46 A distinguished Milton scholar, Wittreich must have seen what *King Lear* and *Paradise Lost* share: each is a literary masterpiece developing from and in tension with biblical narrative, vision, and imagery, a rich history of interpretive cruxes that affect the reading of the work's very foundations, revisited over centuries without definitive resolution, and a significant ultimate turn to psychological and spiritual interior spaces indicated by "the heart." In *Paradise Lost*, given Milton's narrative persona (Milton 2005), who sought a muse preferring "before all temples th' upright heart and pure," and who described his exterior environment as "in darkness and with dangers compassed round," the final book's postlapsarian turn to the "paradise within" was predictable (*Paradise Lost* 1.18, 7.27, 12.587). Shakespeare's Lear dies with what is generally considered to be an outward indication, enigmatic as it may be, but my argument is that the biblical allusion to Luke 17 in Lear's "Look there!" redirects the astute spectator to the interior space of the heart. For Wittreich, Lear's redemption is interior, potentially bearing fruit for the future, but limited to earth. One might note that an interior redemption is perfectly compatible with an eternally significant one, as far as Christianity is concerned. For Milton, the fruit of apocalypse transcends this world, involved in Christian doctrines of the afterlife and the resurrection of the body.

47 Wittreich argues that Lear "incorporates no messianic vision" and "the personal tragedy is accentuated by irony—there is a reunion without a restoration, but the tragedy of history is alleviated, the possibility for *history* as a tragicomedy is allowed for in a play where evil is self-consuming and goodness triumphant in the calm, if not secured order, at its end" (Wittreich 1984, p. 42).

are imperfect. The difficulty comes in deciding what to make of the parallels that do exist, allowing even for the consideration of her association with Christ being ironic. The passages that mark Cordelia as a potential redeemer and that have generated so much critical attention have already been mentioned; Cordelia might redeem nature from the general curse (4.6.202) and more particularly redeem Lear from all his personal sorrows (5.3.264). She, like Christ, (especially in his Sermon on the Mount and in his confrontation of the Pharisees' hypocrisy) emphasizes the importance of the heart. Her name, as fortunately in the source texts, may be linked to the Latin *cors, cordis*, drawing attention to the inner life and spiritual integrity she epitomizes, and preparing the spectator for her role as Love in action; her patience and sorrow, smiles and tears in response to news of her father, become a "better way," which Peter Milward reads as suggestive of the "more excellent way" of Love as expressed in 1 Corinthians 13 (Lear 4.3.16–19; Battenhouse 1994, p. 449). She sheds tears of compassion as holy water (4.3.31). The "love, dear love" she has for Lear eventually leads her to prison and to pay (unwittingly) the ultimate price for that love—the loss of her very life (4.4.28).

*Lear* is filled with emphatic repetitions, and the story of Lear's dependence on Cordelia might be summarized by them from 4.7 onward. When Lear wakes from a healing sleep with fresh garments, his half-belief that the lady in front of him might be his child Cordelia is met with Cordelia's "And so I am, I am" (4.7.70). Her response is simple and profound. The repeated "I am" draws attention to the name by which YHWH identifies himself to Moses in the burning bush (Exodus 3:14), an Old Testament account that the early fathers of the Christian Church read as typological of the incarnation or resurrection of Christ.48 It is also the name Jesus uses to identify himself in John 8:58: "Verely, verely I say unto you, before Abraham was, I am." The significance of such a statement was not lost on Jesus' Jewish audience, who tried to stone him for blasphemy. Given the surrounding evidence for her position as a Christ-figure, Cordelia's emphatic "I am" could be read as a similarly significant statement. She is the voice that leads Lear's exodus through fire to freedom.

The second emphatic repetition to note immediately follows Lear's response to Cordelia's self-identification. Facing the daughter he has wronged, Lear says,

If you have poison for me, I will drink it.

I know you do not love me, for your sisters

Have, as I do remember, done me wrong.

You have some cause, they have not. (4.7.72–75)

Cordelia's response—"No cause, no cause"—again and at once simple and profound, signifies her forgiveness, although Lear is still too "far wide" to grasp that his petition for her to "forget and forgive" had been answered before he found the strength to ask (4.7.76, 50, 83–84). The words "no cause" may carry no particular biblical allusion, but the experience of unmerited forgiveness wed to intimations of prevenient grace is biblical in concept. At their capture in 5.3, Lear anticipates a life in prison with Cordelia involving a ritual of blessing and forgiveness as well as praying, singing "like birds i'the cage," laughing at "gilded butterflies," and taking up "the mystery of things" (5.3.8–17). Lear has not forgotten the "cause" Cordelia could bring against him, but his exuberance in the assurance that to Cordelia this is "no cause" to mention at all brings him to a nearly ecstatic vision of repeatedly asking (and receiving) her forgiveness. He goes with her to prison in contentment, if not joy.

The next significant set of emphatic repetitions, however, marks an utterly devastating change in fortune. Lear's poetic vision for life with Cordelia in prison is reduced to animal wails: "Howl, howl, howl, howl!" (5.3.255). For what is life without the beloved? "Cordelia, Cordelia ... " (5.3.269); "No, no, no ... " (5.3.304); "Never, never, never, never, never" (5.3.307). The agony is fresh, the tone is hollow. A newfound hope has been wrenched from Lear just as he had begun to see his daughter's true

48 See, for example, *The Life of Moses* 2.17–26 (Gregory of Nyssa 1978, pp. 58–61) and *On the Holy Trinity* 2.13 (Augustine 2007, pp. 48–49).

value. The biblical allusions sprinkled throughout the play lead the spectator to consider the world of *Lear* in the light of Christianity, introducing the concepts of hope, redemption, and even resurrection; nonetheless, a spectator or reader might determine the ultimate effect of introducing such biblical allusions and Christian references is to intensify the devastation at its conclusion. As the play's last scene unfolds *The Tragedy of King Lear* remains a tragedy. The pagan setting remains pagan. The absent gods remain absent. To this environment is added extraordinary suffering, agonizing grief at the violent death of a beloved daughter, and, finally, the death of the weary protagonist. Yet, at Lear's last moment, he inserts one final, enigmatic, emphatic repetition: "Look there, look there!"

#### **5. "Look There" in** *Lear* **and Luke 17**

Without desiring to brush away the rich ambiguities and interpretive cruxes of the tragedy's ending, or smooth away the sorrow, in this last section I seek to illumine one corner of the critical conversation by examining what I consider to be a profoundly relevant scriptural echo in Lear's last words in the First Folio. I am unaware of any scholarly examination connecting Lear's "Look there, look there!" to Luke 17:20–23, yet making this connection adds relevant layers of meaning enhanced by their shared themes of apocalypse, kingdom, sight/insight, and the importance of the heart. The potential allusion bears upon the interpretation of Cordelia as living Christ-figure, then as the piteous image of innocence martyred, and finally as a sign of the interior space one might call the kingdom of the heart. Such an allusion challenges our reading of the play's presentation of "last things," providing some guidance in what one might look for at the play's ending—and where one might look for it.

Among the gospel narratives, the Book of Luke has had special literary influence, and it remains one of the most important biblical sources for Shakespeare. Donald Thomas Carlson, arguing for a "Lucan parallel" in *The Tempest*, lists reasons Shakespeare may have been especially drawn to the gospel of Luke. Carlson tentatively suggests that Luke's traditional occupation as physician would make him a suitable authority to introduce into plays with purgatorial or purgative themes; the content of Luke's gospel prevalently addresses the theme of forgiveness. Furthermore, Luke was held to be the most literary of the evangelists; he includes more parables than the other gospels do, and his figures of speech might appeal to a poet and dramatist (Carlson 1991, pp. 1–3). Samuel Taylor Coleridge wrote in his *Notebooks* that the literary quality of Luke far excelled the Gospel of Matthew, in the way a "splendid poem" by Southey or Scott far outshines its source, a "rude tale in an old chronicle" (qtd. in Jeffrey 1992, p. 466). To the literary qualities of Luke, one might add strong socio-political concerns. As Jeffrey has argued, "More than any other writer in the New Testament, Luke reveals in-depth acquaintance with contemporary political and economic realities ... . Luke emphasizes uprightness as adjunct to piety, stresses proper use of wealth, and encourages a broad social outreach which embraces women, the afflicted, and other marginal people" (Jeffrey 1992, p. 466). In this respect, Luke teaches what Lear learns.

The presence of the Gospel of Luke as intertext to Shakespeare's *King Lear* is unmistakable. A frequently noted example of this occurs as Cordelia returns to Albion in Act 4. As she prepares for battle with the British powers, she says, "O dear Father, / It is thy business that I go about" (4.4.23–24), alluding to the words of the boy Jesus in the temple, as described in Luke and only Luke among the canonical gospels. In the biblical story, Mary and Joseph return from observing the Passover in Jerusalem to discover that the twelve-year-old Jesus is not among their company of travelers. After three days' search, Mary finds her son in the temple courts talking with the teachers of the Law. She reacts with questioning, perhaps even chastening words: "Sonne, why hast thou thus dealt with us? behold, thy father and I have sought thee with very heavie hearts" (Luke 2:48). Jesus responds, "How is it that yee sought me? knew yee not that I must goe about my Fathers busines?" (Luke 2:49). Luke remarks that Mary and Joseph "understood not the word that he spake to them" (v. 50). Lear also lacks full understanding of the wisdom of his child, and the difficulties the boy Jesus and Cordelia share in explaining their actions to their parents have been noted by Skulsky (1966, p. 13). Cordelia's arrival in Dover with an army is motivated by "love, dear love, and our aged father's right" (4.4.28). While one critic has associated Cordelia with the socially outcast woman who anoints Jesus' feet in Luke 7 (and thence Lear with Christ), in going about her father's business, seeking to restore his kingdom to him, she more directly presents herself as a young Christ-figure in the place where she will soon lose her life.49

Luke's parables, especially the series of forgiveness parables in Luke 14–16, also influence *Lear.* Parallels between *Lear* and the parable of the rich man and Lazarus in Luke 16:19–31 have already been mentioned in consideration of Lear's and Gloucester's developed sympathy with the poor; parallels have also been drawn between Kent and the shrewd manager in Luke 16:1–13, and between Lear and the prodigal son in Luke 15:11–32.50 Each of these parables is exclusive to the gospel of Luke. The comparison between Lear and the prodigal son is the most prevalent one. In Shakespeare's play, the roles of father and child are reversed: Lear, the "child-changed father," generally is considered the reckless prodigal who must "come to himself" before reuniting with the daughter whom he had rejected, and who yet loves him, restoring him with compassion and a kiss (*Lear* 4.7.17, 26–29; Luke 15:17, 20). The parable's central concern of forgiveness for the repentant is enhanced with the image of new garments signifying an unmerited fresh start; in *Lear* it is Cordelia who arranges "fresh garments" to be put on the king as he sleeps (4.7.20–22). When Lear wakes, Cordelia imagines her father's past sorrows including "hoveli[ing] with swine"—the very bottom of fortune's wheel as experienced by the young Jewish prodigal in Jesus' parable (4.7.39; Luke 15:15–16). The prodigal son's return to the father becomes an occasion for great rejoicing: "For this my sonne was dead, and is alive againe: and he was lost, but he is found" (v. 24). In *Lear*, in the 4.7 reconciliation scene where the bulk of allusions to the prodigal son parable may be found, Lear is also in a sense recalled to life, even though in his shame (and perhaps desire for purgatorial fires) he repines, "You do me wrong to take me out o'the grave" (4.7.45)

With such correspondences, one might not be surprised to discover other parallels between *King Lear* and the gospel of Luke. Luke also contains two chapters (17 and 21) that are concerned with apocalypse. St. John's vision on Patmos is not the only reference to apocalypse in Christian sacred scripture; the gospel accounts record Jesus' teachings on the topic. The description of the "dayes of vengeance" in Luke 21 resounds in Gloucester's litany of environmental, social, and political troubles in Act 1, scene 2:

Love cools, friendship falls off, brothers divide; in cities, mutinies; in countries, discord; in palaces, treason; and the bond cracked 'twixt son and father ... Machinations, hollowness, treachery, and all ruinous disorders follow us disquietly to our graves. (*Lear* 1.2.106–9, 113–114)

In Luke 21, "The dayes of vengeance" are marked by betrayal by "parents ... brethren, and kinsmen, and friends" (v. 16), "warres and seditions" (v. 9), kingdoms rising against kingdoms (v. 10), and situations where "mens hearts shal faile them for feare" (v. 26). Gloucester attributes the ruptures in nature and natural bonds he observes to "late eclipses in the sun and moon" that "portend no good to us" (1.2.103); Luke 21 prophesies "signes in the sun, and in the moone, and in the starres, and upon the earth trouble among the nations with perplexitie; the sea and the waves shall roare" (v. 25; cf. references to the turbulent sea in *Lear* 3.1.4–6, 3.4.10, 3.7.58–60, 4.4.1–2). Jesus' instructions to his disciples, "By your patience possess your soules" (v. 19) and "Look up ... for your redemption draweth nigh" (v. 28) might also be associated with the persistent question of Lear's own patience and Edgar's final petition, "Look up, my lord" (5.3.311). The parallels between Gloucester's apocalyptic vision and Luke 21 could be analyzed in far greater depth, but it is the other apocalyptic chapter, Luke 17, that concerns *Lear* most.

49 For the association of Cordelia with the woman in Luke 7:37–50, see (Lefler 2010).

50 For the parable of the shrewd manager and *Lear*, see (Brisman 1998). For the parable of the prodigal son and *Lear*, see (Snyder 1966; Milward 1969; Cunningham 1984; Tippens 1988).

Amid longstanding concern about where and how Lear looks, what pagan and Christian elements may be permitted, and what to make of apparently biblical language and imagery in the play, no one has yet examined in Lear's last words a significant and troublesome biblical allusion to Luke 17. Richmond Noble finds allusions to 22 biblical passages in *Lear*, and in appendix records allusions throughout Shakespeare's plays to multiple verses from twenty-one of Luke's twenty-four chapters, but in either case provides nothing for Luke 17 (Noble 1970, pp. 294–95). With a more inclusive approach and an eye for the probable rather than the certain, Naseeb Shaheen finds allusions from each of Luke's chapters in Shakespeare (171 verses or passages from Luke in total, many of these alluded to more than once in Shakespeare's works); he lists twelve references to Luke 17 in Shakespeare's plays, but none in *Lear* (Shaheen 1999, pp. 808–812). Among these, he identifies allusions to verse 29 most frequently (four times, in *Twelfth Night, Richard 2, Othello*, and *Pericles*), but this is due to the interjection "Fire and Brimstone," often used comically in Shakespeare. Like *Lear*, much of *Luke* 17 is apocalyptic in topic, but Joseph Wittreich's scholarship on apocalypse in *Lear* does nothing with this particular chapter. Yet there is good reason for including Luke 17 among the apocalyptic biblical texts that shape Lear, for this chapter shares with *Lear* an interest in the topics of kingdom, divine judgment, sight, insight, revelation, and the importance of both the inner spiritual realm and active love.

Luke 17 begins with Jesus warning his disciples against offending "litle ones," exhorting them to extravagant forgiveness, and assuring them of the extraordinary power of faith. The third verse, "If thy brother trespasse against thee, rebuke him: and if he repent, forgive him," might be compared with Edgar's challenge, duel, and then desire to "exchange charity" with his brother Edmund (5.3.124–38, 164). The center of Luke 17 includes the parable of the unthanked servant (cf. Kent) and the story of Jesus healing the ten lepers, of whom only one returned to thank his healer; this section shares with *Lear* the themes of dutiful service and gratitude/ingratitude.51 The rest of the chapter concerns the apocalyptic message about the "comming of the kingdome of heaven," the anticipated appearance of "false Christes," and "After what maner Christe's comming shal be," as expressed in the argument of Chapter 17 in the 1595 Geneva-Tomson Bible, the version Richmond Noble gives good evidence for having been in Shakespeare's possession (Noble 1970, pp. 58–69). Indeed, Shakespeare's play might be illuminatingly read alongside the whole of Luke 17, but the particular verse deserving emphasis is Luke 17:21. Here it is in context, from the Geneva-Tomson translation:

20And when he was demaunded of the Pharises, when the kingdome of God should come, he answered them, and said, The kingdome of God commeth not with observation.

21Neither shall men say, Lo here, or lo there: for behold, the kingdome of God is within you.

22And he said unto the disciples, The dayes will come, when ye shal desire to see one of the dayes of the Sonne of man, and ye shal not see it.

23Then they shall saye to you, Beholde here, or beholde there: but goe not thither, neither follow them.

24For as the lightening that lighteneth out of the one parte under heauen, shineth unto the other part under heaven, so shall the Sonne of man be in his day.

25But first must he suffer many things, and be reproved of this generation.

The "Lo here, or lo there" of Luke 17:21 (rendered "loo here loo there" in the Tyndale (1534), "Lo here, or lo there" in the Great Bible (1539), and "lo here, lo there" in The Bishop's The Bishop's Bible (1568)) is similar enough to Lear's "Look there, look there!" to warrant further investigation. Similarly, the "Beholde here, or beholde there" in verse 23 ("Se here se there" in the Tyndale, and "See here, see there" in the Great Bible and the Bishop's Bible) invites comparison with Albany's exhortation,

51 The good servant of Luke 17 calls himself "unprofitable" because he is simply doing his duty; the parable is referred to in the Elizabethan homily "Of the Misery of All Mankinde" to emphasize that no one is good but God (Lancashire 1994).

"O see, see!" (5.3.303). Perhaps this allusion has been overlooked because today we may not readily think of 'lo' as a shortened form of 'look,' although the *OED* confirms this (see the second etymology given *sv*. *lo, int.*1). Granted, where the biblical passage has "here ... there" Shakespeare has emphatic repetitions, but in context the effects are similar. In Luke 17:21, the "here" and "there" of purported locations of the kingdom of God are not contrasted with each other, but paired together in contrast with the authentic location of that spiritual realm: "within you."52

If Lear's last words indeed allude to Luke 17, how does this affect our reading of the play? Is the last scene "the promised end," as Kent inquires, "or the image of that horror," as Edgar suggests? Or is it something else? In Luke, Jesus warns his disciples not to believe those who, saying "lo here, lo there," point to a partially visible apocalypse or to the coming of the Kingdom of God. This coming, Luke states, will be self-evident, like lightning stretching from heaven to heaven (v. 24). We, with Lear, have seen a storm in the play, and the raw power of Nature, but the indeterminacy—or at least, the disputability—of the play's conclusion suggests that the kingdom of God has not come at the end of *Lear*, that this is not the promised end. "Goe not thither, neither follow them," Jesus admonishes. There are false Christs. In this, I can agree with Wittreich: "For all the suggestions of end-time that are to be found in *King Lear*, the play does not produce the promised end—defiantly resisting, instead, the expectations built by its apocalyptic reference" (Wittreich 1984, p. 32). Eclipse-driven hype remains the mark of Gloucester's superstition, and matter for Edmund's scorn. The same allusion to Luke 17 that may be used to support the redemptive role of Cordelia also presents the possibility that Lear has become an unwittingly false prophet. If Lear's "Look there" is regarded as a reference to the eschaton, there remains the possibility that Lear's final words misdirect us—that at the play's close, the audience left darkling, there is only the tragic image of a promised horrific end that, like the thud of a Tenebrae *strepitus*, reverberates no hollowness. We would then have the corpse of a Christ-figure, but no Resurrection, and no Second Coming. If one accepts apocalyptic references in *Lear's* final scene as well as the terms of Luke 17:24 for identifying apocalypse, the very fact that the vitality of Cordelia (and thus the redemption of Lear) is disputed will indicate her role as Christ figure has reached its limits in her death. "Ye shal desire to see one of the dayes of the Sonne of man, and ye shal not see it."

If Lear's final indication, whether heavenly or earthly, is indeed a misdirection, wittingly or unwittingly, one still must consider what to make of the corpse onstage. I am assuming Lear's "look there!" points to the body of dead Cordelia—not outward to a vast and meaningless abyss, nor upward to a spirit blissfully ascending to the heavens. Lear's reference to her lips in the preceding line turns the spectator's attention with him to the body of his daughter. But what ought one make of this body? Is it a sacred relic, or a lump of clay? Performance history cannot settle the issue, only present to us a range of options. In Max Reinhart's 1925 production, as Marvin Rosenberg records, "Cordelia lay limp in Klöpfer's arms as if taken down from the cross of life" (Rosenberg 311); this may be contrasted with Benedict Nightingale's description of Sir Robert Stephens's 1993 performance: "On 'she's dead as earth,' the last word full of disgust, Stephens actually kneed the body onto its back as if it were a slab of meat" (Ogden and Scouten 1997, pp. 242–43). Frequently in performance the sacred and the profane are mingled, especially where the aged king's regard for his daughter's corpse leads to awkward exposure of his own failing strength, as in the case of Tommaso Salvini's *Lear* (1883–1887): "not allowing anyone but himself to touch the beloved body, [Lear] must drag it in with difficulty" (qtd. in Rosenberg 312).

52 The 1560 Geneva notes provide an alternate translation for "within you": "*Or, among you*." Calvin's explication of Luke 17: 21–22 in *The Institutes* 2.15.4 reinforces the primary choice of *within* in the Geneva translations while maintaining the relevance of the alternative *among*, for, as he argues, "[Christ] reigns ... both within us and without us" (Calvin 1863, vol. 1, p. 429). In the context of Jesus' apocalyptic statements in the synoptic gospels, the Lucan reference to the kingdom of God as "within" [ἐντóς in the original Greek] is peculiar, for the parallel verses Matthew 24:33 and Mark 13:29 both have "near, at the doors" [ἐγγύς... θύαις]. To the aforementioned reasons for considering Luke's special influence on Lear one might add a shared emphasis on psychological or spiritual interior spaces in Luke 17 and *King Lear*. The parallels promote consideration of an allusion in Lear's final words to the "Lo there" of Luke 17:21 rather than to the correlative verses of Matthew 24:23 and Mark 13:21.

What the theater has not resolved, the scholarly battle lines of the Christianizers and the Existentialists have brought to the level of overdetermination or aporia. The internal evidence of the play cannot resolve it—the absence and silence of the gods neither proves nor disproves the operation of a spiritual realm extending to an afterlife, and even Kent's expectations, implicit in "Vex not his ghost" and "I have a journey, sir" do not establish assurances of any such afterlife within the world of the play (5.3.312, 320). The previously considered biblical allusions clearly present Cordelia as a Christ-figure with redemptive potential—but the text does not show that potential actualized in Lear's pagan world beyond the life of the king, and with her body cradled in his at the end of the play, it is just as difficult to prove that Cordelia's role as redemptrix is ultimately ironic as it is to prove that this piteous Deposition scene is pointing toward a Christian perspective on resurrection and redemption.

If Cordelia is a Christ figure, and Lear's last command is to look upon her corpse, the final words of Lear usher the Jacobean playgoer into one of the heated religious issues of the English Reformation, the image debate in early modern England. What if the body of the hanged Cordelia becomes an object of veneration? Perhaps Lear's fixation on the corpus would be an indication for the Protestant playgoer that Lear is indeed deluded, clinging to a creed outworn. Perhaps the spectacle would be received more sympathetically as a variation of the supreme image evoking pity, a pietà, with the father cradling the dead daughter in his lap, evoking the ghosts of the old Catholicism.53 For Cherrell Guilfoyle, who has reminded readers of *Lear* that the crucifixion of Jesus was traditionally referred to as a hanging (Acts 10:39; Guilfoyle 1989, p. 62), Lear carrying the dead Cordelia onstage "concentrate[s] attention on the relation between Lear and the body of his daughter, and the powerful symbolism of the Deposition and pietà is fed into this final icon" (Guilfoyle 1989, p. 63). For the early modern English Protestant audience, however, there is always the threat that the icon could become an idol.54

53 Stephen Greenblatt has argued in *Hamlet in Purgatory* that Shakespeare "had a particular interest in digging up and redeploying damaged or discarded institutional goods, cultural memories that he returned to his contemporaries and bequeathed to the future" (Greenblatt 2013, p. xiv). Dennis Taylor and David Beauregard have edited a volume of essays, *Shakespeare and the Culture of Christianity in Early Modern England*, based on the premise that "the ghost of the old Catholicism haunts Shakespeare and his Elizabethan world" (Taylor and Beauregard 2003, p. 12). The question of where Shakespeare's personal religious convictions lay is thorny and not always scholarly. Hannibal Hamlin does a fine job summarizing the key issues and arguments, and remarks that, while arguments for Shakespeare's Catholicism are "gaining the ascendancy," it is also true that "the Catholic Shakespeare remains especially popular among Catholic scholars" (Hamlin 2013, p. 75). In the case of *King Lear*, one should note that arguments for *Lear* intimating a Catholic perspective need not be among those arguing for the ultimate redemption of Lear. For Beauregard, the final scene "seems designed as a secular imitation of Michelangelo's Pieta" and "suggests that Shakespeare conceives of nature in Catholic rather than Protestant terms," but ultimately "portrays the deficiency, indeed the horror, of a world apparently without grace and certainly without redemption" (Beauregard 2008, pp. 205, 217).

54 The image of Cordelia's corpse is a contentious but ambiguous one. Treated as a religious image, it cannot settle recent heated debates about Shakespeare's own religious convictions, or even whether his sympathies tended toward the old Roman Catholicism or some sort of Protestantism. On one hand, Erasmus's *Praise of Folly* provides a notable example of a Catholic humanist satirizing over-attention to religious images; on the other, the Protestant view of images was not uniformly iconoclastic, especially among English Protestants (Davis 2013, pp. 68–69). In one of his sermons John Donne wrote, "there is no necessity of pictures; but will not every man add this. That if the true use of Pictures be preached unto them, there is no danger of an abuse" (qtd. in Davis 2013, p. 68). Donne's measured tolerance of images if properly explained may be contrasted with the Elizabethan Homily Against Peril of Idolatry, which insists that "idolatrie is to Images, specially in Temples and Churches, an inseparable accident (as they terme it) so that Images in Churches, and idolatrie, go alwayes both together, and that therefore the one cannot bee avoyded, except the other (specially in all publike places) bee destroyed" (Lancashire 1994). The image debate continued into the Jacobean period, with the king himself articulating his position in his 1609 *Premonition to all most Mighty Monarches, Kings, Free Princes, and States of Christendome*:

I am no *Iconomachus*; I quarrell not with the making of Images, either for publike decoration, or for mens private uses: But that they should bee worshipped, bee prayed to, or any holinesse attributed unto them, was never knowen of the Ancients: And the Scriptures are so directly, vehemently and punctually against it, as I wonder what braine of man, or suggestion of Sathan durst offer it to Christians. (James 1918)

While many early modern Protestants considered venerating religious images idolatrous, there were those whose nuanced positions permitted the use of images as an aid to spiritual devotion. Lutherans, for example, permitted crucifixes, and the reformer Peter Vermigli, whose *Loci Communes* was published in London in 1583, proposed that Jesus "may be resembled and painted out" (Davis 2016, pp. 126–27; Davis 2013, pp. 105–8). Conversely, John Calvin, in his sermons on Deuteronomy (also published in London in 1583), argued against any images of Christ: "Yes, and therefore whenever a crucifix stands

In accordance with Jesus' warning in Luke 17:25, perhaps one is foolish even to bother to "look there" at all.

In terms of the early modern image debate, an eikon or image may not be an idol if it serves as an aid to worship something or someone beyond it. For many Protestant Reformers, images, like sacraments, are properly useful only when clearly associated with the Word of God.55 What sacred word might be associated with the image of the dead Cordelia? Even the iconoclast might agree that the wrongful use of images is found in the heart of the worshipper, not in the image itself. In the last scene of *Lear*, even amid all the pathos, we have limited access to the heart of Lear in his last moments of life. One might recollect Alison Shell's suspicion of the "dangerously limited manner" of Lear's redemption (Shell 2010, p. 193).

If the early modern theatergoer saw in the body of Cordelia an imitation of a religious image, what reference might be discovered in the spectacle? What word might be on her unmoving lips? We are commanded to gaze at the dead Cordelia, and left wondering if there is "aught within that little-seeming substance," challenged to decide whether, even in her death, we can yet see the inner value of the princess, that she is herself a dowry (1.1.199, 243). Outwardly, the body of Cordelia is a picture of death, suffering, and injustice. Inwardly, she becomes a sign of truth, love, and sacrifice—not a thing to be worshipped, but a visual aid to worship. Such an image serves as a reminder of the words she had once spoken: "love, dear Love ... "; "I am, I am"; "no cause, no cause." The lips may serve as the outward indication of the heart (cf. Luke 6:45, Matthew 12:34), but Cordelia and Kent have shown that, while there are occasions for speaking out, there are also occasions when one cannot heave one's heart into one's mouth. For those who best know Cordelia's heart, her "Nothing, my lord" is perhaps as meaningful and virtuous as "love, dear Love" (1.1.87, 4.4.28). Her compassionate action on Lear's behalf signified by the latter phrase is motivated by her personal integrity under pressure, signified by the former. It takes five tragic acts for Lear to know and articulate the value of such a heart.

We are at a crux. Cordelia may become for the spectator a false Christ, an ineffectual Messiah, or an idol—but for those who might see her heart—feelingly, not with ocular observation—even in her death the spectacle of her body on stage might serve as true icon, referring beyond itself to the truth and love Lear has come to recognize and cherish—the truth and love that, in the midst of great suffering, has transformed him.

In Luke 17, Jesus does not simply negate the storm-chasers. By pointing forward to an unmistakable day of revelation, he silences speculative rumors, but he also directs his disciples to the most immediate place of redemption: "The kingdome of God is within you." It is the interior space of the self—it is the heart—that for now must carry the kingdom of God. And perhaps this is what Lear ultimately sees in Cordelia, and in the process of such a revelation, sparks in himself.

After all, the richest portion of the kingdom has ever been interior. On a literal level, Lear begins the play intending to award his youngest daughter the "more opulent" middle regions of his domain, thereby creating a buffer kingdom separating the lands subjected to the belligerent whims of his first two daughters, their husbands, and their armies (1.1.86). The Fool knows that Cordelia was central to Lear's original plans, not only for the "kind nursery" Lear expects from her for his own person, but also for the peaceful influence her governance would provide the kingdom. According to the Fool's raillery, Cordelia is the nutritious meat of an egg, while Goneril and Regan are the empty half-shells surrounding her (1.4.148–54).  For more on reconsidering iconoclasm in early modern England, see (Budd 2000).

55 See (Hutchinson 2017). The Protestant Reformers frequently referred to sacraments as "visible words" that are nevertheless *not* self-explanatory, and consequently must be joined to the Word of God to be received in understanding and faith. The position is articulated in John Calvin's *Short Treatise on the Lord's Supper* (sect. 48), which supports its position with reference to Augustine's *Tractates on the Gospel of John* (Tractate 80). David J. Davis connects Protestant liturgical emphasis on the Word to the early modern image debate: "[A]lthough no longer points of reverence, [religious images] continued to thrive as points of reference" (Davis 2013, p. 69).

(1.5.19–24). She is the natural locus of wisdom, or would have been, the Fool implies, had Lear kept her inheritance in place. As it stands, however, the Fool chides, "Thou hast pared thy wit o'both sides and left nothing i'the middle. Here comes one o' the parings" (1.4.177–79). The Fool's announcement of Goneril's entrance makes it clear that "nothing I' th' middle" is a lament over the loss of Cordelia as ruler over an interior kingdom. Her substantial political worth as implied in Act 1 is all the more evident in the beginning of Act 2, where Curan informs Edmund of the rumors of imminent war between Albany and Cornwall (2.1.7–12). And yet, from the first mentioning of her heart, Cordelia's association with an interior kingdom is not only physical, but spiritual.

Lear is not redeemed upon evangelical Christian terms. He has not in a burst of illumination received a glimpse of a future Christian era and accepted Jesus Christ as Savior. Lear is not even redeemed in the sense in which Dante redeems a few of his favorite pagans, granting Ripheus and Trajan a place in paradise through divine grace and through their personal virtue. If Lear is redeemed, he is redeemed as a pagan, but through a journey understandable to a Christian audience. If he is in some sense saved, he is saved by Cordelia's heart: by her truth and love.

It is necessary to permit ambiguity. The history of the debate over the ending of *Lear* is too rich to resolve or explain in a way that satisfies all tastes and accounts for all perspectives within a single thesis. Nonetheless, given the profound thematic and topical parallels between *Lear* and Luke 17, I remain surprised that Lear's final words have not previously been explored in relation to Luke 17:20–21. It bears repeating: acknowledging this allusion does not remove all ambiguities. Lear's command to "Look there" may yet be the mark of delusion or unwitting deception. Even so, one might arrive at the same conclusion through two pathways. One might "look there" at Cordelia, not as an idolater nor as an iconoclast, but as a sensitive spectator, seeing the body of Cordelia as a religious image properly, as a visual that evokes sincerity in feeling and in worship and leads beyond itself to the Word. Alternatively, mindful of the allusion to Luke 17, one might choose to ignore the command to "Look there" and consider instead how "the kingdom of God is within" the self, and within one's own community. The result is the same: a turn toward a realm that is seen "not with observation" but feelingly, the realm of love resulting in humility, hope, compassion, and active and beneficent service. Hearts work best in *King Lear* when they are stubborn in their commitment to truth and virtue, and yet fragile in their compassionate response to suffering.

Even as her corpse lies in Lear's arms, Cordelia as image might yet be going about her father's business. If we, like Mary and Joseph, do not have the insight to fully understand this image, and the words she has spoken that lie behind it, who could blame us? But perhaps Lear, who began the play by seeking partial, outward manifestation of his daughters' love—through words if not through deeds—has come to realize what is in Cordelia's heart—not only her innocence, for that he discovered earlier, but also a certain sacred, living kingdom. Here, in the heart, is the apocalypse, understood properly as a revelation, and the anagnorisis of the tragedy, and the promise of life to come. Perhaps Lear's last words point to the apocalyptic warnings of Luke 17, as well as to Job and one of the most vivid intimations of the doctrine of the resurrection of the body in Hebrew sacred scripture:

"For I am sure that my redeemer liveth, and he shall stand the last on the earth. And though after my skinne wormes destroy this body, yet shall I see God in my flesh. Whom I my selfe shall see, and mine eyes shall beholde, and none other for me, though my reins are consumed within me." (Job 19:25–27) 56

Shakespeare's play is profoundly, fantastically, exuberantly ambiguous. Perhaps this is partly because the existence and location of kingdom must be decided in the heart of the reader. To each his own. Broadening the context of our intertext, one may find in Luke 17:33 the promise that "Whosoever

56 In Hebrew sacred scriptures, the reins (kidneys) were the seat of affections or feelings, in correspondence with our metaphoric understanding of the heart today.

will seek to save his soule shall lose it; and whosoever shall lose it, shall get it." Perhaps it is only as he loses it that Lear can be every inch a king.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The author declares no conflict of interest.

#### **References**

Cunningham, John. 1984. *King Lear*, the Storm, and the Liturgy. *Christianity and Literature* 34: 9–30. [CrossRef]

Frye, Roland Mushat. 1963. *Shakespeare and the Christian Doctrine*. Princeton: Princeton University Press.

Greenblatt, Stephen. 2013. *Hamlet in Purgatory*. Princeton: Princeton University Press.

Kott, Jan. 1974. *Shakespeare, Our Contemporary*. Translated by Boleshaw Taborski. New York: Norton. Kronenfeld, Judy. 1992. "So Distribution Should Undo Excess, and Each Man Have Enough": Shakespeare's *King Lear*—Anabaptist Egalitarianism, Anglican Charity, Both, Neither? *ELH* 59: 755–84. [CrossRef]

Marx, Steven. 2000. *Shakespeare and the Bible*. Oxford: Oxford University Press.

Shakespeare, William. 2001. *Shakespeare's Sonnets*. Edited by Katherine Duncan-Jones. London: Thomson Learning. Shakespeare, William. 2014. *The Complete Works of Shakespeare*, 7th ed. Edited by David Bevington. Boston: Pearson. Shakespeare, William. 2016. *The Norton Shakespeare*, 3rd ed. Edited by Stephen Greenblatt, Walter Cohen,

Tiffany, Grace. 2018. Paganism and Reform in Shakespeare's Plays. *Religions* 9: 214. [CrossRef]

Van Domelen, John E. 1975. Why Cordelia Must Die. *South Central Bulletin* 35: 132–35. [CrossRef]

Vickers, Brian. 2016. *One King Lear*. Cambridge: Harvard University Press.

Wells, Stanley. 2000. Introduction. In *King Lear*. Edited by Stanley Wells. Oxford: Oxford University Press, pp. 1–80.

Wittreich, Joseph. 1984. *"Image of That Horror": History, Prophecy, and Apocalypse in King Lear*. San Marino: Huntington Library.

© 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

*Article*


**3. Results**

Figure 1 and Table S1 show the percentages stratified by age among persons who suffered from CVDs in the working and general populations. WRCVDs had greater percentage contributions, than in the general population, among persons aged 45–54 (42.16%) and 35–44 years (25.49%) in the working population. In contrast, higher CVD attack rates were found in the older age group ≥65 years (61.69%) in the general population than in the working population.

**Figure 1.** Comparisons of percentage of persons suffering from WRCVDs and CVDs in the working and general populations in Taiwan, 2006–2013, stratified by age. WRCVDs: work related cerebrovascular and cardiovascular diseases. CVDs: cerebrovascular and cardiovascular diseases. y: year.

Table 1 reports the number of event and annual age-specific CVD attack rates (per 100,000) in the working and general populations. In the working population, WRCVD attack rates increased approximately four-fold from 2006 to 2013 (2.10 to 8.60 per 100,000 persons). In the same interval, CVD rates in the general population slowly increased (1113.55 to 1853.32 per 100,000 persons) approximately two-fold. A significant age trend was shown in the general population, but such a trend was not seen in observations of WRCVDs.

**Table 1.** Annual event number and age-specific attack rates (per 100,000) of WRCVDs and CVDs in working and general populations.

**Table 1.** *Cont.*

Event/attack rates (per 100,000) are shown. WRCVDs: work related cerebrovascular and cardiovascular diseases. CVDs: cerebrovascular and cardiovascular diseases.

The trends of annual age-specific WRCVD attack rates and CVD attack rates are displayed in Figure 2a,b. WRCVD attack rates generally increased with age (shown in Figure 2a). Moreover, in the general population, a marked increase occurred in the age group ≥65 years, which had the highest CVD rates (as shown in Figure 2b).

(**a**)

**Figure 2.** *Cont*.

**Figure 2.** Trends of annual age-specific WRCVD rates and CVD rates (**a**) in the working population and (**b**) in the general population. WRCVDs: work related cerebrovascular and cardiovascular diseases. CVDs: cerebrovascular and cardiovascular diseases.

(**b**)

An age–period model was used to estimate the RR and 95% CI for WRCVDs and CVDs, and results are shown in Table 2. The population aged ≥65 years was a very different population in the working population than in the general population. Therefore, persons aged ≥65 years old were excluded from the final analysis.

In the working population, period RRs were strongly significant in 2007 and 2010~2013 as compared to 2006 as the reference. An approximate four-fold increase in the WRCVD risk was indicated from 2006 to 2010–2013. Such significant effects of WRCVDs were also found in workers aged 25–64 years. The RRs for WRCVDs increased with age, but we found that the risk rose only two-fold. The highest risk (RR = 1.84; 95% CI = 1.37–2.46) in the 55–64-year age group was shown in comparison to that aged 35–44 years. In the general population, all RRs for CVD onset in each period and age group were significant.

In order to examine the evolution of workers suffering CVD risk disparities across periods and ages, we presented the RRs of CVDs in Table 2. For each concentration of work effect, adjusted RRs were calculated using RRs from the working and general populations. The adjusted RR slightly increased over time, with a considerable increase in 2012 (adjusted RR = 3.84; 95% CI: 2.38–5.61). Of note, there was an observed increase in the adjusted RR in the age group 25–34 years (adjusted RR = 1.08; 95% CI: 0.66–1.94), which significantly decreased in workers aged ≥45 years. At 55–64 years of age, contributions of the effect of work on the CVD risk were slight (adjusted RR = 0.29) but still strongly significant (95% CI: 0.20–0.37).

PARs contributed by working were also calculated using standardized rates. After age and year standardization, the PAR of working exposure was 13.45% (95% CI = 13.2–13.7%). There was a decreasing PAR trend in the age categories 15–24, 25–34, 35–44, 45–54, and 55–64 years, and the percentages were 17.64% (95% CI = 17.4–17.9%), 16.89% (95% CI = 16.7–17.1%), 16.46% (95% CI = 16.2–16.7%), 10.6% (95% CI = 10.4–10.8%) and 0.65% (95% CI = 0.58–0.69%) when standardized by year.

#### **4. Discussion**

As far as we know, this is the first longitudinal study to present the attributes of WRCVDs considered as occupational diseases by workers' compensation systems for comparison to all CVDs in the general population. By comparing two population-based databases from national labor and health insurance, we found disparities between the working and general populations in CVD attack rates. A PAR of 13.45% was contributed from working exposure in populations aged 15–64. The contribution from occupations to CVD risk significantly decreased with age, from an RRadjusted of 0.63 at 45–54 years to an RRadjusted of 0.29 at 55–64 years, when compared to the reference group (persons aged 35–44 years) The PARs of working exposure also decreased with increasing age. This demonstrates that work and work-related factors are very significant risk factors in younger populations.

Three major findings were shown when we looked at temporal and age differences from the age–period analysis. First, WRCVDs and CVDs attacks increased with aging and period in populations aged 15–75 years from 2006 to 2013. However, their performances were different. Second, the magnitude of the differences in CVDs between the working and general populations substantially varied by age, with the largest disparities observed particularly among young and middle-aged adults in the main labor force. A pattern of adjusted RRs and PAR was shown, with significantly higher impacts focused on WRCVDs in young workers. In contrast, aging prominently led to increased CVD onset in the general population. Finally, disparities in period-specific adjusted RRs from CVDs for 2009 and 2013 were modest. However, they were all >1, indicating a substantial improvement in the reporting and registration of job-related CVDs after the revised guidelines were promulgated.

In our study, the age–period model was used to adjust for age and period influences [22], and RRs denoted the ratios of morbidity rates as a relative indicator for the reference group after adjustment. Taking account of background age and period trends, RRadjusted was used to adjust residual confounding in the general population. In our observations, the annual CVD attack rates from 2006 to 2013 ranged from 1114 to ~1853 per 100,000. These findings are similar to those in developed countries including the United States, Australia, and Britain [23,24]. As far as we know, age is the strongest risk factor for CVDs in the population, and the aging of the population is projected to continue. We adjusted for the age effect in our age–period model analysis. In addition, the NHIRD population is a representative sample of the general population in Taiwan, which was good for excluding residual confounding.

In our analysis, the working population WRCVD attack rate increased with age. However, the age distribution of CVD events differed between the two populations. Among 109,236 CVD events in the general population, 61.69% were among people aged ≥65 years. However, among 408 WRCVDs, 42.16% were among workers 45–54 years old and 25.49% were among workers 35–44 years old. After eliminating background residual confounding, attributable work-related excessive CVD risk mainly occurred in workers aged 45–54 and 35–44 years. The effect was huge, i.e., fourfold (RRadjusted from 0.29 at 55–64 years to 0.6–1.0 at 35–54 years). A Scottish study indicated that premature death from coronary heart disease remains a major contributor to the most affluent groups aged 35–44 and 45–54 years [25,26]. Since middle-aged workers in Japan have been reported to experience prolonged working hours and occupational stress related to CVD risk [27], much evidence has focused on associations between CVDs and occupational factors such as working hours and stress [28].

In a worldwide diagnosis of guidelines for occupational CVDs made in different periods, the governments of Taiwan, Japan, and Korea only recognize CVDs caused by overwork as WRCVDs. The Taiwan Labor Department published "Guidelines for the Diagnosis of Work-Related Cardiovascular Diseases" in 2004 and revised it to be more sensitive in December 2010. Our study showed the higher adjusted RRs of CVDs in 2007 and 2012. The WRCVD attack rate increased from 5.71 in 2010 to 8.60 in 2013 per 100,000 people in the post-2010 revised guideline period. Similarly, the Japanese government recognized WRCVD diagnostic criteria in late 2001, and a gradual increase was found in total compensated CVD occupational diseases [15]. Nevertheless, the Korean government produced occupational health standards in 2003 and found that compensated CVDs accounted for 26% of the total compensated diseases in 2003, which was a dramatic increase, but the proportion dropped to 7% by 2009 [1]. Reducing compensatory CVDs may be attributable to many preventive activities carried out by governments and employers, but occupational health policy advocacy may increase the annual recognition of WRCVDs. The possible directions need further study.

We provided an exploratory descriptive tool to examine the occupation-attributed relative risk by age and period by taking account of the residual confounding of unknown background factors. Most notably, the present study is the first to examine combined national labor and health insurance databases, which was ideal and strengthened the results. The CVD diagnosis was performed according to ICD-9 codes. WRCVD events were identified through the application and review of guidelines from the government, which identified occupational causes of acute circulatory diseases. The population size was representative and was based on national insurance databases of the workforce and general population. Therefore, the findings in this study are reasonable to present as epidemiological evidence.

Three limitations should be considered in this study. First, the application accuracy of occupational diseases is related to a willingness to recognize occupational causes of injuries or health problems. These assessments included personal exposures to environmental risk factors, for example, from evidence of job insecurity, working hours, job intensification, and management [29,30]. This might vary by age, period, social culture, and country. Problems are also related to the historical background of workers' demands for protection and prevention or compensation and their employers seeking to deny or reduce their liability for work-related diseases and injuries. Second, CVD identification in the general population is based on ICD-9 codes. Due to data extraction limitations, all attack cases included recurring events. However, the stratum-specific rate ratio may have a lower impact in estimation because the extraction criteria for each group are the same. Finally, most WRCVD registered events are recorded for males. The estimations are unstable in some strata in separating by gender. This issue should be considered in the future.

#### **5. Conclusions**

CVDs occurred in different periods and age groups in the two insurance system databases. The relative effects attributed to work were more severe in the younger population. Persistent intensive assessment and management of overwork and preventing WRCVDs among young workers are important [31,32]. It should be noted that monitoring regimens across subgroups, as well as the most effective timing and efficacy of primary, secondary, and tertiary preventive interventions for public health policies should be determined in future studies.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1660-4601/16/6/961/ s1, Table S1: Percentage stratified by age and year among persons who suffered CVDs in the working and general populations.

**Author Contributions:** Data curation, Y.-Y.H. and R.W.; funding acquisition, C.-H.B.; investigation, C.-H.B.; methodology, C.-H.B.; project administration, C.-H.B.; supervision, C.-H.B.; writing—original draft, Y.-Y.H.

**Funding:** This study was supported by the Institute of Labor, Occupational Safety, and Health (awarded to ILOSH) and Ministry of Labor, and Ministry of Science and Technology (MOST 107-2314-B-038-072-MY3) in Taiwan.

**Acknowledgments:** This work was supported by the Council of Labor Affairs, Institute of Labor Occupational Safety and Health in Taiwan.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

International Journal of *Environmental Research and Public Health*


**1. Introduction**

Fucosterol is abundant and one of the dominant sterols in marine macroalgae [1]. The purest form of fucosterol and its potency were first identified and observed in the brown macroalga *Fucus vesiculosus* by Heilbron et al. [2]. Fucosterol is a stigmasterol bond isomer expressed by the empirical formula C29H48O. The fucosterol content in macroalgae ranges from 4 to 95% of the total phytosterol content [3]. Brown macroalgae contain higher levels of fucosterol than green and red macroalgae. The fucosterol content in brown macroalga *Ecklonia radiata* ranged between 312.0 μg/g dry weight in leaves and 378.1 μg/g dry weight in stipes (98.6 and 98.9% of total sterols, respectively) [4]. In the brown macroalgae *Himanthalia elongata*, *Undaria pinnatifida*, and *Laminaria ochroleuca*, fucosterol was observed

**Citation:** Meinita, M.D.N.; Harwanto, D.; Tirtawijaya, G.; Negara, B.F.S.P.; Sohn, J.-H.; Kim, J.-S.; Choi, J.-S. Fucosterol of Marine Macroalgae: Bioactivity, Safety and Toxicity on Organism. *Mar. Drugs* **2021**, *19*, 545. https://doi.org/ 10.3390/md19100545

Academic Editors: Marco García-Vaquero and Brijesh K. Tiwari

Received: 10 September 2021 Accepted: 24 September 2021 Published: 27 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

predominantly in 83–97% of the total sterol content [5]. Fucosterol was also reported to be dominant in *Stephanocystis hakodatensis* (formerly *Cytoseira hakodatensis*) and *Sargassum fusiforme*, which contained 65.9% and 67% of fucosterol, respectively [6].

Brown macroalgae are widely used as food and herbal medicine in Southeast Asia and several European countries. In Europe, brown macroalgae have been used to treat goiter and obesity [7]. In East Asia, brown macroalgae from the genera *Laminaria*, *Undaria,* and *Sargassum* (formerly *Hizikia*) are widely consumed daily and used as herb medicine [8–12]. Hence, the bioactive properties of brown macroalgae have drawn the attention of researchers. Previous studies have investigated fucosterol properties and their potential bioactivities. The antioxidant effect of fucosterol was reported by Lee et al. [13]. Furthermore, Jung et al. [14] investigated the anti-inflammatory properties of fucosterol in LPS-stimulated conditions. Fucosterol has the potential to inhibit particulate-induced inflammation and oxidative stress in the alveolar cell line A549. Through regulation of the FoxO signaling pathway, fucosterol exhibits anti-obesity characteristics by suppressing adipogenesis in 3T3-L1 preadipocytes [15]. In addition, fucosterol protects human neuroblastoma cell line SH-SY5Y cells from amyloid-induced neurotoxicity [16] and affects human lung cancer cells by inducing apoptosis and cell cycle arrest and targeting the Raf/signaling mitogen-activated protein kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway [17]. Based on these studies, fucosterol can potentially be developed for use in nutraceutical and pharmaceutical fields. However, before further developing fucosterol properties, information on the safety and toxicity of fucosterol is required to comprehend the optimum and sustainable benefits of fucosterol as a functional agent. This study reviews the current scientific literature regarding the bioactivity, safety, and toxicity of fucosterol extracted from marine macroalgae. In addition to the bioactivity of fucosterol, we investigated the safety and toxicity of fucosterol in various organisms, including bacteria/fungi, animal cell lines, human cell lines, and animals. Through this review article, we express our hope that the applications of fucosterol from marine algae can be further developed in the nutraceutical and pharmaceutical industries.

#### **2. Results and Discussion**

Studies on the bioactivity, safety, and toxicity levels of fucosterol from marine macroalgae conducted from 2002 to 2020 were reviewed, and an increasing trend was observed (Figure 1). This indicates that fucosterol has drawn additional research attention in recent years.

**Figure 1.** Number of publications on the safety and toxicity of fucosterol published in each year.

Articles discussing the bioactivity, safety, and toxicity of fucosterol were categorized with respect to the various organisms or cells whose treatment they describe (Figure 2). Published studies on the safety and toxicity of fucosterol from marine algae have focused on its effects on bacteria and fungi (21%), animal cell lines (14%), human cell lines (38%), and animals (26%). The safety and toxicity of fucosterol have been studied both in vitro and in vivo. No clinical study of fucosterol has been conducted to date. Therefore, the investigation of the safety and toxicity of fucosterol at the clinical stage might be challenging.

**Figure 2.** Numbers of publications on safety and toxicity of fucosterol categorized according to the treated organisms or cells.

The numbers of publications on the safety and toxicity of fucosterol from various sources of macroalgae are shown in Figure 3. Sixteen marine algae species belonging to Dictyotaceae, Sargassaceae, Alariaceae, Lessoniaceae, and Fucaceae families have been studied in relation to their fucosterol bioactivity, safety, and toxicity on bacteria, fungi, animal cells, human cells, and animals. Among the 16 marine algae, *Sargassum fusiforme* (formerly *Hizikia fusiformis*) has become the greatest marine macroalgal source for fucosterol that has been studied. Over the last 10 years, studies on the bioactivities and nutritional and pharmacological properties of *S. fusiforme* have increased steadily. Most of the studies on the bioactivity of *S. fusiforme* have focused on its antioxidant (15.09%), anticancer and antitumor (15.09%), anti-inflammatory (11.32%), photoprotective (11.32%), and neuroprotective (11.32%) properties [18]. Figure 3 shows that the study of fucosterol in *S. fusiforme* has focused on its antioxidant, anti-osteoarthritic, anti-inflammatory, anti-photoaging, antidiabetic, hepatoprotective, and algicidal effects. *Ecklonia cava* subsp. *stolonifera* (formerly *Ecklonia stolonifera*) is the second most frequently reported macroalgal species that has been studied for its fucosterol content. *Ecklonia* species have been known as potential source of bioactive compounds [19]. Studies on the safety and toxicity levels of fucosterol obtained from *Ecklonia stolonifera* were mostly conducted on animal cell lines, human cell lines, and animals. Fucosterol from *Ecklonia stolonifera* has been studied for its antidiabetic, anti-obesity, anti-neurological, and hepatoprotective effects. The safety and toxicity levels of fucosterol obtained from *Ecklonia cava* subsp. *stolonifera* were mostly studied in animals.

**Figure 3.** Numbers of publications on safety and toxicity of fucosterol classified according to sources of macroalgae.

#### *2.1. Characteristics and Structure of Fucosterol*

Generally, fucosterol could be obtained by extracting dry powder of macroalgae using MeOH, EtOH, or *n*-hexane solvents [13,20–24]. The extracts were then partitioned via solvent fractionation [13,25]. After solvent dissolution under reduced pressure, the organic extracts were fractionated using silica gel column chromatography with a mixture of solvents of increasing polarity [14,22,23,26]. The fraction was eluted using a solvent to remove fatty acids, which were then analyzed further [26].

Currently, fucosterol analysis and identification are carried out using physical properties and spectroscopic methods, including 1H-NMR and 13C-NMR, as well as via comparison with published data, and thin-layer chromatography (TLC) analysis [20]. According to the molecular formula of fucosterol, one hydroxy group must be attached to C-28 in an *R* or *S* configuration. An olefin proton signal and two sets of two olefin signals indicate the presence of a tri-substituted double in the fucosterol side chain [22]. Infrared (IR) absorption peaks of fucosterol at 3400 and 1600 cm−1 were attributed to the hydroxyl and olefin groups, respectively. Fucosterol derivatives, namely 24*R*,28*R*- and 24*S*,28*R*-epoxy-24- ethylcholesterol, and 24*R*-saryngosterol have also been used in octadecyl silica gel (ODS) column chromatography [21]. The structure of fucosterol is shown in Figure 4.

**Figure 4.** Chemical structure of fucosterol.

#### *2.2. Bioactivity of Fucosterol*

Fucosterol of marine macroalgae exhibited antidiabetic, anti-obesity, anti-osteoarthritic, immunomodulatory, anticancer, anti-inflammatory, anti-photoaging, hepatoprotective, anti-neurological, antioxidant, and antimicrobial activities (Figure 5).

**Figure 5.** Bioactivities, safety, and toxicity levels of fucosterol derived from macroalgae.

## 2.2.1. Antidiabetic Activity

Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body cannot use insulin effectively. One of the antidiabetic effects of fucosterol obtained from *Eisenia bicyclis* and *Ecklonia cava* subsp. *stolonifera* is characterized by inhibition of enzymes, such as rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), α -glucosidase, and PTP1B. The docking simulations clearly demonstrated negative binding energy for fucosterol ( −8.2 kcal mol−1 for RLAR and −8.5 kcal mol−1 for HRAR), implying a higher affinity and stronger binding competence for the active site of the enzyme [20]. These results were confirmed by Jung et al. [27], who stated that *Ecklonia stolonifera*-derived fucosterol reduced insulin

resistance by decreasing PTP1B expression and activating insulin signaling pathways. Fucosterol from *Sargassum fusiforme* also showed strong PTP1B inhibition at low concentrations [28]. Streptozotocin-induced diabetic rats treated with fucosterol from *Pelvetia siliquosa* via an orally administered dose of 30 mg/kg showed a decrease in serum glucose levels and inhibition of its accumulation. However, orally administered doses of 300 mg/kg are required for epinephrine-induced diabetic rats to inhibit blood glucose levels and degrade glycogen [29]. These findings illustrate that fucosterol extracts from *Eisenia bicyclis*, *Ecklonia cava* subsp. *stolonifera*, *Sargassum fusiforme*, and *Silvetia siliquosa* have antidiabetic potential that can be developed in the future.