.'},{id:"B122",body:'Morris VA, Zhang A, Yang T, Stirewalt DL, Ramamurthy R, Meshinchi S, Oehler VG. MicroRNA-150 expression induces myeloid differentiation of human acute leukemia cells and normal hematopoietic progenitors. PLoS One. 2013;8(9):e75815. DOI: 10.1371/journal.pone.0075815.'},{id:"B123",body:'Xu L, Liang YN, Luo XQ, Liu XD, Guo HX. [Association of miRNAs expression profiles with prognosis and relapse in childhood acute lymphoblastic leukemia]. Zhonghua Xue Ye Xue Za Zhi. 2011;32(3):178.'},{id:"B124",body:'Mashima R. Physiological roles of miR-155. Immunology. 2015;145(3):323. DOI: 10.1111/imm.12468.'},{id:"B125",body:'Squadrito ML, Etzrodt M, De Palma M, Pittet MJ. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol. 2013;34(7):350. DOI: 10.1016/j.it.2013.02.003.'},{id:"B126",body:'Chaudhuri AA, So AY, Sinha N, Gibson WS, Taganov KD, O’Connell RM, Baltimore D. MicroRNA-125b potentiates macrophage activation. J Immunol. 2011;187(10):5062. DOI: 10.4049/jimmunol.1102001.'},{id:"B127",body:'Liu Y, Lai L, Chen Q, Song Y, Xu S, Ma F, Wang X, Wang J, Yu H, Cao X, Wang Q. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol. 2012;188(11):5500. DOI: 10.4049/jimmunol.1103505.'},{id:"B128",body:'Chen S, Zhang Y, Kuzel TM, Zhang B. Regulating tumor myeloid-derived suppressor cells by microRNAs. Cancer Cell Microenviron. 2015;2(1). DOI: 10.14800/ccm.637.'},{id:"B129",body:'Sasaki K, Kohanbash G, Hoji A, Ueda R, McDonald HA, Reinhart TA, Martinson J, Lotze MT, Marincola FM, Wang E, Fujita M, Okada H. miR-17-92 expression in differentiated T cells—implications for cancer immunotherapy. J Transl Med. 2010;8:17. DOI: 10.1186/1479-5876-8-17.'},{id:"B130",body:'Donatelli SS, Zhou JM, Gilvary DL, Eksioglu EA, Chen X, Cress WD, Haura EB, Schabath MB, Coppola D, Wei S, Djeu JY. TGF-beta-inducible microRNA-183 silences tumor-associated natural killer cells. Proc Natl Acad Sci U S A. 2014;111(11):4203. DOI: 10.1073/pnas.1319269111.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Barbara Seliger",address:"barbara.seliger@uk-halle.de",affiliation:'
Institute of Medical Immunology, Martin-Luther University Halle-Wittenberg, Germany
Institute of Medical Immunology, Martin-Luther University Halle-Wittenberg, Germany
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Bacher, Linda Clipson, Leta S. Steffen and Richard B.\nHalberg",authors:[{id:"43769",title:"Prof.",name:"Richard",middleName:null,surname:"Halberg",fullName:"Richard Halberg",slug:"richard-halberg"},{id:"186456",title:"Dr.",name:"Jeff",middleName:null,surname:"Bacher",fullName:"Jeff Bacher",slug:"jeff-bacher"},{id:"194172",title:"Ms.",name:"Linda",middleName:null,surname:"Clipson",fullName:"Linda Clipson",slug:"linda-clipson"},{id:"194173",title:"Dr.",name:"Leta",middleName:null,surname:"Steffen",fullName:"Leta Steffen",slug:"leta-steffen"}]},{id:"52558",title:"Microsatellite Instability in Colorectal Cancer",slug:"microsatellite-instability-in-colorectal-cancer",signatures:"Narasimha Reddy Parine, Reddy Sri Varsha and Mohammad Saud\nAlanazi",authors:[{id:"185797",title:"Dr.",name:"Narasimha Reddy",middleName:null,surname:"Parine",fullName:"Narasimha Reddy Parine",slug:"narasimha-reddy-parine"},{id:"186429",title:"Prof.",name:"Mohammad",middleName:null,surname:"Alanazi",fullName:"Mohammad Alanazi",slug:"mohammad-alanazi"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"67457",title:"Chemical and Biological Characteristics of Ficus carica L. Fruits, Leaves, and Derivatives (Wine, Spirit, and Liqueur)",doi:"10.5772/intechopen.86660",slug:"chemical-and-biological-characteristics-of-ficus-carica-l-fruits-leaves-and-derivatives-wine-spirit-",body:'
1. Ficus carica L. fruits, leaves, and derivatives (wine, spirit, and liqueur)
Ficus carica L. is one of the oldest plants cultivated by humans [1]. It is native to the Southwest Asia and spread worldwide in places with typically mild winters and hot dry summers [2]. Fruits and leaves have been widely used as valuable food for people and as folk medicine due to their therapeutic effects [1, 3]. According to the FAO (2013–2017), most of the world’s fig production occurs in the Mediterranean basin. The 10 main world producers include countries such as Turkey, Egypt, Morocco, Algeria, Iran, and Syrian Arab Republic. Spain is the only European country included in the list, and the American countries, United States of America and Brazil, are also included [4].
Since ancient times, F. carica has been ever present in different cultures. It was the first tree mentioned in the Bible and the figs the first nourishment of human beings according to the Jewish Talmud. Fig tree was linked to the paradise according to the Islamic culture, and in ancient Greece it was considered a gift from Demeter, the earth mother [5].
Figs and leaves are used in their primary and processed form to produce different traditional and industrial products (infusions, jams, wines, spirits, liqueurs, etc.). The fig is a very perishable product, and for this reason it is mainly utilized as dried fruit [6]. Either way, dry or fresh figs are well known for their nutritive value due to the high contents in minerals (mainly calcium and others like copper, manganese, magnesium, potassium, etc.), fats (source of energy), sugars, and other non-nutritive components such as water, fiber, and antioxidants like phenolic compounds [1, 6, 7]. On the other hand, infusions, decoctions, or other preparations of fig leaves have been traditionally used in the treatment of different diseases due to the therapeutic effects associated with its chemical composition [8]. For all the aforementioned, F. carica has been included in occidental pharmacopeias (such as the Spanish and British pharmacopeias) and in therapeutic guides of herbal medicine (including the Physician’s Desk Reference (PDR) for herbal medicine) [9].
The study of the extraction of phytochemicals from plants and the use of these compounds as additives has been of great importance as an efficient and safe way to add supplements in foods, to produce what is known as nutraceutical and functional food (food with a relevant effect on health or reduction in disease risk) [10]. More recently, the main objective of F. carica phytochemicals extraction has been based not only on finding the best extraction conditions but also the use of green extraction methods such as ionic liquids or deep eutectic solvents, environmentally friendly and sustainable for sample preparation [8]. Despite all the properties and uses found in raw materials, the scarce amount of works related to the chemical composition and biological activities of alcoholic products derived from fig fruits and leaves, specifically, wine [11, 12, 13], spirits [14, 15, 16, 17], and liqueurs is worth mentioning [18, 19]. Furthermore, despite the mentioned characteristics of the leaves and the great tradition in using this part of the plant in the production of liqueurs [20], this is not reflected in the works cited. An outline of the process followed in the production of these beverages from the raw materials of F. carica to the final product can be seen in Figure 1. In all these products, the biotechnological step of alcoholic fermentation is required to transform the sugars present in the fruit into alcohol and produce the value-added corresponding alcoholic beverages of commercial importance. The use of yeasts (endogenous or exogenous) and controlled conditions (pH, temperature, etc.) is necessary to obtain a high-quality final product. In addition, during this fermentation process, and other processes taking place such as maceration and maturation of the beverage, new chemical compounds are produced that will contribute to the final profile of the beverages [21, 22].
Figure 1.
Manufacturing process of Ficus carica L. wine, liqueur, and spirit from raw materials to the final beverage.
In the next section, the different chemical compounds (phytochemicals) as well as the biological properties from both F. carica raw materials and alcoholic-derived products will be addressed in more detail.
2. Phytochemical composition of fig fruit, leaf, and the alcoholic products, liqueurs, and spirits
Phytochemicals or plant secondary metabolites are non-nutritive plant metabolites which are essential for plant survival and proper growth and reproduction [23]. Many of these components have bioactivities toward animal biochemistry and metabolism with the ability to provide health benefits. F. carica plant owns the highest diversity of compounds with the higher quantities of all classes of compounds (except aldehydes and monoterpenes) mainly in leaves, followed by fruits pulps and peels [2, 9, 24].
Phytochemical studies on raw materials (fruits and leaves) and derived products (wine, liqueur, and spirit) of F. carica revealed the presence of numerous bioactive compounds including volatiles, organic acids, phytosterols, triterpenoids, fatty acids, phenolic acids, flavonoids, coumarins, and few other classes of secondary metabolites shown in Figure 2.
Figure 2.
Chemical structures of different phytochemicals (volatile compounds, organic acids, triterpenoids, sterols, fatty acids, phenolic acids, flavonoids, and coumarins) present in fig fruits, leaves, spirits, and liqueurs.
2.1 Volatile compounds
Aroma is an important attribute of the sensory appreciation of a product and is usually used as a criterion for its quality assessment. It is a defining element of the distinct flavor of individual foods. The ripening period has an important role in the volatile composition, and many volatiles are produced during different developmental stages of plant tissues such as flowering, ripening, or maturation [1]. These volatiles are known as primary aromas, and they are responsible for varietal aromas [25]. These compounds are accumulated in plant storage sites and are released from the surface of the leaf, making this part of the F. carica the largest holder of compounds (except aldehydes and monoterpenes, in highest amounts in fruits [9]). On the other hand, in products such as wine, spirits, and liqueurs elaborated from fruits of F. carica, other types of aromas come from the different processing steps. Secondary aromas (the greatest pool of volatiles) are mainly produced by yeast as metabolism by-products, while tertiary aromas of finished alcoholic beverages are compounds that illustrate the changes made in the sample matrix during the storage and maturity stages [25].
Fruits [1, 2, 26, 27] and leaves [2, 8] of F. carica as well as derived products such as the alcoholic beverages, fig liqueurs [28], and spirits [14, 15, 17] consist of various volatile compounds which are identified and distributed by distinct chemical classes, such as terpenes (monoterpenes and sesquiterpenes), alcohols, aldehydes, ketones, esters, and miscellaneous compounds.
2.1.1 Terpenes
Terpenes, such as monoterpenes (C10) and sesquiterpenes (C15), are the largest class of plant secondary metabolites, as can be seen in Figure 2. The high vapor pressures of these compounds, at normal atmospheric conditions, allow their significant release into the air [1]. Monoterpenes such as linalool (1) and epoxylinalool (34) (more important than linalool) are related with their important role in the attraction of specific pollinators, the fig/wasp linkage [1]. Although sesquiterpenes represented just the ∼3% of the total volatiles in Tunisian cultivars, it was the main class of compounds identified in leaves, and germacrene D, β-caryophyllene, and τ-elemene are the major compounds detected [9].
α-Pinene (31), one of the main monoterpenes mentioned in different works, has only been found in fruits, while the sesquiterpenes β-elemene (39), β-cubebene (60), α-ylangene (61), β-bourbonene (62), (+)-ledene (viridiflorene) (66), and α-gurjunene (67) are compounds exclusively identified in leaves [1, 2, 9]. The monoterpenes citronellol acetate (7), (E)-geranyl acetone (12), (+)-sylvestrene (16), p-mentha-1,3,8-triene (17), cumene (26), o- and p-cymene (27, 28), and nerol oxide (33) and the sesquiterpenes (E)-nerolidol (35), farnesyl acetate (36), α-curcumene (37), β-bisabolene (38), τ-elemene (40), (−)-δ-cadinol (45), cadina-1 (10),4-diene (48), cadalene (49), α-calacorene (50), valencene (51), acoradiene (53), δ-guaiene (α-bulnesene) (55), α-guaiene (56), isocaryophyllene (57), γ-patchoulene (65), and α-cedrene (68) are compounds only identified in Portuguese monovarietal fig spirits [14]. Linalool acetate (2), geraniol (4), (Z)-8-hydroxylinalool (5), neral (β-citral) (6), geranyl vinyl ether (8), ethyl linalool (9), nerol (10), dihydrocitronellol (11), geranial (α-citral) (13), ocimene (14), p-menth-3-ene (19), α-terpinolene (21), α-terpineol (23), pulegone (24), isodihydrocarveol (25), borneol (30), and (Z)- or (E)-linalool oxide (34), as monoterpenes, and cadina-1,4-diene (47) and dihydroactinidiolide (52), as sesquiterpenes, were identified in synthetic liqueurs elaborated from different Greek F. carica varieties [28].
On the other hand, common terpenes were found in different F. carica parts and/or fig spirits and synthetic liqueurs. Menthol (18), τ-muurolene (44), and τ-cadinene (46) are common compounds found in fruit and leaves [2, 9]. The monoterpenes β-pinene (32) and eucalyptol (29) and the sesquiterpene (E)-α-bergamotene (54) were identified in different fig cultivars from different countries and also in fig liqueurs, while the monoterpenes linalool (1) and linalool oxide (furanoid) (epoxylinalool) (34) were isolated in fig fruits and spirits [2, 9, 28].
Other common terpenes were identified in different fig samples such as α-terpinene (20) in fig spirits and synthetic liqueurs; limonene (15), α-cubenene (59), copaene (63), and germacrene D (41) in fig fruits, leaves, and spirits; α-guaiene (57), aromadendrene (64), and α-muurolene (43) in fig leaves and spirits; and finally, β-caryophyllene (58) in fruit, leaves, spirits, and synthetic liqueurs, while α-caryophyllene (42) in fig leaves, spirits, and synthetic liqueurs [1, 2, 9, 14, 28].
2.1.2 Alcohols, aldehydes, ketones, and esters
Alcohols, ketones, and esters are the more developed compound classes in ripened fruits, representing 41% of total aroma [1].
Different alcohols were identified in fruits [(Z)-3-hexen-1-ol (78)], leaves [2-methyl-1-butanol (76) and 1-heptanol (80)], spirits [methanol (69), ethanol (70), 1-propanol (71), 1-butanol (72), 2-methyl-propanol (isobutyl alcohol) (74), 1-hexanol (79), octanol (81), and decanol (83), among others], in both fruits and leaves [1-penten-3-ol (75), benzyl alcohol (85), and (E)-2-nonen-1-ol (82)] [2, 9], leaves and spirits [1-heptanol (80)] [9, 14], and finally in raw materials and spirits [3-methylbutanol (77), phenylethyl alcohol (84)] [2, 9, 14, 15]. Methanol (69), a toxic compound formed by hydrolytic demethoxylation of esterified methoxyl groups of the pectin polymer by pectic enzymes, with a marked maximum methanol content in fruit spirits of 1500 g/hL of pure alcohol (Regulation (EC) No 110/2008), was present in fresh and dried fig spirits [14]. It should be emphasized that its concentration depends on the technological characteristics of the manufacturing process. Higher quantities were found in spirits prepared from fresh figs because this compound is naturally present in fruits and decreased in spirits prepared using fermentations with immobilized yeast cell technology [15]. In addition, greater amounts of higher alcohols [2-butanol (73) + 1-propanol (71) + 2-methyl-propanol (74) + butanol (72) + 2-methylbutanol (76) + 3-methylbutanol (77)] were also found in samples of spirits made from dried figs (approx. > 350 g/hL absolute alcohol), being indicative of worse quality of these samples [14].
The aldehydes present exclusively in fruits are heptanal (92), octanal (95), nonanal (96), 2-methyl-butanal (87), (Z)-2-heptenal (93), (E, E)-2,4-heptadienal (94), (E)-2-octenal (97), and (E, Z)-2,6-nonadienal (98) [2, 9]. Furfural (99) and 5-hydroxymethylfurfural (100), toxic compounds originated during the fired pot-still distillation process at high temperatures, and acetaldehyde (86) were identified in spirits [14, 15]. Meanwhile, common aldehydes identified in fruits and leaves were 2-methyl-butanal (87), 3-methyl-butanal (88), (E)-2-pentenal (89), hexanal (90), and (E)-2-hexenal (91); benzaldehyde (101) was present in fruits and spirits [2, 9].
The first major compound found in non-pollinated and pollinated figs was the ketone 3-hydroxy-2-butanone (acetoin) (102) [1]. Other ketones, 6-methyl-5-hepten-2-one (104) and 3-pentanone (103), were identified in, respectively, fruits (pulps and peels) and leaves of Portuguese fig varieties [2, 9].
Esters are the major contributors to fruit aroma and are the most important in ripe figs. They are produced through the esterification of alcohols and acyl-CoAs derived from both fatty acid and amino acid metabolism, in a reaction catalyzed by the enzyme alcohol-o-acyltransferase [1]. These compounds are much less developed in non-pollinated fruits, and its content decreases when using immobilized cell application during the fermentation process. In spirits, esters represent the largest class of volatiles (∼95% of total volatiles), particularly the fatty acid ethyl esters such as ethyl decanoate, ethyl octanoate, and ethyl dodecanoate. The second and third major compounds identified in fruits from Tunisian varieties were butyl acetate (108) and isoamyl acetate (107) with banana odor [1]. This last compound was also present in fig spirits [14]. Other ester identified in fruits was ethyl salicylate (113). Methyl butanoate (106), hexyl acetate (110), and ethyl benzoate (111) were found in leaves [2, 9], while methyl hexanoate (109) was a common compound in fruits and leaves and methyl salicylate (113) in fruits, leaves, and spirits [2, 9, 14]. Many methyl and ethyl esters and other esters were identified in fig spirits and are common to other alcoholic beverages. The study comparing dried and fresh fig spirits showed that dried fig spirits presented ethyl acetate (105) in higher proportion than fresh fig spirits. This compound results from the growth of acetic acid bacteria during the fermentation in aerobic conditions [14].
2.1.3 Miscellaneous compounds
The norisoprenoid β-cyclocitral (114) present in leaves and fruits [2, 9] and β-damascenone (115) characteristic of different fig spirits and synthetic fig liqueurs [14, 28] and finally the phenylpropanoids [(eugenol (116), cinnamic alcohol (117), cinnamic aldehyde (118)] and indole (120) in fruits [9] and s-nonalactone (119) [2] in leaves were other volatile compounds detected in different fig samples.
2.2 Organic acids, phytosterols, triterpenoids, and fatty acids
Some organic acids isolated from fruits and leaves of F. carica were the shikimic (122), malic (123), oxalic (124), fumaric (125), and citric (126) acids [2, 9, 24, 29], while the quinic acid (121) was reported only in leaves [2, 9].
Phytosterols are found in most plant foods, with the highest concentrations occurring in vegetable oils. Sterols (modified triterpenes) like β-sitosterol (137) [24] and the triterpenoids methyl maslinate (127), oleanolic acid (128), taraxasterol (129), w-taraxasterol ester, calotropenyl acetate (130), bauerenol (131), 24-methylenecycloartanol (132), lupeol (133), and lupeol acetate (135) have been reported in fig leaves [2, 9], and betulinic acid (134) in fruits [3], while stigmasterol (136) was reported in both [29, 30].
Dried and fresh fruits of F. carica showed polyunsaturated fatty acids with 84 and 69% of total fatty acids, respectively. Linoleic acid (139), in fresh and dried fruits, was the only polyunsaturated fatty acid identified. With respect to monounsaturated fatty acids, oleic acid (138) is the most abundant in fruits [9].
2.3 Phenolic acids, flavonoids, and coumarins
Among the different chemical structures found in F. carica, one of the most important for biological uses is the phenolic compounds. These play many physiological roles in plants and are also favorable to human health [2]. Fruits and leaves presented qualitative differences in phenolic acids. Leaves were richer in phenolic derivatives formed by conjugation with sugars (the hydroxybenzoic derivatives: gallic acid di-pentoside, syringic acid hexoside, vanillic acid hexoside deoxyhexoside, and the dihydroxybenzoic acids hexoside/hexoside pentoside) and organic acids including malic (the hydroxybenzoic derivative, syringic acid malate, and the hydroxycinnamic derivatives, caffeoylmalic acid, coumaroylmalic acid, sinapic acid malate, and ferulic acid malate) and quinic acid (the hydroxycinnamic derivative coumaroylquinic acid) [31, 32]. The signal of hydroxycinnamics was higher in extracts from leaves. On the other hand, in general, free forms of hydroxycinnamic acids such as caffeic acid (141), and the hydroxybenzoic acids, gallic (148) and syringic (149) acids, were only present in fruits [32]. Also the ferulic acid hexoside and the coumaroyl and ferulic hexosides were present in fruits. Moreover, the following compounds were common to both leaves and fruits: the hydroxybenzoic acids, di-/hydroxybenzoic acids and vanillic acid; the hydroxybenzoic derivatives, dihydroxybenzoic acid attached to hexoside/hexoside pentoside/pentoside/di-pentoside, vanillic acid glucoside, and gallic acid di-pentoside; and the hydroxycinnamic acids, ferulic acid (140) and the chlorogenic (3-O-caffeoylquinic acid) (144) and neochlorogenic (5-O-caffeoylquinic acid) (145) acids. The common hydroxycinnamic derivatives present in fruits and leaves were caffeoylquinic acid hexoside, dihydrocaffeic acid hexose, and the sinapic acid hexoside [2, 9, 24, 32].
Flavonols such as quercetin (151) and glycosylated flavonols such as rutin (quercetin-3-O-rutinoside) (154) (major individual phenolic identified in fruits [2]), isoquercetin (quercetin-3-O-glucoside) (155), quercetin 3-O-(6′-O-malonyl)-glucoside (157), quercetin di-deoxyhexoside hexoside, and quercetin O-di-hexoside were confirmed in fresh and dried figs and leaves [32]. Nicotiflorin (kaempferol-3-O-rutinoside) (152) and quercetin-acetilglucoside (156) were reported in fruits, while astragalin (kaempferol 3-O-glucoside) (153) only in leaves [2, 3, 9, 24, 31, 33].
Free flavones such as luteolin (158) and apigenin (159) are present in fig fruits and leaves. Also, the glycosylated flavones, isoorientin (luteolin 6-C-glucoside) (160), orientin (luteolin 8-C-glucoside) (161), cynaroside (luteolin 7-O-glucoside) (162), vitexin (apigenin 8-C-glucoside) (164), isochaftoside (apigenin 6-C-glucoside 8-C-arabinoside) (165), and apigenin 6-C-hexose-8-C-pentose [which could be identified as schaftoside (apigenin 6-C-glucoside 8-C arabinoside)], were detected in both plant parts. However, apigenin 7-rutinoside (163) and luteolin 6C-hexose-8C-pentose were present in fruits [2, 9, 33].
Another group of flavonoids identified was the flavanones, with the compounds eriodictyol (166) and eriodictyol hexoside in fruits and naringenin (167) in fruits and leaves. The flavanonol taxifolin (dihydroquercetin) (168) was identified in fruits [32]. The flavanols, (+)-catechin (169) in fruits and leaves and (−)-epicatechin (170) in leaves, were also identified [3, 33].
Genistein (173) and hydroxygenistein methyl ether malonylhexoside in leaves and prenylhydroxygenistein, prenylgenistein (171), biochanin A (genistein 4′-methyl ether) (172), and cajanin (7-methoxy 2′-hydroxy genistein) (174), in fruits and leaves, were the isoflavones identified [2, 3, 9, 24, 31, 33].
Different anthocyanin pigments, some of them containing cyanidin or pelargonidin as aglycones, as well as rutinose and glucose substituting sugars and acylation with malonic acid, were found in skin and pulp from different varieties of Iberian fresh figs with different colors (black, red, yellow, and green). These compounds include (epi)-catechin-(4-8)-cyanidin-3-glucoside, (epi)catechin-(4?8)-cyanidin-3-rutinoside,(epi)catechin-(4,8)-pelargonidin 3-rutinoside, 5-carboxypyranocyanidin-3-rutinoside, cyanidin-3-malonylglicosyl-5-glucoside, cyanidin-3-malonylglucoside, cyanidin-3-glucoside (175), cyanidin-3,5-diglucoside (176), cyanidin 3-O-rutinoside (as the main anthocyanin in different commercial fig varieties [2]) (178), pelargonidin-3-glucoside (179), pelargonidin-3-rutinoside (180) and peonidin-3-rutinoside (181). In addition, 5-carboxypyranocyanidin-3-rutinoside, a cyanidin 3-rutinose dimer, and five condensed pigments containing C–C linked anthocyanins and flavanol (catechin and epicatechin) residues were identified [9].
Coumarin (182); the hydroxycoumarins esculetin hexoside, dihydroxycoumarin, umbelliferone (7-hydroxycoumarin) (183), and prenyl-7-hydroxycoumarin; and the furocoumarins psoralen (187) and bergapten (5-methoxypsoralen) (188) were isolated from F. carica fruits and leaves [32]. Simple coumarins 6-carbaxyl-umbelliferone, phellodenol A (184), and murrayacarpin B (185) and the furocoumarins hydroxypsoralen, hydroxypsoralen hexoside, 4′,5′-dihydropsoralen (190), angelicin (isopsoralen) (189), isopentenoxypsoralen, oxypeucedanin, psoralic acid glucoside and marmesin (191) were isolated from leaves [2, 9, 31, 32].
3. Biological studies in fruit, leaf, and fig spirits and liqueurs
The leaves and fruits of F. carica are important in traditional medicine [24]. Many biological activities have been evaluated and confirmed on F. carica extracts, and the bioassay-guided fractionation in most cases allowed to assign the chemical structures responsible of such biological effects, thereby ratifying some of its folkloric uses [9]. In this section we analyzed the potential health-promoting constituents of fig fruits, leaves, and derived products, fig liqueurs, and spirits [6].
3.1 Antioxidant capacity
Among the different phytochemicals studied in F. carica, phenolic compounds are among the most important with antioxidant capacity (AC). Many of these compounds are able to act as antioxidants by different ways: reducing agents, hydrogen donators, free radical scavengers, singlet oxygen quenchers, and so forth [2].
3.1.1 Fig spirits and liqueurs
The antioxidant capacity (AC) by ABTS [2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonate)] and DPPH (1,1-diphenyl-2-picrylhydrazyl) assays and the total phenolic content (TPC) by Folin–Ciocalteu method were evaluated in different fig spirits and liqueurs [34]. Fig liqueurs showed high values of TPC and AC (ABTS), close to the values of other fruit spirits with highest AC such as green walnut, carob pod, and mulberry. Fig spirits presented high (third value of 15 samples) AC by ABTS assay and among the highest TPC values. However, no DPPH scavenging activity was shown for fig liqueurs and spirits.
3.1.2 Leaf extracts
The maximum total flavonoid content (25.04 mg/g) with marked scavenging activities against hydroxyl and superoxide anion free radicals in a concentration-dependent manner were found in ethanolic (40%) leaf extracts of F. carica (solid to liquid ratio 1:60 g/mL, temperature extraction of 60°C, and 50 min of ultrasonic treatment) [6].
3.1.3 Fruit extracts
Several works studied the AC of fruit extracts. Extracts from six commercial fig varieties were evaluated for AC by ferric reducing antioxidant method (FRAP) and also for TPC and total flavonoid content (TFC) and amount and profile of anthocyanins. The extracts exhibiting the highest AC contained the highest levels of TPC and TFC and anthocyanins (cyanidin-3-O-rutinoside as the main compound) [2, 6]. In another work, two fruit extracts [water (WE) and crude hot water-soluble polysaccharide (PS)] were evaluated for AC using the in vitro scavenging abilities on DPPH, superoxide, and hydroxyl radicals and reducing power assays. Both extracts have notable scavenging activities on DPPH [WE (EC50, 0.72 mg/ml) and PS (EC50, 0.61 mg/ml)], while PS showed highest scavenging activity on superoxide radical (EC50, 0.95 mg/ml) and hydroxyl anion radical (43.4% at concentration of 4 mg/ml) [6].
Ethanolic extracts from the white Beni Maouche Algerian figs were compared with carob pods and holm oak acorns [7]. Fig extracts presented lower efficacy to scavenge DPPH (20.54 ± 0.30%) than ABTS radicals (68.98 ± 0.12%) and higher reducing ability in phosphomolybdenum assay (638.23 ± 0.43 mg GAE/100 g). This extract (73.17 ± 0.16%) also inhibited the formation of the complex Fe2+-ferrozine and was also able to scavenge H2O2 efficiently. The extracts from the three fruits evaluated (carob, acorns, and figs) showed no significant differences in nitric oxide (NO) radical scavenging activities [7].
3.2 Reactive oxygen species production, xanthine oxidase inhibition assay, and study of oxidative stress
3.2.1 Fruit extracts
The production of reactive oxygen species (ROS) in the presence of ethanolic fig extract was measured by chemiluminescence using lucigenin. This method is widely used to determine the rate of superoxide radicals in human neutrophils. Fig extract inhibited the chemiluminescence of lucigenin and ROS production and differed from each other according to the concentration of the sample and the incubation time. After 15 min of treatment, the extract tested at the highest concentration (250 μg/mL) seemed to reach its higher level of lucigenin inhibition, value 44% below that obtained with diphenylene iodonium (0.2 mM), the standard selective inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase tested [7].
Ethanolic fig extracts were able to inhibit the activity of the enzyme xanthine oxidase (XO), an enzyme that generates reactive oxygen species. Different extract concentrations were evaluated (50, 250, and 500 μg/mL), and at 250 μg/mL, ethanolic extracts presented the best inhibition, although its value is much lower (practically half) of that obtained with the positive control allopurinol, a drug clinically used for gout treatment. The extracts tested at 500 μg/mL showed a decrease in the inhibition of XO activity as the result of its prooxidant effect. The strong correlation coefficients between XO inhibition activity and phenolic compounds and flavonoids demonstrate the inhibition activity of XO [7].
3.2.2 Leaf extracts
Oxidative stress is the disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses. The role of these free radicals in the production of tissue damage in diabetes mellitus was studied in rats divided into four groups: streptozotocin-induced diabetic rats, diabetic rats that received a single dose of a basic fraction of F. carica leaf extract, diabetic rats that received a single dose of a chloroform fraction of the extract, and normal rats. Antioxidant status was affected in the diabetes syndrome, and F. carica extracts showed that they normalize it. Diabetic animals exhibited higher values for erythrocyte catalase activity, plasma levels of vitamin E, monounsaturated and polyunsaturated fatty acids, saturated fatty acids and linoleic acid than that of the control group. Both F. carica fractions showed that they normalize the values of the diabetic animal’s fatty acids and plasma vitamin E values. They showed statistically significant differences as a function of diabetes with the vitamin E/C 18:2 ratio being normalized by the administration of the chloroform fraction (to 152.1 ± 80.3 μg/mg) and the vitamin A/C 18:2 ratio being raised relative to the untreated diabetic rats by the administration of the basic fraction (91.9 ± 14.5 μg/mg) [2].
3.3 Inhibitory activities of the enzymes α-amylase, α-glucosidase, and pancreatic lipase
3.3.1 Fruit and leaf extracts
The treatment of diabetes and obesity using the inhibition of carbohydrate (α-amylase and α-glucosidase) and lipid (pancreatic lipases)-digesting enzymes is used to reduce the digestion and absorption of carbohydrates and lipids and also to reduce significantly the blood glucose and body fat levels. Ethanolic extracts from fruits and leaves, in relation to hexane, ethyl acetate, and aqueous extracts, presented the higher α-amylase and α-glucosidase and pancreatic lipase inhibitions at the higher concentration tested (500 μg/mL). At this concentration, similar values to that of the standard acarbose were found for α-amylase and α-glucosidase inhibitions in fruit ethanolic extracts [35].
3.4 Antidiabetic, hypocholesterolaemic, and hypolipidemic activities
3.4.1 Leaf extracts
Different works on antidiabetic activity were carried out using methanolic and aqueous leaf extracts [2, 6]. The maximum glucose-lowering effect in induced diabetic rats with alloxan was observed with methanolic extracts at a concentration of 200 mg/kg and after 21 days. At these conditions, results were similar to those obtained with metformin (medication used for the treatment of type 2 diabetes). On the other hand, a clear hypoglycemic effect and reduction of total cholesterol and total cholesterol/HDL cholesterol ratio of the oral or intraperitoneal administration of aqueous leaf extracts in relation to the control group was observed in diabetic rats induced with streptozotocin.
In other work, an 8-week-old rooster’s liver with high abdominal fat was used to evaluate the potential of leaf fig extract as food supplement to decrease hepatic triglyceride (TG) content and secretion of TG and cholesterol from the liver. Results showed that the leaf extract reduced the contents to the basal level in a concentration-dependent manner [2]. Another work about the intraperitoneal administration of leaf decoction extracts (50 g dry wt/kg body wt) in hypertriglyceridemia-induced rats with 20% emulsion of long chain triglycerides (LCTG) indicated a decrease in the LCTG content of 84% after 60 min and a reduction of 69% after 2 h. The results suggest the existence of compound/s in fig leaf decoction that influence the lipid catabolism [6].
3.5 Hepatoprotective activity
3.5.1 Leaf extracts
The hepatoprotective activity of methanolic leaf extract in carbon tetrachloride-induced hepatotoxicity in rats was evaluated, and the activity was comparable to that of the known hepatoprotective silymarin [6].
Petroleum ether leaf extract also showed significant reversal of biochemical, histological, and functional changes in oral rifampicin (50 mg/kg)-induced hepatotoxicity in rats [2].
3.6 Anti-herpes simples virus (HSV)
3.6.1 Leaf extracts
Water leaf extract presented low toxicity and directly killing virus effect of HSV on baby hamster kidney fibroblasts (BHK21), primary rat kidney (PRK), and human epithelial (Hep-2) cells with a maximum tolerated concentration (MTC) of 0.5 mg/mL [2]. Ethyl ethanoate and hexane fractions of methanolic extracts also showed anti-HSV-1 effect [24].
3.7 Immunomodulatory activity
3.7.1 Leaf extracts
Administration of ethanolic leaf extract presented immune modulatory activity in cellular and humoral antibody response according to various hematological and serological tests [6].
3.8 Anti-inflammatory activity
3.8.1 Leaf extracts
Different (petroleum ether, ethanolic, and chloroform) leaf extracts showed a significant reduction on carrageenan-induced paw edema in rats and a greater anti-inflammatory effect in relation to indomethacin, a standard nonsteroidal drug used for this effect [6].
3.9 Irritant potential
3.9.1 Leaf extracts
Methanolic leaf extract and isolated triterpenoids [methyl maslinate (127), calotropenyl acetate (130), and lupeol acetate (135)] exhibited irritant potential on open mice ears and were the most potent and persistent irritant effects [2].
3.10 Antimicrobial, nematicidal, and anthelmintic activities
3.10.1 Leaf extracts
Methanolic leaf extracts showed strong antibacterial activities against oral bacteria, Streptococcus gordonii, S. anginosus, Prevotella intermedia, Actinobacillus actinomycetemcomitans, and Porphyromonas gingivalis, with minimum inhibitory (MIC) and bactericidal (MBC) concentrations of 0.156–0.625 mg/ml and 0.313–0.625 mg/ml, respectively. These antibacterial effects may be related to some phenolic compounds isolated such as flavonoids [6]. Acetone leaf extract possessed antibacterial activity against Staphylococcus species and antifungal activity against Fusarium solani, F. lateritium, F. roseum, Daporuthe nonurai, and Bipolaris leersiae [24]. Leaf extract also showed strongest nematicidal activity against the nematodes Bursaphelenchus xylophilus, Panagrellus redivivus, and Caenorhabditis elegans with 74.3, 96.2, and 98.4% mortality, respectively, within 72 h [2].
3.10.2 Fruit extracts
Fruit extract was found useful in protecting from bacterial pathogen attack in tomatoes [6]. Anthelmintics are drugs that either kill or expel infesting helminths living in the gastrointestinal tract or tissues. Helminths cause numerous damages to the host, for example, injury to organs, intestinal or lymphatic obstruction, causing blood loss, depriving it of food, and secreting toxins [36]. The potential of cysteine proteinases extracted from figs as a potential anthelmintic was evaluated. The experiments were carried out in vitro using the rodent gastrointestinal nematode Heligmosomoides polygyrus. A marked damage was visible within a 2-h incubation period of cysteine proteinases on the cuticle (loss of surface cuticular layers) of adult male and female H. polygyrus worms. The results (efficacy and mode of action) proved the potential use of cysteine proteinases as anthelmintics [6].
3.11 Antipyretic activity
3.11.1 Leaf extracts
To evaluate the antipyretic activity, different doses (100, 200, and 300 mg/kg body wt. p.o.) of ethanolic leaf extracts showed significant dose-dependent reduction in normal body temperature and yeast-induced elevated temperature (pyrexia) in albino rats. The antipyretic effect of this extract was comparable to that of the standard antipyretic agent paracetamol at 150 mg/kg body wt., p.o. The effect extended up to 5 hours after drug administration compared to that of paracetamol (150 mg/kg.b.wt., p.o.) [2, 6].
3.12 Antituberculosis activity
3.12.1 Leaf extracts
Colorimetric microplate-based assay of methanolic (80%) leaf extract exhibited effect against Mycobacterium tuberculosis strain H37Rv with MIC value of 1600 μg/mL [2].
3.13 Anti-calpain activity
3.13.1 Fruit extracts
Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. These enzymes have been linked to the modulation of memory and are keys to the pathogenesis of Alzheimer disease [37]. Calpain activity was examined after treatment of cells with dry extracts. Fig extracts decreased the fluorescence of the fluorogenic calpain substrate tert-butoxycarbonyl-Leu-Metchloromethylaminocoumarin (t-boc-LM-CMAC) and consequently inhibited the activity of calpain. Fig extracts showed the same capacity to inhibit calpain as carob and holm oak acorn extracts. The incubation time (2, 4, and 6 h) and the concentrations tested (25, 100, and 250 μg/ml) had no effect on the inhibitory activity of calpain in the presence of fig extracts. After 2 h of treatment, the extracts already inhibited more than 50% for all the concentrations tested. This inhibitory activity of the studied extracts could be attributed to its chemical composition that contains several antioxidant groups, especially phenolic compounds such as flavonoids and flavonols [7].
3.14 Diuretic activity
3.14.1 Fruit extracts
Ethanolic fruit extracts were evaluated for the diuretic activity on individual rat through the control of the parameters, total urine volume, and urine concentration of Na+, K+, and Cl−. Results showed a marked diuresis of ethanolic fruit extract treatment in rats based on the increase in urine volume and cation and anion excretions [6].
3.15 Immunity activity
3.15.1 Fruit extracts
The immunity activities of crude hot water-soluble polysaccharide (PS) were evaluated using the carbon clearance test and serum hemolysin analysis in mice. The PS (500 mg/kg) had a significant increase in the clearance rate of carbon particles and serum hemolysin level of normal mice [6].
3.16 Antispasmodic activity
3.16.1 Fruit extracts
Fig aqueous-ethanolic extract was investigated for antispasmodic effect (suppression of muscle spasms) on rabbit jejunum preparations. The extracts (0.1–3.0 mg/mL) produced relaxation of spontaneous and low K+(25 mM)-induced contractions and with insignificant effect on high K+ (80 mM). Similar results were observed with cromakalim, a potassium channel-opening vasodilator. This spasmolytic activity of F. carica fruits is probably due to the activation of K+ATP channels [2, 6].
3.17 Antiplatelet activity
3.17.1 Fruit extracts
Proteases derived from fig aqueous-ethanolic extract were investigated on human blood coagulation using ex vivo model of human platelets from volunteers free of medications for 1 week. Extracts at 0.6 and 1.2 mg/mL repressed the human platelet aggregation with the agonists adrenaline and adenosine 5′-diphosphate (ADP). Ficin, a mixture of proteases derived from figs, seems to be responsible for the activation of blood coagulation factor X (vitamin K-dependent plasma glycoprotein with pivotal role in hemostasis) [2, 6, 38].
4. Conclusions
Since ancient times, the fruits and leaves of F. carica have been used as food and for their different therapeutic effects. In recent years several scientific works have analyzed the chemical composition of both parts of the plant to know more in depth the phytochemical compounds responsible for the biological properties demonstrated in several in vitro and ex vivo tests. In addition, the use of new environmentally friendly extraction processes, such as ionic liquids or deep eutectic solvents, and the use of fig phytochemicals as additives for new food applications (nutraceuticals and functional foods) are highly researched topics in recent times. However, research on different alcoholic beverages derived from both parts of the plant, such as wine, liqueur, and spirit, is still scarce. These beverages represent an important source of sustenance for the local economy of different countries from the Mediterranean basin, so that their study could provide an improvement in the quality of the products and publicize the chemical and biological properties derived from their consumption.
Acknowledgments
This work received financial support from the project INTERREG—MD.Net: When Brand Meets People. R. Rodríguez-Solana acknowledges the financial support from the Foundation for Science and Technology, Portugal (Grant SFRH/BPD/103086/2014).
Conflict of interest
The authors declare no conflicts of interest.
\n',keywords:"antioxidant capacity, biological activities, enzyme inhibitory activity, fig fruit, fig leaf, fig liqueur, fig spirit, fig wine, phenolic content, volatiles",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67457.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67457.xml",downloadPdfUrl:"/chapter/pdf-download/67457",previewPdfUrl:"/chapter/pdf-preview/67457",totalDownloads:150,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 21st 2019",dateReviewed:"May 5th 2019",datePrePublished:"July 31st 2019",datePublished:null,readingETA:"0",abstract:"Ficus carica L. is a native plant to Southwest Asia and widely spread from ancient times in the Mediterranean region. Its fruits (figs) and leaves present important nutritional components (vitamins, minerals, sugars, amino acids, etc.) and health-related effects due to their phytochemical composition. Numerous bioactive compounds, such as phenolic compounds (phenolic acids), flavonoids (flavonols, flavones, and anthocyanins), coumarins, sterols, and volatiles (monoterpenes, sesquiterpenes, norisoprenoids, ketones, alcohols, esters, etc.), among others, have been isolated from fruits and leaves of F. carica that are the main ingredients used in the production of different alcoholic beverages such as wine, liqueur, and spirit. This chapter aims to review the different chemical and biological characteristics found both in raw materials (fruits and leaves) and in the final product (wine, liqueur, and spirit) that have been consumed and known throughout human history.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67457",risUrl:"/chapter/ris/67457",signatures:"Raquel Rodríguez Solana and Anabela Romano",book:{id:"8152",title:"Modern Fruit Industry",subtitle:null,fullTitle:"Modern Fruit Industry",slug:null,publishedDate:null,bookSignature:"Ph.D. Ibrahim Kahramanoglu, Prof. Nesibe Ebru Yaşa Kafkas, Prof. Ayzin B. Küden and Dr. Songül Çömlekçioğlu",coverURL:"https://cdn.intechopen.com/books/images_new/8152.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"178185",title:"Ph.D.",name:"Ibrahim",middleName:null,surname:"Kahramanoglu",slug:"ibrahim-kahramanoglu",fullName:"Ibrahim Kahramanoglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"193464",title:"Prof.",name:"Anabela",middleName:null,surname:"Romano",fullName:"Anabela Romano",slug:"anabela-romano",email:"aromano@ualg.pt",position:null,institution:{name:"University of Algarve",institutionURL:null,country:{name:"Portugal"}}},{id:"232009",title:"Dr.",name:"Raquel",middleName:null,surname:"Rodríguez-Solana",fullName:"Raquel Rodríguez-Solana",slug:"raquel-rodriguez-solana",email:"rrsolana@ualg.pt",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Ficus carica L. fruits, leaves, and derivatives (wine, spirit, and liqueur)",level:"1"},{id:"sec_2",title:"2. Phytochemical composition of fig fruit, leaf, and the alcoholic products, liqueurs, and spirits",level:"1"},{id:"sec_2_2",title:"2.1 Volatile compounds",level:"2"},{id:"sec_2_3",title:"2.1.1 Terpenes",level:"3"},{id:"sec_3_3",title:"2.1.2 Alcohols, aldehydes, ketones, and esters",level:"3"},{id:"sec_4_3",title:"2.1.3 Miscellaneous compounds",level:"3"},{id:"sec_6_2",title:"2.2 Organic acids, phytosterols, triterpenoids, and fatty acids",level:"2"},{id:"sec_7_2",title:"2.3 Phenolic acids, flavonoids, and coumarins",level:"2"},{id:"sec_9",title:"3. Biological studies in fruit, leaf, and fig spirits and liqueurs",level:"1"},{id:"sec_9_2",title:"3.1 Antioxidant capacity",level:"2"},{id:"sec_9_3",title:"3.1.1 Fig spirits and liqueurs",level:"3"},{id:"sec_10_3",title:"3.1.2 Leaf extracts",level:"3"},{id:"sec_11_3",title:"3.1.3 Fruit extracts",level:"3"},{id:"sec_13_2",title:"3.2 Reactive oxygen species production, xanthine oxidase inhibition assay, and study of oxidative stress",level:"2"},{id:"sec_13_3",title:"3.2.1 Fruit extracts",level:"3"},{id:"sec_14_3",title:"3.2.2 Leaf extracts",level:"3"},{id:"sec_16_2",title:"3.3 Inhibitory activities of the enzymes α-amylase, α-glucosidase, and pancreatic lipase",level:"2"},{id:"sec_16_3",title:"3.3.1 Fruit and leaf extracts",level:"3"},{id:"sec_18_2",title:"3.4 Antidiabetic, hypocholesterolaemic, and hypolipidemic activities",level:"2"},{id:"sec_18_3",title:"3.4.1 Leaf extracts",level:"3"},{id:"sec_20_2",title:"3.5 Hepatoprotective activity",level:"2"},{id:"sec_20_3",title:"3.5.1 Leaf extracts",level:"3"},{id:"sec_22_2",title:"3.6 Anti-herpes simples virus (HSV)",level:"2"},{id:"sec_22_3",title:"3.6.1 Leaf extracts",level:"3"},{id:"sec_24_2",title:"3.7 Immunomodulatory activity",level:"2"},{id:"sec_24_3",title:"3.7.1 Leaf extracts",level:"3"},{id:"sec_26_2",title:"3.8 Anti-inflammatory activity",level:"2"},{id:"sec_26_3",title:"3.8.1 Leaf extracts",level:"3"},{id:"sec_28_2",title:"3.9 Irritant potential",level:"2"},{id:"sec_28_3",title:"3.9.1 Leaf extracts",level:"3"},{id:"sec_30_2",title:"3.10 Antimicrobial, nematicidal, and anthelmintic activities",level:"2"},{id:"sec_30_3",title:"3.10.1 Leaf extracts",level:"3"},{id:"sec_31_3",title:"3.10.2 Fruit extracts",level:"3"},{id:"sec_33_2",title:"3.11 Antipyretic activity",level:"2"},{id:"sec_33_3",title:"3.11.1 Leaf extracts",level:"3"},{id:"sec_35_2",title:"3.12 Antituberculosis activity",level:"2"},{id:"sec_35_3",title:"3.12.1 Leaf extracts",level:"3"},{id:"sec_37_2",title:"3.13 Anti-calpain activity",level:"2"},{id:"sec_37_3",title:"3.13.1 Fruit extracts",level:"3"},{id:"sec_39_2",title:"3.14 Diuretic activity",level:"2"},{id:"sec_39_3",title:"3.14.1 Fruit extracts",level:"3"},{id:"sec_41_2",title:"3.15 Immunity activity",level:"2"},{id:"sec_41_3",title:"3.15.1 Fruit extracts",level:"3"},{id:"sec_43_2",title:"3.16 Antispasmodic activity",level:"2"},{id:"sec_43_3",title:"3.16.1 Fruit extracts",level:"3"},{id:"sec_45_2",title:"3.17 Antiplatelet activity",level:"2"},{id:"sec_45_3",title:"3.17.1 Fruit extracts",level:"3"},{id:"sec_48",title:"4. 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Enhanced and green extraction polyphenols and furanocoumarins from fig (Ficus carica L.) leaves using deep eutectic solvents. Journal of Pharmaceutical and Biomedical Analysis. 2017;145:339-345. DOI: 10.1016/j.jpba.2017.07.002'},{id:"B9",body:'Barolo MI, Mostacero NR, López SN. Ficus carica L.(Moraceae): An ancient source of food and health. Food Chemistry. 2014;164:119-127. DOI: 10.1016/j.foodchem.2014.04.112'},{id:"B10",body:'Dillard CJ, German JB. Phytochemicals: Nutraceuticals and human health. Journal of the Science of Food and Agriculture. 2000;80(12):1744-1756. DOI: 10.1002/1097-0010(20000915)80:12<1744::AID-JSFA725>3.0.CO;2-W'},{id:"B11",body:'Ruiz SRC. Caracterización de vinos de higo (Ficus carica L.) seco obtenidos por hidratación y triple maceración-Fermentación. Ciencia & Desarrollo. 2017;13:58-62'},{id:"B12",body:'Kadam NU, Upadhye AA, Ghosh JS. Fermentation and characterization of wine from dried Ficus carica (L) using Saccharomyces cerevisiae NCIM 3282. International Food Research Journal. 2011;18(4):1569-1571'},{id:"B13",body:'Lansky EP, Paavilainen HM, Pawlus AD, Newman RA. Ficus spp.(fig): Ethnobotany and potential as anticancer and anti-inflammatory agents. Journal of Ethnopharmacology. 2008;119(2):195-213. DOI: 10.1016/j.jep.2008.06.025'},{id:"B14",body:'Rodríguez-Solana R, Galego LR, Pérez-Santín E, Romano A. Production method and varietal source influence the volatile profiles of spirits prepared from fig fruits (Ficus carica L.). European Food Research and Technology. 2018;244(12):2213-2229. DOI: 10.1007/s00217-018-3131-3'},{id:"B15",body:'Miličević B, Ačkar Đ, Babić J, Jozinović A, Miličević R, Oroz M, et al. Impact of the fermentation process with immobilized yeast cells on the aroma profile and sensory quality of distillates produced from two fig (Ficus carica L.) cultivars. Poljoprivreda. 2017;23(1):49-55. DOI: 10.18047/poljo.23.1.8'},{id:"B16",body:'Ruiz SRC. 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DOI: 10.2478/aoas-2018-0037'},{id:"B24",body:'Salem MZ, Salem AZM, Camacho LM, Ali HM. Antimicrobial activities and phytochemical composition of extracts of Ficus species: An overview. African Journal of Microbiology Research. 2013;7(33):4207-4219. DOI: 10.5897/AJMR2013.5570'},{id:"B25",body:'Morales ML, Fierro-Risco J, Callejón RM, Paneque P. Monitoring volatile compounds production throughout fermentation by Saccharomyces and non-Saccharomyces strains using headspace sorptive extraction. Journal of Food Science and Technology. 2017;54(2):538-557. DOI: 10.1007/s13197-017-2499-6'},{id:"B26",body:'Ware AB, Kaye PT, Compton SG, Van Noort S. Fig volatiles: Their role in attracting pollinators and maintaining pollinator specificity. Plant Systematics and Evolution. 1993;186(3–4):147-156. DOI: 10.1007/BF00940794'},{id:"B27",body:'Gibernau M, Buser HR, Frey JE, Hossaert-McKey M. Volatile compounds from extracts of figs of Ficus carica. Phytochemistry. 1997;46(2):241-244. DOI: 10.1016/S0031-9422(97)00292-6'},{id:"B28",body:'Palassarou M, Melliou E, Liouni M, Michaelakis A, Balayiannis G, Magiatis P. Volatile profile of Greek dried white figs (Ficus carica L.) and investigation of the role of β-damascenone in aroma formation in fig liquors. Journal of the Science of Food and Agriculture. 2017;97(15):5254-5270. DOI: 10.1002/jsfa.8410'},{id:"B29",body:'Soni N, Mehta S, Satpathy G, Gupta RK. Estimation of nutritional, phytochemical, antioxidant and antibacterial activity of dried fig (Ficus carica). Journal of Pharmacognosy and Phytochemistry. 2014;3(2):158-165'},{id:"B30",body:'Joseph B, Raj SJ. Pharmacognostic and phytochemical properties of Ficus carica Linn–An overview. International Journal of Pharmtech Research. 2011;3(1):8-12'},{id:"B31",body:'Takahashi T, Okiura A, Saito K, Kohno M. Identification of phenylpropanoids in fig (Ficus carica L.) leaves. Journal of Agricultural and Food Chemistry. 2014;62(41):10076-10083. DOI: 10.1021/jf5025938'},{id:"B32",body:'Ammar S, del Mar Contreras M, Belguith-Hadrich O, Bouaziz M, Segura-Carretero A. New insights into the qualitative phenolic profile of Ficus carica L. fruits and leaves from Tunisia using ultra-high-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry and their antioxidant activity. RSC Advances. 2015;5(26):20035-20050. DOI: 10.1039/C4RA16746E'},{id:"B33",body:'Veberic R, Colaric M, Stampar F. Phenolic acids and flavonoids of fig fruit (Ficus carica L.) in the northern mediterranean region. Food Chemistry. 2008;106(1):153-157. DOI: 10.1016/j.foodchem.2007.05.061'},{id:"B34",body:'Santos C, Botelho G, Caldeira I, Torres A, Ferreira FM. Antioxidant activity assessment in fruit liquors and spirits: Methods comparison. Ciência e Técnica Vitivinícola. 2014;29(1):28-34. DOI: 10.1051/ctv/20142901028'},{id:"B35",body:'Mopuri R, Ganjayi M, Meriga B, Koorbanally NA, Islam MS. The effects of Ficus carica on the activity of enzymes related to metabolic syndrome. Journal of Food and Drug Analysis. 2018;26(1):201-210. DOI: 10.1016/j.jfda.2017.03.001'},{id:"B36",body:'Das SS, Dey M, Ghosh AK. Determination of anthelmintic activity of the leaf and bark extract of Tamarindus indica Linn. Indian Journal of Pharmaceutical Sciences. 2011;73(1):104-107. DOI: 10.4103/0250-474X.89768'},{id:"B37",body:'Trinchese F, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, et al. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. The Journal of Clinical Investigation. 2008;118(8):2796-2807. DOI: 10.1172/JCI34254'},{id:"B38",body:'Richter G, Schwarz HP, Dorner F, Turecek PL. Activation and inactivation of human factor X by proteases derived from Ficus carica. British Journal of Haematology. 2002;119(4):1042-1051. 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