Phenylalanine Butyramide: A Butyrate Derivative as a Novel Inhibitor of Tyrosinase.

Metabolites resulting from the bacterial fermentation of dietary fibers, such as short-chain fatty acids, especially butyrate, play important roles in maintaining gut health and regulating various biological effects in the skin. However, butyrate is underutilized due to its unpleasant odor. To circumvent this organoleptic unfavorable property, phenylalanine butyramide (PBA), a butyrate precursor, has been synthesized and is currently available on the market. We evaluated the inhibition of mushroom tyrosinase by butyrate and PBA through in vitro assays, finding IC50 values of 34.7 mM and 120.3 mM, respectively. Docking calculations using a homology model of human tyrosinase identified a putative binding mode of PBA into the catalytic site. The anti-aging and anti-spot efficacy of topical PBA was evaluated in a randomized, double-blind, parallel-arm, placebo-controlled clinical trial involving 43 women affected by photo-damage. The results of this study showed that PBA significantly improved skin conditions compared to the placebo and was well tolerated. Specifically, PBA demonstrated strong skin depigmenting activity on both UV and brown spots (UV: -12.7% and -9.9%, Bs: -20.8% and -17.7% after 15 and 30 days, respectively, p < 0.001). Moreover, PBA brightened and lightened the skin (ITA°: +12% and 13% after 15 and 30 days, respectively, p < 0.001). Finally, PBA significantly improved skin elasticity (Ua/Uf: +12.4% and +32.3% after 15 and 30 days, respectively, p < 0.001) and firmness (Uf: -3.2% and -14.9% after 15 and 30 days, respectively, p < 0.01).

Split-Mouth Comparison of Pain and Healing Associated With the Electrocautery and Bur Abrasion Methods in the Treatment of Depigmentation: A Case Report.

The most common aesthetic issue that affects people's smiles is gingival pigmentation, especially in those with high smile lines. This pigmented gingiva is thought to be naturally occurring melanin pigments that add to the gingiva's endogenous pigmentation. The goal of plastic periodontal surgery known as "gingival depigmentation" is to lighten the dark gingiva by scraping off the gingival epithelium. Gingival depigmentation has been performed with a variety of techniques, including bur abrasion, scraping, partial thickness flap, cryotherapy, electrocautery, and laser. The present case comprised a split-mouth design in which depigmentation using an electrosurgical unit and soft tissue trimming bur was used for the maxillary sections, and evaluated the difference in pain felt by the patient and healing of the surgical site between the sites treated with the electrosurgical unit and bur abrasion method. A visual analog scale (VAS) was used to quantify pain felt by the patient on the seventh day, whereas healing was assessed on the seventh day and at a one-month interval visually. The results of this study showed that the electrocautery-treated site showed better results in terms of pain experienced by the patient and also with the surgical site healing.

Asymmetric preservation of choroidal pigmentation simulating choroidal nevus in two siblings with Waardenburg syndrome type 2A.

INTRODUCTION: In addition to sensorineural hearing loss, Waardenburg Syndrome (WS) may present with variable pigmentation of skin and choroid, which may simulate other life-threating conditions (e.g. melanoma). CASE REPORT: Two siblings ostensibly presented with unilateral choroidal pigmentary abnormalities concerning for choroidal tumour. Serial ophthalmic examination documented no lesion growth (base or height) whilst the apparent syndromic features (i.e. iris hypochromia, profound sensorineural hearing loss, SNHL), family history (autosomal dominant inheritance) and positive genetic testing (pathogenic MITF variant) led to a revised diagnosis of Waardenburg Syndrome type 2A. CONCLUSION: Sectoral preservation of choroidal pigmentation in WS is rarely associated with choroidal malignancy. Awareness of syndromic features (e.g. SNHL) and access to genetic testing may facilitate early accurate diagnosis (i.e. allay concern for malignancy), enable treatment of modifiable features (e.g. SNHL) and identify other affected relatives.

Cancer Therapy-induced Dermatotoxicity as a Window to Understanding Skin Immunity.

Pruritus, rash, and various other forms of dermatotoxicity are the most frequent adverse events among patients with cancer receiving targeted molecular therapy and immunotherapy. Immune checkpoint inhibitors, macrophage-targeting agents, and epidermal growth factor receptor/MEK inhibitors not only exert antitumor effects but also interfere with molecular pathways essential for skin immune homeostasis. Studying cancer therapy-induced dermatotoxicity helps us identify molecular mechanisms governing skin immunity and deepen our understanding of human biology. This review summarizes new mechanistic insights emerging from the analysis of cutaneous adverse events and discusses knowledge gaps that remain to be closed by future research.

Phenylthiourea-mediated experimental depigmentation reduces seizurogenic response of pentylenetetrazol in zebrafish larva.

Zebrafish larvae exposed to chemoconvulsants show behavioral seizures and electrographic abnormalities similar to the other mammalian models, making it a potential tool in epilepsy research. During the embryonic stage, zebrafish remains transparent which enables real-time developmental detection and in-situ gene/protein expression. However, pigmentation during the larval stage restricts transparency. Phenylthiourea (1-phenyl-2-thiourea; PTU) is a commonly used pigmentation blocker that maintains larval transparency. It is widely used along with chemoconvulsants to study in situ expressions in epileptic larvae, however, its effect on seizures largely remains unknown. Therefore, in the present study, the effect of PTU-mediated depigmentation was studied on pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. After spawning, the fish embryos were subjected to standard depigmentation protocol using 0.13 mM PTU. At 7-days post fertilization seizures were induced using 8 mM PTZ. PTU exposure significantly reduced PTZ-mediated hyperactive responses indicated by decreased distance travelled and swimming velocity of the larvae. Furthermore, PTU-exposed depigmented larvae also showed an increase in the latency to the onset of PTZ-mediated clonic-like seizures. The results concluded that PTU depigmentation protocol reduces the seizurogenic response of PTZ, hence its usage for imaging zebrafish larvae must be carefully monitored to avoid erroneous results.

Novel Germline KIT Variants in Families With Severe Piebaldism: Case Series and Literature Review.

INTRODUCTION: Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the KIT gene. METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing. RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease. CONCLUSION: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.

Comparative Assessment of Gingival Depigmentation Using Scalpel Versus Microneedling With Ascorbic Acid: A Randomized Controlled Trial.

Background Gingival pigmentation (GP), characterized by the presence of melanin in the gingival tissues, is a common aesthetic concern in dental practice. While it poses no inherent health risks, the visible discoloration may cause psychological distress for individuals seeking optimal dental aesthetics. Understanding the efficacy of various methods is essential for refining treatment strategies and enhancing patient satisfaction in the realm of gingival depigmentation (GD). Aim The objective of the study was to compare the effectiveness of scalpel and microneedling (MN) with ascorbic acid in the treatment of GD. Materials and methods Sixteen patients who had a complaint of GP were included in the study, of whom eight were allocated for depigmentation with a scalpel, and the other eight patients were treated with the MN technique with ascorbic acid. Postoperative wound healing scores were evaluated on the first and seventh days, respectively. The intensity of depigmentation was assessed at baseline, in the first month, and at the end of the third month, respectively. Results The mean Dummett-Gupta Oral Pigmentation Index (DOPI) score at baseline was 2.65±0.16 and 2.61±0.17 in the surgical and microneedling groups with ascorbic acid, respectively. The mean DOPI score at the end of the third month was 1.67±0.39 and 0.87±0.17 in the scalpel and MN with ascorbic acid groups, respectively. There was a statistically significant difference between the scalpel and MN with ascorbic acid groups at the end of the first and third months, respectively, where MN with ascorbic acid showed aesthetically pleasing outcomes. Patients treated with the scalpel technique showed incomplete healing and ulceration on the first and seventh days after the procedure when compared to the MN technique with ascorbic acid. The healing index scores were statistically significant in the MN with ascorbic acid group. Conclusion The MN technique with ascorbic acid is a successful technique for treating GD. It showed aesthetically gratifying outcomes when compared to the conventional surgical technique.

A Minimally Invasive Technique for the Management of Physiologic Gingival Melanin Hyperpigmentation: A Case Series.

An attractive smile enhances an individual's self-confidence. The overall harmony of a smile can be attributed to the interplay of the teeth's shape, color, and position along with the gingival tissue. Gingival pigmentation is observed across all human races, exhibiting variations from one race to another. Typically, gingival hyperpigmentation results from the abnormal buildup of melanin in the gingival tissue, imparting a dark appearance on the gums. Various procedures, collectively known as gingival depigmentation, are employed to address gingival hyperpigmentation. While the initial outcomes of depigmentation procedures are often promising, one common issue associated with them is the potential for re-pigmentation. This article aims to evaluate the clinical effectiveness and patient-reported outcomes of intraepidermal (oral mesotherapy) vitamin C injection for nonsurgical management of physiologic gingival melanin hyperpigmentation.

Study on the effect of different durations of decalcification and depigmentation on programmed death ligand 1 immunohistochemical staining.

Background: Programmed death ligand 1 (PD-L1) score is an important companion diagnosis to predict the response to immunotherapy. Immunohistochemistry can accurately assess the expression of PD-L1 in routine paraffin-embedded tissue. However, whether decalcified or depigmented tissue is still accurate and can be used as a companion diagnosis is controversial. This study attempts to resolve this controversy by analyzing the effects of decalcification and depigmentation at different times on PD-L1 expression. Methods: Placental tissues were selected for tissue microarray, decalcification was performed according to time gradients of 6, 12, 24, 36, and 48 h, and depigmentation was performed according to time gradients of 1, 5, 15, 30, and 60 min. The intensity of PD-L1 expression at different time points was observed and quantified. Ten PD-L1-positive esophageal squamous carcinoma samples were selected for decalcification treatment, and the PD-L1. Combined Positive Score (CPS), Tumor Proportion Score (TPS) and Immunocyte Proportion Score (IPS) and the positivity rates were compared before and after decalcification. Results: After the placenta was decalcified, the intensity of PD-L1 positivity diminished, and the average optical density (AOD) value decreased with the prolongation of decalcification time and decreased significantly (P<0.05) at 24 h compared with the control group, and significantly (P<0.01) at 36 and 48 h compared with the control group. The intensity of PD-L1 positivity was weakened considerably after the treatment with potassium permanganate depigmentation. In addition, the AOD value decreased significantly (P<0.01) after the depigmentation time reached 5 min compared with the control group. Ten cases of PD-L1 positive esophageal squamous carcinoma were treated with 24 h decalcification, although the PD-L1 score decreased to a certain degree (P>0.05), and the positivity rate could reach 90%. After 36 h treatment, PD-L1 scores decreased, the CPS and IPS scores decreased significantly (P<0.05), and the positive rate was only 50%. Conclusions: Potassium permanganate depigmentation significantly reduces PD-L1 expression, even for a shorter time, affecting the accuracy of the results. The accuracy of PD-L1 remained high within 24 h decalcification. The above results have certain reference value for clinical selection of immunotherapy.

Topical antibiotics limit depigmentation in a mouse model of vitiligo.

Oral neomycin administration impacts the gut microbiome and delays vitiligo development in mice, and topical antibiotics may likewise allow the microbiome to preserve skin health and delay depigmentation. Here, we examined the effects of 6-week topical antibiotic treatment on vitiligo-prone pmel-1 mice. Bacitracin, Neosporin, or Vaseline were applied to one denuded flank, while the contralateral flank was treated with Vaseline in all mice. Ventral depigmentation was quantified weekly. We found that topical Neosporin treatment significantly reduced depigmentation and exhibited effects beyond the treated area, while Bacitracin ointment had no effect. Stool samples collected from four representative mice/group during treatment revealed that Neosporin treatment aligned with reduced abundance of the Alistipes genus in the gut, while relevant changes to the skin microbiome at end point were less apparent. Either antibiotic treatment led to reduced expression of MR1, potentially limiting mucosal-associated invariant T-cell activation, while Neosporin-treated skin selectively revealed significantly reduced CD8+ T-cell abundance. The latter finding aligned with reduced expression of multiple inflammatory markers and markedly increased regulatory T-cell density. Our studies on favorable skin and oral antibiotic treatment share the neomycin compound, and in either case, microbial changes were most apparent in stool samples. Taken together, neomycin-containing antibiotic applications can mediate skin Treg infiltration to limit vitiligo development. Our study highlights the therapeutic potential of short-term antibiotic applications to limit depigmentation vitiligo.

Rapid resolution of non-segmental vitiligo in a patient treated with abrocitinib: A case report.

Vitiligo is a common, autoimmune, depigmenting disorder of the skin. Janus Kinase inhibitors have emerged as promising topical and oral therapeutic options for vitiligo. There have been no reports of vitiligo being treated with oral Abrocitinib, a selective Janus Kinase 1 inhibitor approved for the treatment of moderate to severe atopic dermatitis. Here, we present a 61-year-old male with acrofacial vitiligo who had repigmentation plateau with twice daily tacrolimus 0.1% ointment, oral ginkgo biloba, and oral minipulse prednisone × 4 months; however, they had significant improvement after taking abrocitinib 100 mg per day for 2 months. He was able to transition topical tacrolimus twice weekly monotherapy for maintenance. This report shows that oral Janus Kinase inhibitors may be a useful option for the treatment of recalcitrant vitiligo. Results of ongoing randomized control trials are needed to determine the durability and safety of oral Janus Kinase inhibitors long-term.

Laser-Assisted Gingival Depigmentation: A Case Report.

The gingiva's colour varies in different individuals and is assumed to be related to cutaneous pigmentation. The most frequent natural pigment causing endogenous gingival pigmentation is melanin, a brown pigment. Depigmentation is a therapy of choice when individuals are concerned about their appearance and demand it for their aesthetic satisfaction. It is not a clinical indication. This article demonstrates gingival depigmentation using a laser diode with a 90-day follow­up. A 23-year-old male patient visited the Periodontology Department, complaining of poor aesthetics owing to dark-coloured gums. Depigmentation with a laser diode was selected as the treatment plan for both the maxillary and mandibular arches, at an interval of a week. The choice of a procedure is largely influenced by the gingival thickness, the clinician's experience, the patient's preferences, and the rate of recurrence. According to reports, using lasers produces better aesthetic outcomes and has a low recurrence rate.

Spotting the Pattern: A Review on White Coat Color in the Domestic Horse.

Traits such as shape, size, and color often influence the economic and sentimental value of a horse. Around the world, horses are bred and prized for the colors and markings that make their unique coat patterns stand out from the crowd. The underlying genetic mechanisms determining the color of a horse's coat can vary greatly in their complexity. For example, only two genetic markers are used to determine a horse's base coat color, whereas over 50 genetic variations have been discovered to cause white patterning in horses. Some of these white-causing mutations are benign and beautiful, while others have a notable impact on horse health. Negative effects range from slightly more innocuous defects, like deafness, to more pernicious defects, such as the lethal developmental defect incurred when a horse inherits two copies of the Lethal White Overo allele. In this review, we explore, in detail, the etiology of white spotting and its overall effect on the domestic horse to Spot the Pattern of these beautiful (and sometimes dangerous) white mutations.

Population Analysis Identifies 15 Multi-Variant Dominant White Haplotypes in Horses.

The influence of a horse's appearance on health, sentimental and monetary value has driven the desire to understand the etiology of coat color. White markings on the coat define inclusion for multiple horse breeds, but they may disqualify a horse from registration in other breeds. In domesticated horses (Equus caballus), 35 KIT alleles are associated with or cause depigmentation and white spotting. It is a common misconception among the general public that a horse can possess only two KIT variants. To correct this misconception, we used BEAGLE 5.4-phased NGS data to identify 15 haplotypes possessing two or more KIT variants previously associated with depigmentation phenotypes. We sourced photos for 161 horses comprising 12 compound genotypes with three or more KIT variants and employed a standardized method to grade depigmentation, yielding average white scores for each unique compound genotype. We found that 7 of the 12 multi-variant haplotypes resulted in significantly more depigmentation relative to the single-variant haplotypes (ANOVA). It is clear horses can possess more than two KIT variants, and future work aims to document phenotypic variations for each compound genotype.

Potent pigmentation inhibitory activity of incensole-enriched frankincense volatile oil-identification, efficacy and mechanism.

BACKGROUND: Frankincense volatile oil (FVO) has long been considered a side product in pharmaceutical industry since frankincense of large molecular weight is the prime target. However, the volatile oil recycled in the extract process might contain a series of functional actives, serving as promising ingredients in the cosmetic field. METHODS: Gas chromatography-mass spectrometer was utilized to determine the species and amount of active ingredients in FVO. Subsequently, zebrafish models were used to evaluate pigmentation inhibition, ROS elimination and neutrophil activation. In vitro DPPH test was also conducted to consolidate the anti-oxidation efficacy. Based on the test results, network pharmacology was incorporated, where GO and KEGG enrichment analyses were performed to discover the interrelations between active ingredients. RESULTS: About 40 actives molecules were identified, including incensole, acetate incensole, and acetate incensole oxide. The FVO demonstrated great depigmentation activity by suppressing melanin synthesis, as well as providing free radical scavenging and anti-inflammation effect. In network pharmacology analysis, 192 intersected targets were identified. By enrichment analysis and network construction, a series of whitening signal pathways, and hub genes, containing STAT3，MAPK3，MAPK1 were identified. CONCLUSION: The current study quantified the components of FVO, evaluated its efficacy in skin depigmentation, and give pioneering insights on the possible mechanism. The results confirmed that the FVO could serve as whitening agent in topical uses.

Unveiling genetics of non-syndromic albinism using whole exome sequencing: A comprehensive study of TYR, TYRP1, OCA2 and MC1R genes in 17 families.

BACKGROUND: Oculocutaneous albinism (OCA) is a group of skin depigmentation disorders. Clinical presentation of OCA includes defects in melanocyte differentiation, melanin biosynthesis, and melanosome maturation and transport. OBJECTIVES: A molecular diagnostics study of families presenting oculocutaneous albinism. METHODS: In this study, 17 consanguineous OCA families consisting of 93 patients were investigated. Whole Exome Sequencing (WES) of the index patient in each family were performed. Short listed variants of WES were Sanger validated for Mendelian segregation in obligate carriers and other available family members. Variant prioritization and pathogenicity were classified as per the criteria of American College Medical Genetics and Genomics (ACMG). Comparative computational modelling was performed to predict the potential damaging effect of the altered proteins. RESULTS: 15 pathogenic variations: c.132 T > A, c.346C > T, c.488C > G, c.1037G > A in TYR, c.1211C > T, c.1441G > A, c.1706_1707insT, c.2020C > G, c.2402G > C, c.2430del, in OCA2, c.1067G > A in TYRP1 and c.451C > T, c.515G > T, c.766C > T, c.917G > A in MC1R genes were identified. Three variants in OCA2 gene were characterized: c.1706_1707insT, c.2430del, and c.2402G > C, all of which were not reported before in OCA families. CONCLUSION: A few studies focusing on mutation screening of OCA patients have been reported before; however, this study has uniquely presents the Pakhtun ethnic population residing on the North-Western boarder. It explains that TYR, OCA2, TYRP1, and MC1R variations lead to non-syndromic OCA phenotype The overlapping phenotypes of OCA can precisely be diagnosed for its molecular pathogenicity using WES. This study recommends WES as a first-line molecular diagnostic tool, and provides a basis for developing customized genetic tests i.e. pre-marital screening to reduce the disease burden in the future generations.

Management of gingival hyperpigmentation induced by increased ferritin level in a HbS-ß+ thalassemia patient using diode laser.

Diode lasers can be employed for the treatment of gingival hyperpigmentation in HbS-ß+ thalassemia patients due to the advantages that lasers provide including good hemostatic effect and less postoperative complications.

A Comparative Histological Study of Gingival Depigmentation by 808 and 445 nm Diode Lasers.

Introduction: Using lasers in melanin depigmentation is one of the main fields of interest for dental practitioners and patients. However, it is important to know what would happen inside the tissue and how the cells would interact inside the tissue with a laser. Methods: In this study, we used both wavelengths of 445 nm and 808 nm on sheep gingiva to find out the effects and side effects of these diode lasers while using them for gingival depigmentation. Results: After microscopic evaluation, we concluded that 808 nm and 445 nm lasers with a power of 1 W are safe enough to use in the depigmentation of gingiva, and both lasers are highly effective in melanin pigments which are located in basal membrane. Conclusion: The 445 nm blue laser produced a less thermal effect, which means it is safer to be used in gingival hyperpigmentation than a diode laser.

Vitamin C mesotherapy versus diode laser for the esthetic management of physiologic gingival hyperpigmentation: a randomized clinical trial.

BACKGROUND: Physiologic gingival hyperpigmentation is a common esthetic concern that affects individuals of various ethnicities, and can have a significant impact on individual's self-confidence and overall quality of life. Thus, this study aimed to clinically assess the effectiveness of intra-mucosal injection of vitamin C versus 980 nm diode laser for the management of physiologic gingival hyperpigmentation. METHODS: Twenty-six healthy non-smoker individuals with physiologic gingival hyperpigmentation were randomly assigned to two groups. Group I received intra-mucosal injection of vitamin C (L-Ascorbic acid 1000 mg/5 ml), and group II was managed using diode laser (980 nm, 1.5 W, continuous wave mode). Clinical evaluation of pigmentation intensity and distribution was performed preoperatively, and at 1, 2 and 3 months postoperatively using two different color assessment indices; Dummett-Gupta Oral Pigmentation Index (DOPI), and Gingival Pigmentation Index (GPI). Additionally, the study assessed pain intensity and patients' satisfaction. RESULTS: Pigmentation scores decreased significantly between pre-operative visit and different follow-up visits for both treatment modalities (p < 0.0001*). When compared to the vitamin C mesotherapy group, the laser group demonstrated significantly lower gingival pigmentation scores (p < 0.0001*). However, both treatment modalities were equally satisfying for the patients. CONCLUSIONS: Vitamin C mesotherapy and diode laser are both effective in the management of physiologic gingival hyperpigmentation. While diode laser yields better and earlier results, vitamin C mesotherapy offers a cost-effective, safe and minimally invasive approach that is equally satisfying for the patients seeking esthetic enhancements. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov (NCT05608057) on (01/11/2022).