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A Review of the range of effects of niacinamide in human skin

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Abstract
Niacinamide (also known as nicotinamide,
3-pyridinecarboxamide) is the physiologi-
cally active form of niacin or vitamin B3, the
deficiency of which results in the nutritional
disease pellagra with distinct cutaneous
manifestations. Since its discovery and iso-
lation, a host of dermatological therapeutic
benefits and mechanisms have also been
ascribed to this essential water-soluble vit-
amin when used as a topical agent. These in-
clude its apparent role as an anti-acne ac-
tive, an up-regulator of epidermal sphingo-
lipid synthesis, an up-regulator of markers of
epidermal differentiation and dermal prolif-
eration (with concurrent stratum corneum
barrier benefits), and as a moderator of pho-
toimmunesuppression and accompanying
tumor genesis. More recently, fresh evi-
dence points to a role in modifying the cos-
metic appearance of skin through suppres-
sion of epidermal melanosome transfer with
subsequent effect on skin pigmentation and
a role in modifying epidermal surface topo-
graphy. The mechanisms for these cutane-
ous effects are still unclear. However, since
niacinamide is an important precursor of
NADH and NADPH, it has been postulated
that topical application of niacinamide can
promote this reported broad spectrum of
activity through local correction of homeo-
static balance of these two nucleotide coen-
zymes. As there has been a dramatic in-
crease in research into and use of niacin-
amide in recent years, this review will cover
the current scope of knowledge of this im-
portant vitamin, including mechanistic un-
derstanding and cutaneous physiological
activity.
History of Niacinamide
Niacinamide is the amide of vitamin B3, also
known by the pseudonym »Vitamin PP«, that
is, »Pellagra-Preventive«. The name is not
without meaning. The first case of pellagra
was reported in the U.S. in 1902; four
decades of a pellagra epidemic followed
during which, in states south of the Potomac
and Ohio rivers, some 3 million cases and
100,000 deaths were reported [1]. Pellagra
patients presented with a variety of debili-
tating symptoms including, significantly, a
spectrum of cutaneous lesions. Tragically,
this led to the public exclusion of thousands
of victims, who came almost exclusively
from poor, rural, working-class families who
fed themselves on a bland staple diet of
cornmeal, molasses and fatback. Joseph
Goldberger, a Hungarian emigrant who es-
tablished himself as a renowned clinical epi-
demiologist, reversed steadfast medical
opinion that pellagra was an infectious,
communicable disease. He proved that sim-
ple dietary supplementation could both pre-
vent and cure pellagra. In 1927, after 13 years
of work, Goldberg persuaded the American
Red Cross to distribute dried yeast to Mis-
sissippi flood victims and, thus, prevented a
further devastating epidemic. It was not un-
til 1937 that nicotinic acid and its derivatives
(including niacinamide) were shown to be
the elusive »PP« factor. By 1945, Goldber-
ger’s legacy was permanent; public educa-
tion had changed forever the poor diet of the
South and pellagra was eliminated in the
United States.
Physiological Role of Niacinamide
The substituted pyridine derivative niacin-
amide is an essential constituent of the oxi-
doreduction coenzymes nicotinamide ade-
nine dinucleotide (NAD) and nicotinamide
adenine dinucleotide phosphate (NADP)
(Fig. 2). During glycolysis and the TCA cycle,
10 molecules of NAD+(per molecule of glu-
cose) are reduced to 10 NADH by the trans-
fer of a hydride ion to the 4-position of the
niacinamide ring. The hydride ion of NADH
serves effectively as an energy storage unit,
giving up a pair of high-energy electrons to
the mitochondrial electron transport chain
when needed. In this process of oxidative
phosphorylation, electron pairs are trans-
ferred from NADH to a final acceptor (oxy-
gen) via a series of electron carriers. This
transfer of electrons is thermodynamically
A Review of the Range of Effects of
Niacinamide in Human Skin
Paul J. Matts1), John E. Oblong2) and Donald L. Bissett2)
Keywords: Niacinamide, nicotinamide, skin, ceramide, ageing, differentiation, barrier
IFSCC Magazine – vol. 5, no 4 / 2002
1) The Procter & Gamble Company, Rusham Park Technical Centre, Egham, Surrey, UK
Email: matts.pj@pg.com
2) Miami Valley Laboratories, Cincinnati, Ohio, USA
Fig. 1: Pellagra suffer, US South, early 20th
century
The authors acknowledge the Waring Historical
Library of the Medical University of South Caroli-
na, Charleston, SC
286
favorable, i.e., G is negative, and is coupled
to the pumping of protons out of the mito-
chondrial matrix. The flow of protons back
into the matrix, in turn, catalyses the pro-
duction of ATP by F0F1ATP-synthase. Total
energy yield (G’) for this process is high
(–52.7kcal).
Whereas NADH is involved in catabolism,
NADPH tends to serve as an electron (hy-
dride ion) donor in anabolic processes, that
is, biosyntheses. For example, NADPH is the
reducing co-factor used by fatty acid syn-
thetase in lipid biosynthesis and by desmo-
lases and hydroxylases in steroid biosynthe-
sis.
Nicotinamide Coenzymes in Skin
are Depleted with age; Niacin-
amide can Help Normalize this Im-
balance
NADH and NADPH can, thus, be viewed as
fundamental energy »currency« units within
cells, driving the metabolism of cells involv-
ed in both catabolic and anabolic process-
es. There is an increasing pool of evidence
for a decline in systemic and intracellular
concentrations of these two coenzymes
with age in human and animal models [2,3,4]
and recent new data appear to confirm this.
Oblong et al. [5] established human dermal
fibroblast cell lines from a 7-year old and a
72-year old and used these to measure en-
dogenous NADPH/NADP+ratios and total
NADPH + NADP+levels. It was found that
fibroblasts from the aged donor contained
decreased NADP redox ratios and total
NADPH + NADP+levels relative to those
from the young donor (51% and 28% respec-
tively). It does appear, therefore, that there
is a reduction in nicotinamide coenzymes
associated with senescence.
Importantly, Oblong et al. [5] also found that
supplementation of human dermal fibroblast
cultures derived from elderly donors with
14C-niacinamide and 14C-nicotinic acid
(niacinamide precursor) increased intracel-
lular concentrations of NADPH. It appears
that a localized supply of niacinamide, there-
fore, can be utilized by aged cutaneous cells
to restore intracellular nicotinamide coen-
zyme homeostasis.
It is worth noting, however, that despite the
efficacy noted above, nicotinic acid (niacin)
produces a well-documented cutaneous va-
sodilatation (»flushing«) when applied to-
pically. Niacin, therefore, presents a chal-
lenge to cosmetic applications; there are no
such issues with the use of niacinamide.
Aged Fibroblasts Secrete Less
Collagen than Young Cells;
Niacinamide can Stimulate New
Collagen Synthesis
Oblong et al. [5] used 14C-proline to monitor
incorporation of label into collagen protein
secreted from cultured human dermal fibro-
blasts taken from a young (7-year old) and
aged donor (72-year old). 14C-hydroxyproline
(as a marker of newly-synthesized secreted
collagen) and 14C-proline (as a marker of to-
tal protein) were extracted, separated and
quantified using HPLC equipped with a ra-
diometric detector. Results indicated firstly
that dermal fibroblasts from an aged donor
secreted significantly (p<0.05) less collagen
than those from a young donor and, further-
more, that NADPH / NADP redox ratios were
also lower (p<0.05) in fibroblasts from the
aged donor (results were normalized to the
cell number from the respective culture
well). Secondly, it was found that supple-
mentation of the aged cell culture with
niacinamide produced significant increases
in total collagen secreted (by 54%), total pro-
tein secreted (by 41%) and also in the num-
ber of cells (by 20%), relative to a vehicle
control. Importantly, there was also a signif-
icant 35% increase in the collagen / total pro-
tein ratio (relative to a vehicle control), indi-
cating some specificity for collagen biosyn-
thesis and secretion. These data suggest,
therefore, that treatment with niacinamide
would have a positive impact on the dermal
compartment, both in terms of its connective
tissue and gel matrix components. These
effects would be of particular significance in
aged and photodamaged skin.
Niacinamide Up-regulates Epider-
mal Ceramide Synthesis with Con-
current Epidermal Barrier Benefits
Ceramides are now known to play a central
role in the structural and functional integrity
of the stratum corneum barrier function. A
decrease in ceramide fraction has been re-
ported in aged and atopic skin [6]. Tanno et
al. showed that in cultured human epidermal
keratinocytes, niacinamide could induce up
to a 5-fold up-regulation in ceramide syn-
thesis (p<0.05) in a dose-dependent fashion
[7]. Further work by the same group [8]
showed up-regulation of other sphingolipid
fractions (glucosylceramide and sphingo-
myelin) as well as free fatty acid and cho-
lesterol synthesis (by 2.3 and 1.5-fold, re-
spectively). The workers proposed a mech-
anism for these observations based on in-
creased levels of intra-cellular acetyl-CoA
(the precursor common to epidermal lipid
synthesis) and increased expression of ser-
ine-palmitoyltransferase. Tanno et al. [8] al-
so showed that these in-vitro results had
clinical significance in-vivo. Topical applica-
tion of a vehicle containing 2% niacinamide
IFSCC Magazine – vol. 5, no 4 / 2002
Fig. 2: Structure of niacinamide and inclusion within NAD molecule
287
to dry lower legs over 4 weeks induced a
measurable significant increase (p<0.05) in
recovered stratum corneum ceramide and
free fatty acid lipid fractions, vs. a vehicle
control. This was accompanied by a signifi-
cant reduction (p<0.05) in TEWL vs. vehicle
control (–27%). Similar significant reduc-
tions in TEWL vs. a vehicle control were not-
ed also by Ertel et al. [9] after use of a mois-
turizing vehicle containing 2% niacinamide.
Furthermore, they also noted that this posi-
tive barrier effect was accompanied by an
increase in stratum corneum turnover rate
(as measured by dansyl chloride assay). Fi-
nally, Draelos et al. [10] treated 48 female
subjects with stage I/II rosacea with a mois-
turizing vehicle containing 2% niacinamide
for 4 weeks and demonstrated a significant
improvement in global condition (assessed)
in 96% of the subjects at week 4. They de-
monstrated, once again, that this clinical
benefit was accompanied by a significant
improvement in stratum corneum barrier
function.
It appears that topical niacinamide is able to
augment the barrier properties of the skin,
with accompanying clinically relevant ben-
efits, by up-regulating endogenous biosyn-
thesis of epidermal sphingolipids, in partic-
ular, ceramides.
Niacinamide Up-regulates
Biosynthesis of Markers of
Keratinocyte Differentiation
Oblong et al. [5] cultured normal human epi-
dermal keratinocytes to near-confluency
and then supplemented the medium with
niacinamide. Following a 24h incubation,
cells were counted, harvested and prepared
for assay for involucrin (by ELISA) and filag-
grin (by an immunoblot procedure). Results
showed firstly a significant increase (p<0.05)
in the number of niacinamide-treated NHEK
relative to a vehicle control. Secondly, ni-
acinamide-treated NHEK showed an up-
regulation of both involucrin and filaggrin
biosynthesis vs. that induced by a vehicle
control (by 45% and 100% respectively).
These two proteins are both critical to the
differentiation process and the formation of
fully integral keratinized corneocytes; filag-
grin plays a vital role in aggregation and
alignment of keratin tonofilaments in granu-
lar cells and involucrin is an essential pre-
cursor in the formation of the insoluble
cornified envelope surrounding terminal
keratinocytes. In other words, niacinamide
has been shown to both stimulate basal epi-
dermal keratinocytes and to up-regulate
biosynthesis of epidermal intermediates
critical to the formation of a fully functioning
stratum corneum. This may be due to in-
creased intracellular levels of reduced
nicotinamide coenzymes initiated by topical
niacinamide. These effects would be ex-
pected to have a significant positive impact
on ageing epidermal tissue in-vivo.
Niacinamide Helps Prevent
UV-Induced Deleterious Molecu-
lar and Immunological Events
Shen et al. [11] demonstrated the ability of
niacinamide to protect cultured normal hu-
man keratinocytes against reactive oxygen
species induced by UVC irradiation or expo-
sure to hydrogen peroxide. They observed
significant (p<0.05) dose-dependent attenu-
ation of apoptotic morphological changes, a
decrease in p53 induction and a reduction in
DNA ladders for niacinamide-treated cells
vs. those treated with a vehicle control.
These data are consistent with work in ani-
mal models [12] demonstrating clearly the
ability of niacinamide to significantly reduce
both induction of photocarcinogenesis and
photoimmunesuppression. The mechanism
by which niacinamide exerts these effects is
not yet clear.
Niacinamide Inhibits Transfer of
Melanosomes from Melanocytes
to Keratinocytes
Boissy et al. [13] used co-cultures of human
melanocytes and keratinocytes to investi-
gate the ability of niacinamide to reduce pig-
mentation in human skin. Use of immuno-
linked dyes specific for each cell type en-
abled separate counts of keratinocytes,
melanocytes and keratinocytes containing
transferred melanosomes to be performed.
The workers found significant inhibition
(p<0.05) of melanosome transfer to keratino-
cytes from melanocytes incubated in the
presence of niacinamide (by 25-45%). It was
also confirmed that niacinamide had no in-
hibitory effect on melanocyte tyrosinase
activity. These data suggest that treatment
of human skin in-vivo with topical niacin-
amide would lead to a reduction in pigmen-
tation with time via this novel, elegant mech-
anism.
Niacinamide Reduces Human
Skin Hyperpigmentation
Hakozaki et al. [14] performed two studies
demonstrating the effect of niacinamide on
skin hyperpigmentation in-vivo. In the first,
18 female Japanese subjects with hyperpig-
mented facial spots were treated for 8
weeks with a vehicle containing 5% niacin-
amide vs. a vehicle control in a split-face de-
sign. Pigmented spots were qualified and
quantified via algorithmic analysis of high-
resolution digital images and subjective
grading of images. Results of image analysis
showed that 5% niacinamide had induced a
significant (p<0.05) reduction in spot area at
the 4 and 8 week time-points (vs. vehicle
control), accompanied by a significant re-
duction (p<0.05) in graded visible spot pig-
mentation at 8 weeks (vs. vehicle control). In
the second study, 120 female Japanese sub-
jects with facial tanning were assigned to 2
of 3 treatments (SPF 15 sunscreen moistur-
izer, 2% niacinamide in SPF 15 sunscreen
moisturizer and a vehicle control). Subjects
applied treatments split-face for 8 weeks. In
this study overall skin lightness was as-
sessed by analysis of digital images and by
subjective grading. Results of image analy-
sis showed a significant (p<0.05) increase in
skin lightness vs. the sunscreen moisturizer
and vehicle control at the 4 and 6 week time-
points, accompanied by a significant
(p<0.05) increase in graded visible skin light-
ness vs. vehicle control at 4 weeks. These
in-vivo data appear to confirm, therefore,
that the inhibitory role of niacinamide in
melanosome transfer noted in-vitro [13],
does indeed translate to a significant effect
on hyperpigmentation in-vivo.
Regulation of Sebaceous Lipid and
Acne by Niacinamide
Topical niacinamide in the form of a com-
mercial 4% gel (Papulex®) has been shown
to provide potent anti-inflammatory activity
in the treatment of acne vulgaris. Shalita et
al. [15] found that after 8 weeks of usage,
82% of subjects with inflammatory acne
showed an improvement in global evalua-
tion, with a significant reduction in papules /
pustules (–60%) and acne severity (–52%).
Indeed, many practitioners use the treat-
ment citing a combination of efficacy and
lack of bacterial-resistance. Shalita et al.
[15] and others postulate that niacinamide
IFSCC Magazine – vol. 5, no 4 / 2002
288
may act via its apparent antihistaminic ef-
fect, activity as an electron scavenger, or its
inhibition of 3’-5’ cyclic-AMP phosphodi-
esterase activity.
Recent data, however, appear to demon-
strate an altogether more fundamental role
for topical niacinamide in acne treatment.
Biedermann et al. [16] used viable human fa-
cial biopsies (from face-lift surgery) to mea-
sure the effect of niacinamide on sebaceous
lipogenesis. Cultured biopsies were treated
with niacinamide or trans-retinoic acid (tRA)
for 4 days, after which they were incubated
with 14C-acetate. Lipid components were
subsequently isolated, fractionated and
identified using analytical TLC and radiome-
try. Niacinamide produced significant dose-
dependent reductions in total sebaceous
lipogenesis (–42% at 25 mM [p<0.01]). Fur-
thermore, the reduction induced by 25 mM
niacinamide was equivalent to that pro-
duced by 1 µM tRA (–32% [p=0.01]). When
discrete lipid classes were identified and
quantified, it was found that niacinamide
had produced marked reductions in both
triglyceride and fatty acid synthesis vs. the
control (–52% and –46% respectively for 25
mM niacinamide [p<0.05]). It is now known
that triglycerides represent by far the largest
proportion of sebaceous gland lipid (50-
60%); the observed effect of niacinamide on
total lipogenesis is, therefore, probably at-
tributable to triglyceride reduction.
This has important implications for acne
pathogenesis. It is accepted that acne is a
disease involving the pilosebaceous duct
and Propionibacterium acnes. Despite the
on-going debate as to the exact interplay of
these factors, it is without doubt that a sig-
nificant reduction both in total sebaceous
lipid bulk and in the triglyceride fraction
would be expected to impact positively
acne-form skin.
Niacinamide Exerts Multiple
Benefits on the Appearance of
Ageing / Photodamaged Skin,
In-vivo
Bissett et al. [17] studied the effects of topi-
cal niacinamide in ageing human facial skin
in two double-blinded clinical studies. In the
first, 40 female subjects aged 35 - 60 applied
a vehicle and vehicle containing 5% niacin-
amide (randomized split-face) for 12 weeks.
High-resolution digital images were taken at
baseline, 4, 8 and 12 weeks and texture and
hyperpigmentation were evaluated by
judges (comparing blind-coded image pairs,
baseline vs. another treatment time-point).
Judges were able to perceive a significant
improvement in skin texture appearance at
4 weeks (p<0.1) and 12 weeks (p<0.05) and a
significant improvement in hyperpigmented
spot appearance by 8 weeks (p<0.05) (Fig. 3).
In a second study, female subjects aged 35-
60 applied blind-coded products (vehicle
control and vehicle containing 5% niacin-
amide; n=88) split-face for 8 weeks. Skin tex-
ture appearance was assessed as above.
The niacinamide-containing treatment pro-
vided a significant improvement in skin tex-
ture appearance relative to the vehicle con-
trol at the 8 week time-point, confirming the
results of the first study.
This effect on skin surface texture is consis-
tent with that noted in a 10-week clinical
study where Matts & Solechnick [18] used
multiple-angle reflectance spectrophoto-
metry to measure the diffuse component of
skin reflection. They noted a significant in-
crease in the diffuse component of 5%
niacinamide-treated dorsal hand skin vs.
vehicle control after 10 weeks of treatment
(p<0.05), consistent with significant blind
self-rated preferences for texture appear-
ance over vehicle control (p<0.05). This
change was consistent with a shift in texture
distribution towards the finer, anisotropic
features characteristic of younger skin.
Niacinamide is Delivered Effec-
tively from a Range of Vehicles
and Demonstrates Excellent Skin
Compatibility
Franz [19] determined niacinamide absorp-
tion in-vitro through full-thickness abdomi-
nal skin mounted in flow-through diffusion
cells. Franz used acetone as a carrier and
found 28.8% of the starting dose in the re-
ceptor medium at 24 h. Delivery of niacin-
amide (2-20%) from a range of cosmetic for-
mulae (including moisturizers, foundations
and lipsticks) was studied using a modified
in-vitro Franz flow-through cell technique
[20]. For formulae containing 2% niacin-
amide, approximately 10% of the starting
dose was detected in the receptor medium
at 48 h. Importantly, these studies highlight-
ed the apparent independence of niacin-
amide penetration rate from diverse vehicle
matrices.
The Cosmetic Ingredient Review Expert Pan-
el report for niacinamide [21] details a very
wide range of cutaneous tolerance studies
confirming the excellent profile of niacin-
amide as a cosmetic skin care ingredient.
Conclusion
Niacinamide, therefore, has been shown to
be a cosmetic ingredient with an extraordi-
IFSCC Magazine – vol. 5, no 4 / 2002
Baseline 12 Weeks
Fig. 3: Same subject at baseline and after 12 weeks of topical treatment with 5% niacinamide
289
nary breadth and history of cutaneous ben-
efits. It is thought that its fundamental role as
a precursor of reduced nicotinamide coen-
zymes such as NADH and NADPH is pivotal
to its observed effects. It displays distinct
advantages over other ingredients with sim-
ilar benefits, such as retinol, in that it is well
tolerated, and is not subject to oxidation or
photolysis. In short, the multiplicity of effects
and formulation benefits seen with niacin-
amide make it an ideal choice for a variety of
cosmetic products targeting young and old
skin alike.
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IFSCC Magazine – vol. 5, no 4 / 2002
... tinamide can reduce skin hyperpigmentation (as it prevents the trans melanocytes to keratinocytes), in addition to inhibiting protein oxida process that gives the skin a yellowish color [9]. In addition to the antioxidant intrinsic properties of NIC and AA Vitamin B3 (Figure 2), also known as nicotinamide, is a precursor of reduced nicotinamide coenzymes such as NADH and NADPH, which play a key role in the antioxidant cascade in the skin [8]. It can be found in cosmetic products in three forms: nicotinamide (NIC), nicotinic acid, or esters such as benzyl nicotinate and myristoyl nicotinate. ...
... Its use is usually associated with other antioxida oxidation of AA [7]. Vitamin B3 (Figure 2), also known as nicotinamide, is a precursor amide coenzymes such as NADH and NADPH, which play a key rol cascade in the skin [8]. It can be found in cosmetic products in three f (NIC), nicotinic acid, or esters such as benzyl nicotinate and myristoy the most used due to its higher tolerability (usual concentrations rang biocompatibility, standing out for its role as a precursor in the product NADH, which play a role as antioxidants in various intra-and extrac processes. ...
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Vitamins are widely found in nature, for example, in plants and fruits. Ascorbic acid and nicotinamide are examples of these compounds that have potent antioxidant properties, besides stimulating collagen production and depigmenting properties that protect the skin from premature aging. To overcome the skin barrier and reduce the instability of antioxidant compounds, alternative systems have been developed to facilitate the delivery of antioxidants, making them efficiently available to the tissue for an extended time without causing damage or toxicity. The objective of this study was to obtain chitosan biodegradable microparticles containing ascorbic acid and nicotinamide for topical delivery. The microparticles were obtained by spray drying and characterized chemically by means of scanning electron microscopy, infrared spectroscopy, X-ray diffraction, and differential exploratory calorimetry. The drugs were successfully encapsulated and the microparticles showed positive zeta potential. In vitro release assays showed a sustained release profile. The evaluation of ex vivo skin permeation and retention demonstrated low permeation and adequate retention of the compounds in the epidermis/dermis, suggesting the efficient delivery from the obtained microparticles. Antibacterial assays have shown that microparticles can inhibit the growth of microorganisms in a time- and dose-dependent manner, corroborating their use in cosmetic products for application on the skin
... The enriched formulation of the acne stress control serum contains a wide variety of compounds that make it useful for the treatment of acne-prone skin but also for the recent maskne mechanical form. In particular, a key role is played by ceramide's mixture, Niacinamide, 10-Hydroxydecanoic acid (10-HDA) and Sebacic acid [26][27][28]. ...
... The formulation contains a synthetic blend of omega hydroxy acids, sebacic and hydroxy-decanoic acids (10-HAD) that mimics the composition of royal jelly in controlling and reducing excess sebum production [27,28]. Among the main active ingredients, Niacinamide (4%) has anti-inflammatory properties, Ceramides improve barrier function, and Dimethylmethoxy Chormanol provides antioxidant protection to eliminate irritating metabolites caused by acne-related sebum production [26]. Emollients help to soften the external layer of the skin, increasing the ability of the skin to hold water and playing an important role in conferring peculiar rheological properties [32]. ...
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(1) Background: Acne is a widespread skin disease, especially among adolescents. Following the COVID-19 pandemic and the use of masks, the problem has been affecting a greater number of people, and the attention of the skin care beauty routine cosmetics has been focused on the “Maskne”, caused by the sebum excretion rate (SER) that stimulates microbial proliferation. (2) Methods: the present study was focused on the rheological characterization and quality assurance of the preservative system of an anti-acne serum. The biological effectiveness (cytotoxicity—skin and eye irritation—antimicrobial, biofilm eradication and anti-inflammatory activity) was evaluated in a monolayer cell line of keratinocytes (HaCaT) and on 3D models (reconstructed human epidermis, RHE and human reconstructed corneal epithelium, HCE). The Cutibacterium acnes, as the most relevant acne-inducing bacterium, is chosen as a pro-inflammatory stimulus and to evaluate the antimicrobial activity of the serum. (3) Results and Conclusions: Rheology allows to simulate serum behavior at rest, extrusion and application, so the serum could be defined as having a solid-like behavior and being pseudoplastic. The preservative system is in compliance with the criteria of the reference standard. Biological effectiveness evaluation shows non-cytotoxic and irritant behavior with a good antimicrobial and anti-inflammatory activity of the formulation, supporting the effectiveness of the serum for acne-prone skin treatment.
... In addition to these primary materials, secondary anti-oxidants and barrier improvement materials were also included. Niacinamide [37] and caffeine [38] both have antioxidant properties. Both niacinamide [37] and panthenol [39] improve skin hydration and skin barrier, thus reducing the tissue stress associated with poor barrier. ...
... Niacinamide [37] and caffeine [38] both have antioxidant properties. Both niacinamide [37] and panthenol [39] improve skin hydration and skin barrier, thus reducing the tissue stress associated with poor barrier. As effective as these materials are intrinsically, effective scalp delivery vehicles were developed to enable the realization of these activities. ...
Article
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Objective Increasing hair fullness is a global unmet need for many men and women. An approach to the problem is to decrease hair fall or shedding by reducing scalp stratum corneum oxidation and barrier damage to increase hair retention. This study evaluated a combination of functional antioxidants and barrier-enhancing cosmetic ingredients to improve scalp condition thereby enabling stronger hair anchorage and longer retention. Methods Male and female subjects with normal scalp condition and self-perceived hair thinning participated in a 24-week, double-blind, placebo-controlled, randomized clinical study assessing either a regimen of treatment shampoo and leave-on treatment containing functional antioxidant and barrier-enhancing agents or an identical placebo chassis shampoo control. The functional ingredients were piroctone olamine, zinc pyrithione, zinc carbonate, niacinamide, panthenol, and caffeine. At baseline and after 8, 16, and 24 weeks of product use, several measurements were taken: hair shedding, total hair count (by phototrichogram), hair samples, TEWL, and evaluation of biomarkers of scalp and hair conditions. Subjects also completed self-assessment questionnaires. Results Statistically significant effects for functional ingredient-containing treatment regimen versus a placebo control shampoo formulation were observed for reduced hair shedding, increased total hair count, reduced TEWL, and improvement in scalp biomarker values. Subjects also noticed these improvements assessed via self-assessment questionnaires. Conclusions These results establish that use of functional antioxidant and barrier-enhancing agents to further improve scalp condition can enable a reduction in hair shedding and thus an increase in perceived hair fullness. The underlying improvements in scalp condition suggest the hair benefits were achieved as a result of improved scalp skin barrier and scalp condition leading to a viable preventative approach for hair thinning.
... Niacinamide (Nam; aka nicotinamide, vitamin B 3 ) has been used for decades in cosmetic and pharmaceutical products for the treatment of acne, photoageing attributes and barrier integrity improvement. [6][7][8] It has been reported that Nam can protect cells from oxidative stress, UV-induced immunosuppression and metabolic disruption. [9][10][11] Mechanistically, it has become apparent that Nam can have a significant impact on numerous processes associated with skin homeostasis and ageing. ...
... 3 Over the past few decades, Nam has become an important molecule in cosmetic and pharmaceutical products for the treatment of acne, skin photoageing attributes, and barrier integrity improvement. [6][7][8] Nam has been reported to protect cells from oxidative stress, metabolic disruption, and inflammation. 9,10 Relevant to protecting from environmental insults, Nam has also been shown to inhibit acute and chronic damaging effects of UV exposure on skin. ...
Article
Background Macromolecules in skin cells are damaged when exposed to environmental stressors, leading to disrupted cellular function and homeostasis. While epidermal turnover can eliminate some of this damage, autophagy can rapidly remove these defective components. Niacinamide (Nam) is known to induce autophagy and optimizing formulations to maximize this response could provide improved homeostasis in stressed skin. Objective To determine (i) whether Nam can induce autophagy related 5 (ATG5), an autophagy marker, in human keratinocytes and (ii) whether optimized low pH Nam formulations can enhance the response in 3D skin models. Methods Human keratinocytes treated with Nam were evaluated for autophagosome accumulation and induction of ATG5 by gene expression, immunoblotting and immune‐fluorescence microscopy. 3D skin equivalents were topically treated with Nam formulations at pH 5.8 and 3.8. Gene expression profiling and immunoblot analysis of ATG5 were performed. Results Nam treatment of keratinocytes led to an accumulation of autophagosomes with a maximal signal at 48 h. Gene expression of ATG5 was induced by Nam, and immunoblots stained for ATG5 showed a significant increase after 6 h of treatment. Gene expression profiling of 3D epidermal skin equivalents treated with Nam at pH 3.8 showed stronger induction of autophagy‐related genes, including ATG5, compared with pH 5.8 formulas. Enrichment for gene ontology terms on autophagy showed an increased linkage with Nam formulas at pH 3.8. Conclusions We found that Nam induces autophagosome accumulation and ATG5 levels in keratinocytes. We also discovered that a Nam formulation at pH 3.8 can further increase levels of ATG5 in 3D skin models when compared to Nam at pH 5.8. These data support that Nam can induce autophagy in keratinocytes and formulations at pH 3.8 can enhance the impact. We hypothesize that optimized formulations at pH 3.8 can improve skin ageing appearance via autophagy induction.
... Niacinamide (Vitamin B3) is an inactive ingredient included in moisturizers that is the water-soluble physiologically active form of vitamin B3 used in many moisturizers and has a range of dermatological therapeutic benefits [16,72,73]. Niacinamide boosts ceramide production, decreases hyperpigmentation, has anti-inflammatory and antibacterial properties, and aids in anti-aging [16,74]. Flushing is a possible side effect of niacinamide-containing products. ...
Article
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Moisturizers are one of the most widely used preparations in cosmetics and have been extensively used to soften the skin for consumers. Moisturizers work effectively in combating dry skin which may cause pain, tightness, itch, stinging, and/or tingling. The aim of this review is to evaluate published studies on the history, ingredients, preparation processes, characteristics, uses, and applications of moisturizers. Moisturizers bridge the gap between medicine and consumer goods by being used to make the skin more beautiful and healthy. In the future, in moisturizer therapy, the capacity to adapt specific agents to specific dermatological demands will be crucial. Cosmetically, moisturizers make the skin smooth by the mechanism of increasing the water content in the stratum corneum, hence exerting its most vital action, which is moisturizing action and maintaining a normal skin pH.
... Niacinamide is the physiologically active analog of Vitamin B3, which inhibits the transfer of melanosomes to the surrounding keratinocytes and also to disrupt the cell-signaling pathway between melanocytes and keratinocytes as suggested by various in vitro studies. It, however, does not inhibit tyrosinase activity or cell proliferation to affect melanogenesis (Matts et al., 2002). ...
Article
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Hyperpigmentation of the skin refers to a dermatological condition which alters the color of the skin, making it discoloured or darkened. The treatments for hyperpigmentation disorders often take very long to show results and have poor patient compliance. The first‐line treatment for hyperpigmentation involves topical formulations of conventional agents such as hydroquinone, kojic acid, glycolic acid followed by oral formulations of therapeutic agents like tranexamic acid, melatonin, cysteamine hydrochloride. The second‐line approaches include chemical peels and laser therapy given under the observation of expert professionals. However, these therapies pose certain limitations and adverse effects like erythema, skin peeling and drying and require long treatment duration to show visible effects. These shortcomings of the conventional treatments provided scope for further research on newer alternatives for managing hyperpigmentation. Some of these therapies include novel formulations like solid lipid nanocarriers, liposomes, phytochemicals, platelet‐rich plasma, microneedling. This review focuses on elaborating on several hyperpigmentation disorders and their mechanisms, the current, novel and emerging treatment options for management of hyperpigmentation.
... Pellagra symptoms include skin dermatitis, dementia, and diarrhea, all of which can be reversed with Nam supplementation. Over the past few decades, Nam has become an important molecule for usage in cosmetic and pharmaceutical products for the treatment of acne, skin photoaging attributes, and skin barrier integrity improvement (Matts et al., 2002;Wohlrab & Kreft, 2014). It has been reported that Nam can protect cells from inflammation, oxidative stress, and metabolic disruption (Sivapirabu et al., 2009;Zhang et al., 2012) and has been found to mitigate some of the acute and chronic damaging effects of UV exposure on skin (Snaidr et al., 2019). ...
Article
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Alterations in metabolism in skin are accelerated by environmental stressors such as solar radiation, leading to premature aging. The impact of aging on mitochondria is of interest given their critical role for metabolic output and the finding that environmental stressors cause lowered energy output, particularly in fibroblasts where damage accumulates. To better understand these metabolic changes with aging, we performed an in-depth profiling of the expression patterns of dermal genes in face, forearm, and buttock biopsies from females of 20-70 years of age that encode for all subunits comprising complexes I-V of the mitochondrial electron transport chain. This complements previous preliminary analyses of these changes. "Oxidative phosphorylation" was the top canonical pathway associated with aging in the face, and genes encoding for numerous subunits had decreased expression patterns with age. Investigations on fibroblasts from older aged donors also showed decreased gene expression of numerous subunits from complexes I-V, oxidative phosphorylation rates, spare respiratory capacity, and mitochondrial number and membrane potential compared to younger cells. Treatment of older fibroblasts with nicotinamide (Nam) restored these measures to younger cell levels. Nam increased complexes I, IV, and V activity and gene expression of representative subunits. Elevated mt-Keima staining suggests a possible mechanism of action for these restorative effects via mitophagy. Nam also improved mitochondrial number and membrane potential in younger fibroblasts. These findings show there are significant changes in mitochondrial functionality with aging and that Nam treatment can restore bioenergetic efficiency and capacity in older fibroblasts with an amplifying effect in younger cells.
... The key active in the skin care products is niacinamide. This material is known to be effective in improving skin texture, elasticity, fine lines and wrinkles, red blotchiness, hyperpigmentation, sun damage and sallowness seen with ageing [17,18]. Although objective data are not presented in this manuscript, our own data in the study conducted in China and described below showed significant improvement in skin hydration, skin barrier function, and skin elasticity after 8 days of product use. ...
Article
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Importance: Consumers purchase a wide variety of consumer products and come into contact with these products on a daily basis. Manufacturers invest deeply in developing new products or improving existing products, in order to produce a positive impact on the lives of consumers. Objective: The goal of this study was to determine the impact of over-the-counter skin care products on the quality of life (QoL) of female consumers. Design and Measures: A QoL instrument developed for consumer products (the Farage QoL with an added Skin Care Module) was used to assess the impact of a 28-day facial skin care regimen using commercially available products formulated to improve elasticity, firmness and hydration, and to correct age- and sun-related skin color. Responses were collected prior to study commencement, at completion of the product usage stage, and after a period of withdrawal of the product with reversion to a basic skin care regimen. Participants: Two main study groups from Australia included 89 new mothers, i.e., women with children 2 years and under (mean age ± SD was 34 ± 4.8), and a national representative sample of 91 women (45 ± 12). An additional test group from China consisted of 40 younger cosmetic users (25 ± 4.3). The Skin Care Module was not included in the instrument for the third group. Results: After 28-days of usage, both test groups in the main study showed significant improvement in three of five items in the Skin Care Module (improved feelings of empowerment, happiness and self-esteem). Improvements persisted after 2 weeks of product withdrawal. In the main QoL instrument, the New Mothers group showed significant improvement in the Well-Being domain, driven by improvements in the Self-Image and Self Competence subdomains. The National Representative group showed improvements in the Energy and Vitality domain, driven by improvements in the Personal Pleasure, Physical State and Routine Activity subdomains. The additional group in the China study showed results similar to the New Mothers group. Conclusions and Relevance: A quality and efficacious skin care regimen can have a positive impact on the QoL of consumers. Differences in responses of the test groups were likely related to differences in the mean age and differences in time available to look after themselves.
... Nicotinamide (Nam; aka niacinamide, vitamin B3) has been used for decades in cosmetic and pharmaceutical products for the treatment of acne, skin photoaging attributes, and barrier integrity improvement [12][13][14]. It has been reported that Nam can protect cells from oxidative stress, UVinduced immunosuppression, and metabolic disruption [15][16][17]. ...
Preprint
Daily exposure of skin to environmental stressors leads to molecular and morphological changes ascribed as premature aging. These stressors include solar radiation, industrial pollution, fossil fuel and carbon emissions, which cause cellular damage that induces an inflammatory response in skin. Several inflammatory components are known to be involved in triggering the senescence-associated secretory phenotype (SASP) which is known to accelerate aging. It is hypothesized that preventing induction of inflammation by environmental stressors can prevent premature aging. Since it is known that nicotinamide (Nam) has anti-inflammatory properties, we tested whether Nam can inhibit environmental stressor-induced inflammation. Exposure of keratinocytes to UVB, urban dust, diesel exhaust, and cigarette smoke extract stimulated production of the inflammatory mediators PGE2, IL-6, and IL-8 and induced gene expression patterns associated with apoptosis, DNA repair, and cell cycle control. In all cases, Nam treatment significantly inhibited these stress-induced responses. Nam also reduced IL-8 levels stimulated by the combination of topically applied particulate matter (PM2.5) and UV exposure in 3D skin equivalents. Under 5% 02 conditions that more closely mimic physiological 02 levels, Nam had a heightened inhibitory effect on UVB-induced PGE2 levels in keratinocytes. In a UV-challenge study, treatment with Nam reduced skin surface IL-1RA/IL-1 inflammatory biomarkers and erythema that were induced by solar simulated radiation. These findings provide a body of evidence that Nam can mitigate in part the skin’s inflammatory response elicited by exposure to environmental stressors. This supports the potential that Nam can inhibit premature aging and help maintain skin’s functionality and appearance.
Article
Objective To evaluate whether niacinamide (Nam) can mitigate production of inflammatory and senescence‐related biomarkers induced by environmental stressors. Methods Human epidermal keratinocytes were exposed to UVB, urban dust, diesel exhaust, and cigarette smoke extract and treated with Nam or vehicle control. Full thickness 3‐D skin organotypic models were exposed to a combination of UVB and PM2.5 and treated with Nam or vehicle control. Quantitation of the SASP‐related inflammatory mediators PGE2, IL‐6, and IL‐8 was performed on cultured media. UVB‐exposed keratinocytes treated with and without Nam were immunostained for the senescence biomarker Lamin B1 (LmnB1). Transcriptomics profiling of cigarette smoke extract effects on keratinocytes was performed. A placebo controlled double blinded clinical was conducted on 40 female panelists that were pretreated on back sites for two weeks with 5% Nam or vehicle and then exposed to 1.5 minimal erythemal dose (MED) solar simulated radiation (SSR). Treated sites were compared to non‐treated exposed sites for erythema and the skin surface IL‐1αRA/IL‐1α inflammatory biomarkers. Results UVB induced synthesis of PGE2, IL‐8 and IL‐6 and reduced LmnB1 levels in keratinocytes. Urban dust and diesel exhaust only stimulated synthesis of IL‐8 whereas cigarette smoke extract only stimulated levels of PGE2. In all exposures, treatment with Nam significantly mitigated synthesis of the inflammatory mediators and restored levels of UVB‐reduced LmnB1. In the 3D skin equivalent model, Nam reduced IL‐8 levels stimulated by a combination of topical PM2.5 and UV exposure. In a UV‐challenge clinical, pretreatment with 5% Nam reduced erythema and skin surface IL‐1αRA/IL‐1α inflammatory biomarkers that were induced by SSR. Conclusion Since it is known that Nam has anti‐inflammatory properties, we tested whether Nam can inhibit environmental stress induced inflammation and senescence‐associated secretory phenotype (SASP) biomarkers. We show Nam can reduce PGE2, IL‐6, and IL‐8 levels induced by environmental stressors. Additionally, in vivo pretreatment with Nam can reduce UV‐induced erythema and skin surface inflammatory biomarkers. These findings add to the body of evidence that Nam can mitigate the skin’s inflammatory response elicited by environmental stressors. This supports Nam can potentially inhibit senescence and premature aging and thereby maintain skin’s functionality and appearance.
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The use of in vitro preparations of human skin to study percutaneous absorption is widespread. Yet, up to the present time, little has been done to systematically validate this model and demonstrate the extent to which it mimicks in vivo absorption. In this study, the permeability of 12 organic compounds has been evaluated in excised skin and the results compared to those obtained previously by others in living man. With special emphasis being given here to duplicating in vivo conditions, it was possible to demonstrate an excellent qualitative agreement between the two methods. In all cases, the absorption pattern determined in vitro rather precisely paralleled the pattern which was obtained in vivo. Quantitative agreement between the two sets of data was less than perfect, although the in vitro method adequately distinguished compounds of low permeability from those of high permeability and ranked then in approximately the same order found in vivo. This systematic comparison of in vitro with in vivo data was clearly shown how accurately in vitro absorption studies can reflect the living state.
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It is now well established that ageing occurs at the level of individual cells in the skin and other organ systems. Changes in cell behaviour, protein production and gene expression in response to standardized stimuli are readily observed in cultured cells derived from young vs old donors and from photoaged vs sun-protected body sites. Whether these changes are best viewed as a cause or a consequence of ageing cannot be determined at present. Nevertheless, available data now provide cellular and molecular correlates for the well-known differences in clinical responsiveness between newborn, adult and photoaged skin. From this basis, it will hopefully be possible to develop a more comprehensive understanding of cutaneous ageing processes.
Article
It has been reported that aging strikingly decreases in vivo ethanol metabolism in F344 rats without major effects on hepatic alcohol dehydrogenase (ADH) activity. Because hepatic ADH activity is not always rate limiting in the oxidation of ethanol, we measured in vivo ethanol elimination rate (EER), hepatic ADH activity, and the hepatic-cytoplasmic and mitochondrial redox states after acute ethanol application in 2- and 12-month-old F344 rats of both sexes. In male, but not in female, animals EER decreased with age significantly, by 28% (P less than 0.01). The body-to-liver weight ratio was significantly increased in male (39.4 +/- 1.5 vs 46.5 +/- 2.0; P less than 0.05), but not in female, animals with age. Specific activity of ADH was not significantly changed by age, while the activity was significantly reduced with age in male, but not female, rats when related to body weight (5.1 +/- 0.4 vs 3.9 +/- 0.3 mumoles/100 g b.wt./min; P less than 0.05). The cytoplasmic, but not the mitochondrial (NAD+) to (NADH), ratio was significantly decreased with age in male livers (317 +/- 48 vs 793 +/- 128, P less than 0.05), while this was not the case in female livers. In summary, the data show a sex dependence of the effect of age on ethanol metabolism. The observed reduction in in vivo EER with age in male animals is due at least in part to an increased body-to-liver weight ratio, decreased hepatic ADH activity, and reduced availability of NAD+, the cofactor of the ADH reaction. The cause of this may be decreased transport of reducing equivalents through the mitochondrial membrane due to a lack of shuttle systems or a change in the physicochemical properties of the mitochondrial membrane, or decreased reutilization of NADH as NADPH resulting from a reduction of microsomal ethanol oxidation with age.
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Stratum corneum lipids are an important determinant for both water-retention function and permeability-barrier function in the stratum corneum. However, their major constituent, ceramides, have not been analyzed in detail in skin diseases such as atopic dermatitis that show defective water-retention and permeability-barrier function. In an attempt to assess the quantity of ceramides per unit mass of the stratum corneum in atopic dermatitis, stratum corneum sheet was removed from the forearm skin by stripping with cyanoacrylate resin and placed in hexane/ethanol extraction to yield stratum corneum lipids. The stratum corneum was dispersed by solubilization of cyanoacrylate resin with dimethylformamide, and after membrane filtration, the weight of the stratum corneum mass was measured. The ceramides were quantified by thin-layer chromatography and evaluated as microgram/mg stratum corneum. In the forearm skin of healthy individuals (n = 65), the total ceramide content significantly declined with increasing age. In atopic dermatitis (n = 32-35), there was a marked reduction in the amount of ceramides in the lesional forearm skin compared with those of healthy individuals of the same age. Interestingly, the non-lesional skin also exhibited a similar and significant decrease of ceramides. Among six ceramide fractions, ceramide 1 was most significantly reduced in both lesional and non-lesional skin. These findings suggest that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry skin.
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In cultured human skin fibroblasts the glucose flux through the hexose monophosphate shunt (HMS) amounts to 4% of the glucose flux through the glycolytic pathway. Upon in vitro ageing the rate of glucose utilization through the HMS is decreased more than 50%. This decrease in HMS was not caused by a limiting enzymatic capacity since glucose utilization through the HMS could be raised at least 30-fold in both 'young' and 'aged' fibroblasts upon stimulation with phenazine methosulphate. This effect of in vitro ageing upon glucose metabolism was also not due to differences in proliferation rate between 'young' and 'aged' human fibroblasts, since there was no difference in glucose utilization between proliferating and growth-inhibited (confluently cultured) fibroblasts. The NADPH/NADP ratio was found to be decreased by 12% in 'aged' cells.
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Systemic and topical antimicrobials are effective in the treatment of inflammatory acne vulgaris; however, widespread use of these agents is becoming increasingly associated with the emergence of resistant pathogens raising concerns about microorganism resistance and highlighting the need for alternative nonantimicrobial agents for the treatment of acne. Nicotinamide gel provides potent antiinflammatory activity without the risk of inducing bacterial resistance. In our double-blind investigation, the safety and efficacy of topically applied 4% nicotinamide gel was compared to 1% clindamycin gel for the treatment of moderate inflammatory acne vulgaris. Seventy-six patients were randomly assigned to apply either 4% nicotinamide gel (n = 38) or 1% clindamycin gel (n = 38) twice daily for 8 weeks. Efficacy was evaluated at 4 and 8 weeks using a Physician's Global Evaluation, Acne Lesion Counts, and an Acne Severity Rating. After 8 weeks, both treatments produced comparable (P = 0.19) beneficial results in the Physician's Global Evaluation of Inflammatory Acne; 82% of the patients treated with nicotinamide gel and 68% treated with clindamycin gel were improved. Both treatments produced statistically similar reductions in acne lesions (papules/pustules; -60%, nicotinamide vs. -43%, clindamycin, P = 0.168), and acne severity (-52% nicotinamide group vs. -38% clindamycin group, P = 0.161). These data demonstrate that 4% nicotinamide gel is of comparable efficacy to 1% clindamycin gel in the treatment of acne vulgaris. Because topical clindamycin, like other antimicrobials, is associated with emergence of resistant microorganisms, nicotinamide gel is a desirable alternative treatment for acne vulgaris.
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Ultraviolet (UV) B irradiation leads to a potent immunosuppression of the capacity to reject syngeneic, antigenic tumors. If this immunosuppression is critical for the development of most skin tumors, then its prevention should result in prevention of photocarcinogenesis. We previously showed a correlation between the inhibition of photoimmunosuppression and prevention of photocarcinogenesis by dl-alpha-tocopherol, tannic acid, or alpha-difluoromethylornithine. The current study was designed to determine whether topical nicotinamide, the active form of vitamin B-3, or niacin, prevents immunosuppression and skin cancer in UV-irradiated mice. In a passive transfer assay for immunosuppression, splenocytes from UV-irradiated mice enhanced the growth of antigenic tumor challenges in recipient mice. Treatment of the UV-irradiated mice with 40 mumol of nicotinamide twice weekly starting two weeks before UV irradiation and throughout the experiment prevented this immunosuppression. UVB irradiation consisted of five weekly 30-minute exposures to banks of six FS40 Westinghouse fluorescent sunlamps. Mice received approximately 6.2 x 10(5) J/m2 in the passive transfer assays and 1.09 x 10(6) J/m2 in the photocarcinogenesis studies. Application of nicotinamide to UV-irradiated mice reduced skin tumor incidence from 75% to 42.5% (p = 0.016, Cox proportional hazards analysis). Thus topical nicotinamide prevented the immunosuppression and skin tumor induction by UVB irradiation.
Article
Pellagra was in existence for nearly two centuries in Europe before being recognized in the United States, where it was first reported in 1902. Over the next two decades, pellagra occurred in epidemic proportions in the American South. Poverty and consumption of corn were the most frequently observed risk factors. Since the exact cause and cure of pellagra was not known, a culture of "pellagraphobia" formed among the public. Patients were shunned and ostracized. The medical community implicated spoiled corn as the cause of pellagra, which had economic repercussions for agriculturists. Joseph Goldberger, MD, of the United States Public Health Service eventually solved the secret of the malady: faulty diet. Goldberger was able to prevent and induce pellagra by dietary modification, a landmark event in the annals of medicine, nutrition, and epidemiology. His work and the social history of that period are reviewed.
Article
Stratum corneum lipids, particularly ceramides, are important components of the epidermal permeability barrier that are decreased in atopic dermatitis and aged skin. We investigated the effects of nicotinamide, one of the B vitamins, on biosynthesis of sphingolipids, including ceramides and other stratum corneum lipids, in cultured normal human keratinocytes, and on the epidermal permeability barrier in vivo. The rate of sphingolipid biosynthesis was measured by the incorporation of [14C]-serine into sphingolipids. When the cells were incubated with 1-30 micromol L-1 nicotinamide for 6 days, the rate of ceramide biosynthesis was increased dose-dependently by 4.1-5. 5-fold on the sixth day compared with control. Nicotinamide also increased the synthesis of glucosylceramide (7.4-fold) and sphingomyelin (3.1-fold) in the same concentration range effective for ceramide synthesis. Furthermore, the activity of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, was increased in nicotinamide-treated cells. Nicotinamide increased the levels of human LCB1 and LCB2 mRNA, both of which encode subunits of SPT. This suggested that the increase in SPT activity was due to an increase in SPT mRNA. Nicotinamide increased not only ceramide synthesis but also free fatty acid (2.3-fold) and cholesterol synthesis (1.5-fold). Topical application of nicotinamide increased ceramide and free fatty acid levels in the stratum corneum, and decreased transepidermal water loss in dry skin. Nicotinamide improved the permeability barrier by stimulating de novo synthesis of ceramides, with upregulation of SPT and other intercellular lipids.