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The Role of Zinc in the Treatment of Taste Disorders

Authors:
  • Kobe Tokiwa Junior College

Abstract

Although in 1990s the number of patients with taste disorders in USA and Japan was over 1 million people each year, it is annually increasing. Taste disorders are caused by several factors such as genetic disease, head trauma, structural changes, glossodynia, cancer, lifestyle, and others. The role of zinc in the treatment of taste disorders has been studied since the oral administration of zinc by patients was reported to improve their taste disorders. Carbonic anhydrase (CA), a zinc metalloenzyme, has also been studied in association with taste disorders, since the regulation of serum CA levels was shown to influence the effect of orally administrated zinc in the treatment of taste disorders. Zinc is an essential trace element that contributes to the active center of approximately 300 enzymes. Studies have revealed that zinc is involved in various physiological functions. Moreover, some medications have been shown to induce a zinc deficiency, which has been associated with a variety of clinical conditions. Hence, since the relationship between taste disorder and serum zinc concentration have been discussed for long time, taste disorder may be useful in diagnosing zinc deficiency. Moreover, the appearance of the medicine of the zinc-containing supplement type contributes to the treatment of taste disorders due to zinc deficiency. Orally administered zinc has been shown to directly stimulate food intake via neuropeptide in the hypothalamus. Therefore, zinc administration may be potentially used to treat taste disorders as well as several other diseases by stimulating feeding.
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44 Recent Patents on Food, Nutrition & Agriculture, 2013, 5, 44-51
The Role of Zinc in the Treatment of Taste Disorders
Takakazu Yagi1, Akihiro Asakawa2,*, Hirotaka Ueda1, Satoshi Ikeda3, Shouichi Miyawaki4 and
Akio Inui2
1Department of Orthodontics, Medical and Dental Hospital, Kagoshima University, Kagoshima, 890-8544, Japan;
2Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sci-
ences, Kagoshima, 890-8520, Japan; 3Department of Rehabilitation and Physical Medicine, Kagoshima University
Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan; 4Department of Orthodontics and Den-
tofacial Orthopedics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520,
Japan
Received: November 27, 2012; Revised December 27, 2012; Accepted: January 6, 2012
Abstract: In the 1990s the number of patients diagnosed with taste disorders in the USA and Japan was over one million
people each year, and the number is increasing annually. Taste disorders are caused by several factors such as genetic dis-
ease, head trauma, structural changes, glossodynia, cancer, change of lifestyle, and more. The role of zinc in the treatment
of taste disorders has been studied since the oral administration of zinc by patients was reported to improve their taste dis-
orders. Carbonic anhydrase (CA), a zinc metalloenzyme, has also been studied in association with taste disorders, since
the regulation of serum CA levels was shown to influence the effect of orally administrated zinc in the treatment of taste
disorders. Zinc is an essential trace element that contributes to the active center of approximately 300 enzymes. Studies
have revealed that zinc is involved in various physiological functions. Moreover, some medications have been shown to
induce a zinc deficiency, which has been associated with a variety of clinical conditions. Hence, since the relationship be-
tween taste disorder and serum zinc concentration has been discussed for long time, taste disorder may be useful in diag-
nosing zinc deficiency. Moreover, it appears that medicines of the zinc-containing supplement type contribute to the
treatment of taste disorders caused by zinc deficiency. Orally administered zinc has been shown to directly stimulate food
intake via neuropeptide in the hypothalamus. Therefore, zinc administration may potentially be used to treat taste disor-
ders, as well as several other diseases by stimulating feeding. The article presents some promising patents on the role of
zinc in the treatment o f taste disorders.
Keywords: Carbonic anhydrase (CA), feeding, saliva, taste disorder, zinc deficiency, zinc transporter.
INTRODUCTION
Zinc is an ubiquitous trace element that is indispensable
to the growth and development of microorganisms, as well
as plants and animals [1]. Zinc deficiency, which causes a
variety of clinical diseases, was initially recognized in 1961
[2]. The two identified causes of zinc deficiency are low zinc
intake and high intake of processed and prepared foods con-
taining polyphosphoric acid-sodium tripolyphospate blends,
which drains zinc from the body [3].
The oral cavity performs various physiologic functions
that are important for a healthy body. However, oral health
impairment has not been given proper attention by the medi-
cal commun ity because it has been considered a rather mild
disease condition that rarely requires urgent medical inter-
vention. Nevertheless, impaired oral function may directly
affect the quality of life; for instance, loss of appetite can
lead to malnutrition [4]. The number of patients with taste
*Address correspondence to this author at the Department of Psychosomatic
Internal Medicine, Kagoshima University Graduate School of Medical and
Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan;
Tel: +81 99 275 5751; Fax: +81 99 275 5749;
E-mail: asakawa@m2.kufm.kagoshima-u.ac.jp
disorders in the USA was 1.10 million in 1994 (0.6% of the
population aged >18 years) [5]. In Japan, the number of pa-
tients with taste disorders who visited otolaryngological clin-
ics seeking treatment was approximately 1.4 million in 1990
(0.14% of the population aged >20 years) [6]. However, a
Japanese survey conducted in 2003 showed a 1.44-fold rise
in the number of patients with taste disorders [7]. The pri-
mary cause behind this increase is the growth of the elderly
population in Japan (above 65 years old) from 14.9 million
in 1990 to 22.0 million in 2000 [7]. In fact, age-related de-
cline in taste acuity may be both a cause and an effect of zinc
depletion, and it may be associated with an increased re-
quirement of zinc. Moreover, this age-related decline in taste
acuity will likely be observed globally [8-10]. And the re-
sults of the 1994 USA survey also indicated that 40% of pa-
tients with taste and smell disorders were more than 65 years
old [5]. The secondary cause behind this increase is a rise in
the number of young people, especially young women, who
experienced low taste sensitivity in the past decades due to
unbalanced diet habits, which poses a serious problem [7,
11-13]. Since taste buds are known to contain various zinc-
containing enzymes, zinc deficiency will cause taste disor-
ders [7]. The potential ameliorating effect of oral zinc ad-
/13 $100.00+.00 © 2013 Bentham Science Publishers
The Role of Zinc in the Treatment of Taste Disorders Recent Patents on Food, Nutrition & Agriculture, 2013, Vol. 5, No. 1 45
ministration on taste disorders was first described in 1970
[14]. Recently, the mechanism by which zinc affects taste
disorders has been elucidated and the zinc supplementation
studies have been advanced for the treatment of taste disor-
ders. In this review, we describe the relationship between
zinc and taste disorders.
1. THE EFFECT OF ZINC ON TASTE DISORDERS
1.1. Pathophysiology of Zinc
Zinc is typically bound to a number of proteins, including
the group of enzymes referred to as zinc enzymes and zinc-
finger proteins [15]. Carbonic anhydrase (CA) is a zinc met-
alloenzyme that catalyzes the reversible hydration of carbon
dioxide and is involved in the regulation of ions, fluid, and
acid-base balance in various tissues [16]. Zinc contributes to
various homeostatic functions including: growth, develop-
ment, wound healing, immune functions, skin metabolism,
maintenance of central nervous system and retinal function
(participation in vitamin A metabolism), taste and olfaction,
saliva secretion, production and activity of sperm, prevention
of carcinogenesis and aging (participation in superoxide
scavenging), maintenance of gonadal function and pregnancy
(synthesis and secretion of sex hormones), glucose metabo-
lism (synthesis and activity of insulin), and lipid metabolism
[17]. Free zinc is also found in the nervous system and some-
times acts as a neurotransmitter or neuromodulator [18-21].
Zinc secreted into the extracellular space through regulated
secretory pathways acts as a signaling molecule, particularly
in synaptic neurotransmission [22]. Zinc not only maintains
protein structure but also acts as an intracellular signaling
molecule like calcium [23]. Zinc exchange between the in-
side and outside of the cell is known to be mediated by zinc
transporters which have been identified more than 20 and
characterized [23], and they are classified into two families:
zinc transporters (ZnT: vertebrate cation diffusion facilitator
family proteins, Slc30a family) and Zip (Zrt/Irt-like protein,
Slc39a family) [24-26]. Most ZnT transporters are predicted
to have six transmembrane domains (TMDs), while Zip
transporters have eight TMDs. Studies have shown that ZnTs
function to efflux zinc out of the cytoplasm, while Zips are
responsible for transporting zinc in the opposite direction
[23]. The coordinated action of these two zinc transporters is
essential to the maintenance of zinc homeostasis in the cyto-
plasm [23]. Oral zinc sulfate solutions inhibit sweet and bit-
terness taste perception [27, 28]. In humans, normal zinc
concentrations in serum range from approximately 60 mg/dL
to 110 mg/dL [29]. Disruption of zinc homeostasis could po-
tentially cause several changes in cytoplasmic and tissue en-
zyme levels, depending on the extent of zinc deficiency or
excess, and the duration of the disruption as well as its timing.
Excessive zinc intake has been shown to induce copper-
deficiency [30], iron deficiency anemia [31], acute toxication
(diarrhea and/or vomiting) [32], impaired immune response
[33], increased systemic blood pressure, and reduced renal
blood flow in rats [34]. On the other hand, zinc deficiency
reportedly induces a number of pathophysiological condi-
tions such as a decreased taste sensation, hypogeusia, hy-
posmia, growth retardation, dermatitis, alopecia, gonadal
hypofunction, abnormal pregnancy, susceptibility to infec-
tions, delayed wound healing, impaired glucose tolerance,
anorexia, and increased rates of carcinogenesis [15, 35-39].
Moreover, it has been associated with various psychological
and psychiatric conditions such as eating disorders [40], de-
pression [41], and attention deficit disorder [42]. Zinc defi-
ciency causes changes in the levels of leptin [43] or low
gustin concentrations which are the major zinc-containing
protein in human parotid [44]. Acrodermatitis enteropathica,
which is caused by a genetic mutation in a gene (SLC39A4)
that encodes a zinc transporter protein (ZIP4), is associated
with defective zinc absorption through the intestinal cells
[45]. Acrodermatitis enteropathica is a rare autosomal reces-
sive vesicobullous skin disorder characterized by diarrhea,
inflammatory rash around the mouth and/or anus, mouth
ulcers, red glossy tongue, and hair loss [46]. Posteriori zinc
deficiency, which results from reduced dietary zinc intake or
absorption, or increased elimination, is more common than
the deficiencies caused by genetic disorders. For example,
individuals who follow a vegetarian diet, suffer from alco-
holism or anorexia nervosa, or depend on total parenteral
nutrition are at high risk of zinc deficiency [46]. Zinc defi-
ciency also induces the degeneration of soft palate taste buds
in rats, according to electron microscopy observations [47].
1.2. Physiology of Taste Sensation
1.2.1. Neural Circuitry of Taste Sensation
Gustatory receptor cells are located in the taste buds,
which are visible on tongue papillae. The receptor cells are
innervated by afferent neurons. Taste sensation information
from receptor cells in the taste buds is initially transported to
the first relay nucleus, which is the rostral part of the nucleus
of the tractus solitarius (NTS), through branches of the facial
(chorda tympani and greater superficial petrosal), glosso-
pharyngeal, and vagus (superior laryngeal) nerves. In ro-
dents, the second relay nucleus is the parabrachial nucleus
(PBN) of the pons. The third relay is the parvocellular part of
the ventralis posteromedial thalamic nucleus (VPMpc). The
thalamic nucleus then projects to the cortical gustatory area
(CGA) in the insular cortex (IC) [48]. In monkeys and hu-
mans, ascending fibers of neurons in the gustatory area of
the NTS directly reach the VPMpc directly [49]. Functional
magnetic resonance imaging (fMRI) studies have also indi-
cated that the taste stimuli activate the insula and frontal op-
erculum (primary taste cortex) and the orbitofrontal cortex
(secondary taste cortex) in human [50].Taste information is
sent to the reward system and the feeding center via the pre-
frontal cortices such as the mediodorsal and ventrolateral
prefrontal cortices in rodents and the orbitofrontal cortex in
primates [49]. The main components of the reward system
are the ventral tegmental area (VTA) of the midbrain, where
the origin of the mesolimbic dopamine system is located; the
nucleus accumbens (NAc) of the ventral forebrain, which is
an essential interface between motivation (e.g., palatability)
and action (e.g., eating); and the ventral pallidum (VP)
GABAergic system, which is situated between the NAc and
lateral hypothalamus (LH) [49]. Autonomic, behavioral, and
motor responses related to feeding are mainly regulated by
the hypothalamic orexigenic neuropeptides [51]. Furudono et
al. [52] reported that drinking the sweet-tasting saccharin
solution elevated the mRNA levels of orexin in LH and Neu-
ropeptide Y (NPY) in the arcuate nucleus (ARC) of rats.
Moreover, the administration of orexin-A and NPY en-
46 Recent Patents on Food, Nutrition & Agriculture, 2013, Vol. 5, No. 1 Yagi et al.
hanced the in take of saccharin; the intracerebroventricular
(ICV) administration of orexin-A and NPY facilitated gastric
motility and the draining of gastric contents [52]. Orexigenic
signals that facilitate gastric function are transmitted to vari-
ous parts of the brain, including the dorsal motor nucleus of
the vagus, until the activation of the satiety center. Addition-
ally, a brain opioid is produced in the ARC and acts on the
nucleus accumbens that is part of the reward system [53].
Taste is unique among the sensory systems due to its asso-
ciation with reward and aversion. However, it is debatable
how taste system interacts with those regions. We showed a
schematic diagram of hypothetical central projection of taste
information in primates Fig. (1).
1.2.2. Peripheral Taste Sensation: Taste Receptors and
Chemical Tastants
The five basic taste qualities recognized are saltiness,
sourness, sweetness, bitterness, and umami, which is defined
by a savory taste characteristic of the amino acid glutamate
[49]. Each taste cell in the taste buds expresses one of the
five taste receptors that selectively in teracts with chemical
tastants such as sodium chloride, hydrochloric acid, sucrose,
quinine, and umami substances [49]. Taste receptors contain
two G protein-coupled receptor families, T1R and T2R.
Gustducin is a trimetric G-protein complex that is involved
in sweet, bitter, and umami taste transduction [54]. Gust-
ducin-coupled sweet taste receptors have been demonstrated
in the proximal intestine of mice and humans [55]. Since
taste substances must pass through a saliva layer to reach
their recep tor site, taste sensitivity is affected by the interac-
tion between the taste substance and saliva. This process
involves the solubilization of the tastants in saliva, possible
chemical interactions with the various components of saliva,
and the diffusion and dilution of the tastants in saliva [56].
Hence, salivary secretion plays a key role in taste, including
the transport of taste substances and the protection of taste
receptors [56]. Saliva flow rates and composition are also
influenced by the type of taste stimulus [57]. Therefore, im-
paired taste sensitivity could be affected by saliva flow and
chemical interactions between tastants and saliva.
1.3. Classification of Taste Disorders
Taste disorders are classified into two types, on the basis
of the presen ce or absence of taste: ageusia and dysgeusia.
Ageusia is the complete loss of the ability to taste, which is
caused by the redundant gustatory innervation of the tongue.
Dysgeusia is the imp airment of taste sensation and is the
most common type of taste disorder, occurring in about 34%
of all patients with taste disorders [4]. Dysgeusia is classified
into two types: hypogeusia and hypergeusia. Hypogeusia is
defined by a partial loss of the ability to taste. Hypergeusia
refers to enhanced gustatory sensitivity. According to some
reports, sweet dysgeusia sometimes reflects the first sign of
lung tumors [58]. Therefore, dysgeusia may be indicative of
a systemic disease.
Taste disorders can also be classified into three catego-
ries, on the basis of the state of impairment. The first cate-
gory involves external damage to the gustatory papillae and
taste buds, and is caused by dry mouth (xerostomia, hy-
posalivation) [59], tongue coating [60], atrophic glossitis
[61], iatrogenic causes (e.g., dental treatment or exposure to
radiation) [59], burns, exposure to toxic substances [59], and
other external sources of damage. The second category in-
volves internal damage to the gustatory papillae and taste
buds, and is caused by zinc deficiency, aging, excessive
Fig. (1). Summary diagram of the connections between taste input
and the feeding and reward system.
NTS: nucleus of the tractus solitaries; VPMpc: parvocellular part of
the ventralis posteromedial thalamic nucleus; CGA: Cortical gusta-
tory area; IC: insular cortex; PFC: prefrontal cortex; AMY:
amygdala; VTA: ventral tegmental area; NAc: nucleus of accum-
bens; VP: ventral pallidum; LH: lateral hypothalamic area. LH
stimulates gastric function and provides much of the motivation for
feeding. T. Yagi is copyright folder.
The Role of Zinc in the Treatment of Taste Disorders Recent Patents on Food, Nutrition & Agriculture, 2013, Vol. 5, No. 1 47
medication intake, vitamin deficiency, systemic disease (e.g.,
bulimia, anorexia, hypothyreoidismus, Cushing’s syndrome,
diabetes mellitus, liver disease, and others), infections of the
upper respiratory tract [60], and exanthema dysgeusia [60].
The third category involves disturbance of the taste sensation
neural pathway as a result of peripheral or central nerve
damage [60], such as taste bud degeneration occurring after
chorda tympani nerve injury or head trauma [62]. However,
it is possible for taste cells to regenerate, with a half-life of
approximately 10 days [63].
1.4. Taste Disorders Related Zinc Deficiency led by Drug
and the Decrease in Saliva Secretion
Drug-induced taste dysfunction is one of the main forms
of taste disorders [60]. Henkin and Bradley [14] showed that
patients treated with D-penicillamin e manifested with hypo-
geusia symptoms or decreased taste acuity, which they
speculated was due to the D-penicillin sulfhydryl (SH)
group’s metal-chelating effects [14]. Moreover, a wide spec-
trum of drugs has been associated with numerous adverse
orofacial manifestations; particularly, dry mouth, taste disor-
der, oral mucosal ulceration, and gingival swelling due to
zinc-chelating effects [64, 65].
Dry mouth (xerostomia) is associated with glossodynia,
which could indicate diabetes, hypothyroidism, iron or zinc
deficiency, or vitamin B complex (particularly vitamin
B12) deficiency [66]. Histological studies in rats have
shown that the surgical removal o f the 3 major salivary
glands results in pathological changes such as hyperkerato-
sis of the tongue epithelium, shrinkage of taste buds, and
penetration of bacteria into the apical portion of the taste
cells [67]. The Sjögren’s syndrome (SS), which is a sys-
temic autoimmune disease, also exhibits xerostomia and
taste disorder symptoms [68]. Several studies have sug-
gested that taste disorders in SS patients are caused by the
reduction in salivary flow [68]. A recent report demon-
strated that the zinc ion dependent B-cell epitope, which is
associated with primary SS, resides within the putative zinc
finger domain of the Ro60kD autoantigen [69]. Therefore,
zinc therapy could potentially be used to treat taste disor-
ders associated with SS.
2. THERAPEUTIC EFFECT OF ZINC ON TASTE
DISORDERS
2.1. Relationship Between Carbonic Anhydease and
Taste Disorder
Some studies have revealed that carbonic anhydrase (CA)
IV, a zinc metalloenzyme, is found in salivary glands and
has been localized to taste buds in rats [70, 71]. CA plays
several roles in ion transport, saliva production and secre-
tion, and regulation of saliva pH and buffering capacity [72,
73]. Dysgeusia has been reported as a side effect of CA in-
hibitors used in the treatment of glaucoma and high-altitude
sickness [74]. At least 11 cytosolic, membrane-bound, mito-
chondrial, and secretory CA isozymes have been identified
[75-78]. Long-term zinc deficiency reportedly reduces the
gene expression of CA isozyme II, but not that of CA VI, in
the rat submandibular gland [71]. Studies have also shown
that long-term effects in zinc deficient rats caused a decline
in CA activity that was paralleled by decreased sensitivities
of both the gustatory and trigeminal nerves. This suggested
that zinc deficiency could significantly reduce the ability of
the central nervous system to transduce chemical and so-
matic sensations [38, 79].
Henkin et al. demonstrated that orally administrated zinc
treatment affected taste disorders in patients with CA IV
deficiency [80]. Therefore, Zn and CA therapy could be de-
veloped for pharmaceutical application and could potentially
be used to treat hypogeusia [38]. And, the taste test may
have a potential to practical use in the diagnosis of Zn defi-
ciency as a simple and noninvasive method.
2.2. The Suspect of the Effect of Zinc for Treatment of
Taste Disorders
Although some clinical investigations have shown that a
low serum concentration of zinc is one of the systemic fac-
tors that induce taste disorders [14, 81], other reported re-
sults do not support this observation [82-84]. For instance, a
double-blind study showed that zinc sulfate supplementation
was ineffective at treating patients with taste dysfunctions
and the study found no correlation between zinc serum con-
centration and taste function in SS patients [68, 85]. Moreo-
ver, another study reported that zinc sulfate did not favorably
influence the time interval to recovery of taste sensation
among head and neck cancer patients who have undergone
radiotherapy and who suffer from taste disorders [86]. An
experimental study performed on rats showed normal synap-
tic activity between nerve fibers and taste cells upon the sur-
gical removal of major salivary glands [67]. Furthermore,
chorda tympani responses to tastants dissolved in water were
found to be impaired when the tongue was adapted to dis-
tilled water [87]. Therefore, it may be suggested that the de-
crease in taste sensitivity could be simply explained as a
transient reduction in the diffusion of taste substances to the
receptor sites. Further studies are required to understand the
effect of zinc and the influence of saliva on taste disorders.
2.3. The Effect of Zinc Supplement for Treatment of
Taste Disorders
Some orally active Zn (II) complexes have been re-
ported to dramatically ameliorate the pathophysiology of
diabetes mellitus and metabolic syndrome in animal ex-
periments [88]. Although zinc sulfate was frequently used
for zinc deficiency treatment in the past, it was adminis-
tered in capsules that were custom-made by physicians or
pharmacists. Polaprezinc, a zinc-containing compound
formulated as white odorless granules that have been used
for treating peptic ulcer and is currently used for treatment
of oral symptoms in Japan, was shown to correct abnormal
taste preferen ces in rats and to reverse the reduced turnover
rate of taste bud cells [89]. Polaprezinc improves parakera-
tosis and decreases taste bud cell proliferation caused by
zinc deficiency [90]. Moreover, data was collected on the
therapeutic effectiveness of zinc gluconate (140 mg/d for
three months) in the treatment of idio pathic dysgeusia [91].
Since polaprezinc is a commercially available drug, any
pharmacy can dispense it and will receive widespread ac-
ceptance by physicians. The intake strategy of zinc is im-
portant when considering elderly people and patients show-
48 Recent Patents on Food, Nutrition & Agriculture, 2013, Vol. 5, No. 1 Yagi et al.
ing acquired zinc deficiency and inherited zinc deficiency.
Modern health foods containing zinc, zinc supplements,
and polaprezinc will help the prevention of their symptoms
related to zinc deficiency [17]. However, therapeutic guide-
lines for taste disorders are still unclear and warrant further
human research .
In conclusion, given the various physiological functions
of zinc, it is important to understand whether the distur-
bance of taste sensation could occur when using drugs with
zinc-chelating effects. Oral zinc administration may im-
prove taste disorders and saliva flow rates and may concur-
rently stimulate the feeding system through the hypothala-
mus. This mechanism could contribute to the treatment of
oral pathologies, AN, cachexia, and other conditions. Al-
though zinc is important nutrient for taste, there have been
few studies regarding zinc supplimentation using the opti-
mal form. We hope to understand the clinical effects of
zinc via polaprezinc which is stable capsule. However, the
relationship between zinc metabolism and oral manifesta-
tions, including taste disorders, is not fully understood and
requires further examination.
RECENT PATENTS OF ZINC AS A THERAPY OF
TASTE DISORDERS
Here we introduce some of the most recent and important
patents based on the taste sensing system and zinc. Takao et
al. invented a method of examining zinc deficiency taste
disturbance by determining expression level of taste receptor
in patent US 8017336 B2 [92]. It provides a method of test-
ing for the zinc deficiency dysgeusia, which can be charac-
terized by a correlation in the expression levels of a gene
encoding a gustatory receptor belonging to the THTR family
and to the T2R family obtained from a sample derived from
the oral cavity of a subject. This method is able to test dys-
geusia more objectively for it enables the diagnosis of zinc
deficiency dysgeusia without depending on dysgeusia irre-
spective of human feeling.
Suzuki et al. invented the method of measuring taste
using two phase radial basis function neural networks, a
taste sensor, and a taste measuring apparatus in patent US
7899765 B2 [93]. Most of the taste measurements prior to
this were carried out as taste tests relying on human gusta-
tion. In those times, the judgment of taste was influenced
by the physical and psychological conditions of human
tasters. This new technique relies on an array of selective
electrochemical sensors combined with neural network
computing. The system simultaneously provides quantita-
tive information on selected taste causing substances and
quantitative taste levels directly correlating with human
taste perception.
Regarding zinc, there are some methods for utilizing
zinc as treatment [94, 95]. Lang et al. describe the inven-
tion which provides improved dietary supplement formula-
tions for improving and maintaining ocular nutrition [94].
George et al. patented a method of providing zinc to a sub-
ject in need of treatment by administering the subject with
an effective amount of a sustained-release zinc composition
[95]. Present techniques involve pharmaceutical agents or
nutritional supplements for providing zinc to subjects in
need of treatment [94, 95]. Up until 2007, there were two
patents on zinc concerned with foods. Kojima et al.
had invented both Zinc-containing foods in patent
US20040137036 [96], and Zinc-rich foods for the effect of
preventing diabetes in patent US20060057254 [97]. How-
ever, there have b een no remarkable patents since 2007.
However, there is a patent concerned with the form of sup-
plements [98]. Edelman et al. invented an edible emulsions
with minerals in patent US8043648 [98]. This patent de-
scribes an edible water-in-oil emulsion comprising of a
source of mineral and 15 to 95 wt% fat, wherein the min-
eral is present in the aqueous phase.
Lippard et al. invented methods for mobile zinc meas-
urement in patent Wo 2022019864 [99]. This patent relates
to a method for using a zinc sensor compound, which con-
tain an optical reporter, to detect a disease associated with
the disruption of zinc homeostasis [99]. The invention pro-
vides a more convenient, accurate, robust, sensitive and eco-
nomical method for zinc quantification. It is particularly
valuable for rapid and reliable diagnosis of mobile zinc asso-
ciated diseases in various organs. As a result, it offers a
powerful tool for early diagnosis of zinc related diseases
[99].
In addition, as a patent on zinc in the context of sup-
plemental foods, Martinetti et al. invented a higher loading
zinc-containing film in patent US 20120045495 [100]. This
provides oral and personal care compositions comprising a
film entrained in a carrier, in which the film includes a
relatively high concentration of a zinc-containing com-
pound. Such compositions include, for example, denti-
frices.
CURRENT & FUTURE DEVELOPMENTS
In the future, these promising innovations will contribute
not only to the development of better methods to treatment
for taste disorders but also to understanding the importance
of micronutrients including zinc and the relationship be-
tween feeding of zinc and oral function.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant
number 24593103. We are grateful for the receipt of this
patent for this review.
ABBREVIATIONS
AMY = amygdala
CGA = Cortical gustatory area
IC = insular cortex
LH = lateral hypothalamic area.
NAc = nucleus of accumbens
NTS = nucleus of the tractus solitaries
PBN = parabrachial nucleus
VP = ventral pallidum
The Role of Zinc in the Treatment of Taste Disorders Recent Patents on Food, Nutrition & Agriculture, 2013, Vol. 5, No. 1 49
VPMpc = parvocellular part of the ventralis pos-
teromedial thalamic nu cleus
VTA = ventral tegmental area
PFC = prefrontal cortex
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... Yagi et al. [72] pathogenically classified taste disorders into three categories: (1) external damage to lingual papillae and taste buds caused by dry mouth, tongue problem, toxin exposure, iatrogenic disease, etc., (2) internal damage to lingual papillae and taste buds caused by aging, deficient zinc, medication, diabetes mellitus, etc., and (3) disturbance of taste sensation neural pathway resulting from peripheral and central nerve damage. By referring to these categories, the pathogenic mechanisms underlying gustatory sequelae can be discussed by relating taste disorders to viral cellular entry-responsible receptors, decreased saliva secretion, zinc deficiency, disturbed nervous system and inflammation associated with persistent viral infection. ...
... Zinc is an essential element for transmission of tastes, regeneration of taste buds and maintenance of gustatory functions. While zincmetalloenzyme carbonic anhydrase is localized in taste buds of rats, inhibitors of this enzyme induce dysgeusia [72]. Zinc also has the potential to affect ACE2 receptors responsible for the viral cellular entry because ACE2 is one of zincmetalloenzymes to require zinc for the activity. ...
... They found that the number of T2R-positive cells was markedly smaller in zinc-deficient diet rats than in normal diet rats, suggesting that zinc deficiency may affect bitter taste receptor cells. Zinc deficiency also causes the degeneration of taste buds in rat soft palate [72]. ...
Article
Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit a diverse spectrum of clinical manifestations, some of which last for a long time, making a great impact on the healthcare of patients who recovered from coronavirus disease 2019 (COVID-19). Although taste disorders have been well-recognized to be closely associated with COVID-19, understanding of gustatory sequelae is relatively poor compared with oral symptoms in the early phase of COVID-19. The aim of this study was to characterize gustatory dysfunction in COVID-19 survivors by a narrative literature review of follow-up studies and to speculate the pathogenic mechanisms underlying such a persistent symptom. Scientific articles were retrieved by searching PubMed, LitCovid, ProQuest, medRxiv and bioRxiv from 1 April 2020 with a cut-off date of 10 September 2021. The follow-up time periods of the relevant 49 studies ranged from 4 weeks to 12 months. Results of the literature search indicated that ageusia, hypogeusia and/or dysgeusia persist in up to 45.0% of COVID-19 survivors and that the prevalence of these taste impairments varies depending on ethnicity, age, gender and disease severity of patients. Gustatory dysfunction can be detected at high frequency even one year after symptom onset. Persistence of gustatory dysfunction is pathogenically related to expression of SARS-CoV-2 cellular entry-relevant receptors in taste cells and neural cells, decreased saliva secretion, zinc deficiency, disturbed nervous system and inflammation associated with persistent SARS-CoV-2 infection. Given the long-term persistence of gustatory dysfunction in COVID-19 survivors, their discharge from hospital is not the end of disease. Careful attention should be continuously paid to taste perception of post-COVID-19 patients to recover the health-relating quality of life, which is required for health providers, especially dental professionals who not only may experience COVID-19 survivors but also can easily become aware of their taste abnormalities.
... Zinc is found in high concentrations in taste buds where it plays a significant role in the perception of taste and in the nerve transmission of the gustatory stimulus [63]. Although its role in dysgeusia is little known, it is hypothesized to be a cofactor for alkaline phosphatase in the taste buds, thus making it necessary also for the regeneration and maintenance of taste [64]. Furthermore, zinc could influence the concentration of gustine (zinc-dependent enzyme), through the direct or indirect interaction of carbonic anhydrase-6, which can influence the production of the taste buds [65]. ...
... Furthermore, zinc could influence the concentration of gustine (zinc-dependent enzyme), through the direct or indirect interaction of carbonic anhydrase-6, which can influence the production of the taste buds [65]. Therefore, it would appear that zinc deficiency can induce changes in the number, size and structure of taste bud cells, as well as a decrease in nerve sensitivity [64,65]. Thus, it is possible that zinc deficiency reduces the rate of proliferation and regeneration of taste buds [63,64]. ...
... Therefore, it would appear that zinc deficiency can induce changes in the number, size and structure of taste bud cells, as well as a decrease in nerve sensitivity [64,65]. Thus, it is possible that zinc deficiency reduces the rate of proliferation and regeneration of taste buds [63,64]. Confirmation of this hypothesis comes from the evidence that a significant number of COVID-19 patients with worse clinical picture were zinc deficient [66,67]. ...
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Full-text available
Since the worldwide spread of SARS-CoV-2 infection, the management of COVID-19 has been a challenge for healthcare professionals. Although the respiratory system has primarily been affected with symptoms ranging from mild pneumonia to acute respiratory distress syndrome, other organs or systems have also been targets of the virus. The mouth represents an important route of entry for SARS-CoV-2. Cells in the oral epithelium, taste buds, and minor and major salivary glands express cellular entry factors for the virus, such as ACE2, TMPRSS2 and Furin. This leads to symptoms such as deterioration of taste, salivary dysfunction, mucosal ulcers, before systemic manifestation of the disease. In this review we report and discuss the prevalence and socio-demographics of taste disturbances in COVID-19 patients, analysing the current international data. Importantly, we also take stock of the various hypothesized pathogenetic mechanisms and their impact on the reported symptoms. The literature indicated that COVID-19 patients frequently present with gustatory dysfunction, whose prevalence varies by country, age and sex. Furthermore, this dysfunction also has a variable duration in relation to the severity of the disease. The pathogenetic action is intricately linked to viral action which can be expressed in several ways. However, in many cases these are only hypotheses that need further confirmation.
... Among different isozymes, carbonic anhydrase VI was found to be localized in rat taste buds and salivary glands and also in human parotid and submandibular glands [166]. Carbonic anhydrase VI (previously identified as "gustin") is secreted into saliva by the serous acinar cells of the mammalian parotid and submandibular glands [163]. ...
... They speculated that carbonic anhydrase VI could promote the growth and development of taste buds through its effect on taste bud stem cells. Dysgeusia was reported to occur as a side effect of carbonic anhydrase inhibitors used for the treatment of glaucoma and idiopathic dysgeusia was effectively treated with zinc gluconate [166]. Goto et al. [169] investigated the effects of zinc deficiency on carbonic anhydrase activity in the tongue epithelia and submandibular glands of rats that were given free access to zinc-deficient, low-zinc, or zinc-sufficient diets for 6 weeks. ...
Article
Full-text available
Given the ever-progressing studies on coronavirus disease 2019 (COVID-19), it is critical to update our knowledge about COVID-19 symptomatology and pathophysiology. In the present narrative review, oral symptoms were overviewed using the latest data and their pathogenesis was hypothetically speculated. PubMed, LitCovid, ProQuest, and Google Scholar were searched for relevant studies from 1 April 2021 with a cutoff date of 31 January 2022. The literature search indicated that gustatory dysfunction and saliva secretory dysfunction are prevalent in COVID-19 patients and both dysfunctions persist after recovery from the disease, suggesting the pathogenic mechanism common to these cooccurring symptoms. COVID-19 patients are characterized by hypozincemia, in which zinc is possibly redistributed from blood to the liver at the expense of zinc in other tissues. If COVID-19 induces intracellular zinc deficiency, the activity of zinc-metalloenzyme carbonic anhydrase localized in taste buds and salivary glands may be influenced to adversely affect gustatory and saliva secretory functions. Zinc-binding metallothioneins and zinc transporters, which cooperatively control cellular zinc homeostasis, are expressed in oral tissues participating in taste and saliva secretion. Their expression dysregulation associated with COVID-19-induced zinc deficiency may have some effect on oral functions. Zinc supplementation is expected to improve oral symptoms in COVID-19 patients.
... Zinc aids in the synthesis of gustin, a growth factor for taste buds. Decreased salivary gustin causes taste disturbances [25,26]. Zinc also increases salivary calcium, helping taste buds act appropriately [27]. ...
... Various medications may contribute to dysgeusia, as shown in Table 1 [2,6,41,42]. Due to zinc-chelating actions, a broad range of medications have been linked to various adverse orofacial symptoms, including dry mouth, taste disturbances, oral mucosal ulcers, and gingival enlargement [26]. The angiotensin-converting enzyme inhibitor captopril can chelate with serum zinc, causing taste disturbances in 18%e30% of patients, depending on the dose [43]. ...
Article
Background Dysgeusia is a prevalent qualitative gustatory impairment that may affect food intake and quality of life. The facial (VII), glossopharyngeal (IX), and vagus (X) nerves are the three cranial nerves responsible for sensing taste. Typically, dysgeusia is considered a general term for all taste disorders. In addition, dysgeusia may be a symptom of underlying systemic conditions such as diabetes mellitus, chronic kidney disease, respiratory infections, and nutritional deficiencies. Various subjective and objective diagnostic approaches are available to aid clinicians, each with its own set of benefits and drawbacks. Highlights Taste impairment can lead to a lack of enjoyment while eating, food aversion, and malnutrition, resulting in a decrease in the quality of life and loss of muscle mass. Therefore, the present review aims to address the probable etiologies, diagnostic aids, and management of dysgeusia. A broad search for studies was conducted using PubMed, Web of Science, Scopus, and Google Scholar. In addition, relevant studies found in the references of the selected articles were also studied. Conclusion Oral health care providers should be aware of the possible etiologies of dysgeusia, diagnostic tools, and treatment options. Accurate diagnosis of the cause of taste dysfunction has a significant impact on the management of taste impairment.
... A narrative review elucidated the therapeutic effect of the oral zinc administration on taste disorders. Carbonic anhydrase IV, a zinc metalloenzyme, has been reported to play a role in ion transport, saliva production and secretion, and saliva pH regulation [36]. Taken together, the deficiency in dietary zinc from an inadequate diet can lead to the loss of appetite, leading to a vicious cycle of malnutrition among the elderly. ...
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... Çinko suplementasyonunun tat kaybı olan kişilerde olumlu etkilerinin olduğu gösterilmiştir. 44,45 COVID-19 enfeksiyonlu kişilerdeki çinko yetersizliğinin tat ve koku kaybı ile ilişkili olabileceği bildirilmiş ve çinko suplementasyonunun COVID-19 enfeksiyonunda yararlı etkilerinin olabileceği düşünülmüştür. 46 Yapılan bir araştırmada, düşük konsantrasyonlarda çinko ve pirition kombinasyonunun, SARS koronavirüsünün replikasyonunu engellediği gösterilmiştir. ...
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ÖZET Dünya Sağlık Örgütü’nün pandemi olarak kabul ettiği koronovirüs hastalığı (COVID-19) ülkemizde de önemli bir halk sağlığı sorunu haline gelmiştir. COVID-19’u da içeren viral enfeksiyonlardan korunmada ve tedavisinde yeterli ve dengeli bir diyete ek olarak A, C ve D vitamini ile çinko ve selenyum suplementasyonunun yararlı etkilerinin olabileceği belirtilmiştir. Ayrıca, probiyotiklerin viral enfeksiyonlara karşı bağışıklığı arttırabileceği bildirilmiştir. Sağlıklı bir bağışıklık sistemi, bugün için koruyucu ve tedavi edici ilacın mevcut olmadığı COVID-19 pandemisinde en önemli silahtır. Besinler, besin ögeleri veya ilaçlar ile birlikte yürütülecek anti-inflamatuar strateji, COVID-19 yönetimi için uygun bir seçenektir.
... It has been reported that high levels of CA activity were identified in tongue papillae associated with taste buds [83]. Due to the presence of Zn 2+ -binding sites in CA and the regulatory effect of Zn 2+ on enzyme activity, various studies have focused on the effects of Zn 2+ on taste and the treatment of taste disorders [110]. Komai et al. demonstrated that decreased taste sensitivity was associated with decreased CA activity in Zn 2+ -deficient rats [111]. ...
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Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.
... Interestingly, numerous studies have recently reported a great loss in human senses, such as smelling and tasting senses in the start of COVID-19infected patients (Keyhan et al., 2020;Lechien et al., 2020). According to the previous literatures based on zinc deficiency, it has proved that loss in taste could be due to zinc COVID-19-infected patients, and supplementation of zinc has displayed outstanding results in curing the loss of taste (Doty, 2019;Yagi et al., 2013). Collectively, the loss in taste and smell of COVID-19-infected patients may be associated with zinc deficiency. ...
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Emerging viruses are known to pose a threat to humans in the world. COVID-19, a newly emerging viral respiratory disease, can spread quickly from people to people via respiratory droplets, cough, sneeze, or exhale. Up to now, there are no specific therapies found for the treatment of COVID-19. In this sense, the rising demand for effective antiviral drugs is stressed. The main goal of the present study is to cover the current literature about bioactive compounds (e.g., polyphenols, glucosinolates, carotenoids, minerals, vitamins, oligosaccharides, bioactive peptides, essential oils, and probiotics) with potential efficiency against COVID-19, showing antiviral activities via the inhibition of coronavirus entry into the host cell, coronavirus enzymes, as well as the virus replication in human cells. In turn, these compounds can boost the immune system, helping fight against COVID-19. Overall, it can be concluded that bioactives and the functional foods containing these compounds can be natural alternatives for boosting the immune system and defeating coronavirus.
Thesis
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In spite of the promising initial results, μ-PADs are yet not fully commercialized because of the multiple technical challenges such as—1) improper μ-PAD packaging which leads to sample contamination and sample lose due to evaporation 2) Lack of flow control in flow channels, which restricts μ-PAD applications for multistep protocols and hinders the automation of μ-PAD functions 3) Need for sample preparation steps prior to μ-PAD applications, which increases device reliance on external equipment and is not ideal for usage in low-resource environments 4) Poor signal quality in detection zones of μ-PADs, vii which leads to unreliable results 5) Effect of sample matrix and external lighting on colorimetric signals which further decreases the reliability of assay results generated using μ-PADs. In this thesis, we have tackled the challenges explained above by developing a novel μ-PAD fabrication method using plasma processes. 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To validate the incorporation of flow control functionality, we designed a μ-PAD that can sequentially deliver three different reagents, each with different pH, to a detection zone spotted with a pH indicator; change in indicator color was observed over time as different reagents sequentially arrived to the detection zone. Finally, we developed a method to fabricate semi-enclosed μ-PADs directly on commercially available blood separation membrane to incorporate plasma separation functionality on the device itself. This reduces the need to rely on external equipment like centrifuges, which are often used to separate blood plasma from whole blood. Additionally, viii the detection zones of the semi-enclosed μ-PADs on the blood separation membrane were modified with cellulose nanocrystals to enhance color signal quality by increasing the homogeneity of the colorimetric signals across the detection zone. The complete μ-PAD was then used for colorimetric detection of glucose and albumin simultaneously in a whole blood sample. One disadvantage of the blood separation membrane is its brittleness, but we showed that the semi-enclosed μ-PADs can be easily supported by plastic adhesive tape layer to make them mechanically more robust as stand-alone devices, a critical factor for on-field device application. Finally, we tested the compatibility of semi-enclosed μ-PADs with a cell-free expression system to semi-quantitatively measure zinc concentration in a whole blood sample without using any external equipment. We were able to demonstrate the compatibility of cell-free expression system with fiber-based porous substrates. We were also able to show that μ-PADs fabricated on chromatography substrate can detect the presence/absence of analyte in the sample. However, dose-dependent distinct colorimetric signals were not obtained. 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This invention relates to a method for using a zinc sensor compound to detect a disease associated with the disruption of zinc homeostasis, such as prostate cancer. The zinc sensor compound comprises an optical reporter having two or more recognition units where each of the recognition units is capable of associating with at least one zinc ion.
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In recent years, the number of patients visiting outpatient clinics with complaints of abnormal sense of taste and/or olfaction has been on the increase. It has been estimated that about 30% of these patients may have dietary zinc deficiency. This deficiency is more likely to develop among children whose the daily requirement of zinc is greater, among elderly people whose dietary consumption of nutrients is poor and among young women who are often on diets for weight reduction. Zinc deficiency may be associated with a variety of features such as hypogeusia, hyposmia, growth retardation, dermatitis, alopecia, compromised gonadal functions, susceptibility to infections and delayed wound healing. This manuscript reviews zinc physiology (distribution in the body, absorption, transport, metabolism and excretion, physiological functions and factors causing changes in the serum level) and zinc supplementary therapy for better understanding of the clinical features of zinc deficiency.
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A syndrome occurring in males, characterized by severe iron deficiency anemia, hypogonadism, dwarfism, hepatosplenomegaly and geophagia, has been observed in villagers in Iran suffering from malnutrition. Eleven such patients, studied in detail, are described. Despite hepatosplenomegaly, results of the liver function tests were uniformly normal except for the serum alkaline phosphatase, which was consistently elevated. The anemia was not associated with blood loss, hookworm infestation or intestinal malabsorption, and responded promptly to oral iron therapy. Although the diet contained adequate amounts of iron it is believed that the predominantly wheat diet, with its high phosphate content, interfered with absorption because of the formation of insoluble iron complexes. Correction of the anemia resulted in marked decrease in the size of the liver and spleen. Prolonged follow-up of patients receiving a well balanced diet indicates that the endocrine abnormalities of growth and sexual development are reversible. The relationship of geophagia (which occurred in nearly all patients) to this syndrome is not clear, and is discussed. The possibility of zinc deficiency is considered as an explanation of hypogonadism, dwarfism and changes in alkaline phosphate.
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