How to fight acute sun damage? Current skin care strategies.

Excessive exposure to sunlight can contribute for skin photo-damage, such as sunburn, dryness, wrinkles, hyperpigmentation, immunosuppressive events and skin sensitization reactions. The use of aftersun products is an effective strategy to reduce the visible signs and symptoms of acute photodamage in the skin. Aiming to unveil the active ingredients able to offset acute sun damage, this work focuses on the characterization of the aftersun products market. A total of 84 after-sun formulations from 41 international brands currently marketed in Portugal were analyzed concerning the composition described on the product label, identifying natural and synthetic/semi-synthetic ingredients with the ability to mitigate solar-induced effects. The majority of aftersun formulations contained ingredients derived from terrestrial and marine sources (> 80%). An in-depth examination of these compounds is also offered, revealing the top of the most used natural and synthetic/semi-synthetic ingredients present in aftersun products, as well as their mechanism of action. A critical appraisal of the scientific data was made aiming to highlight the scientific evidence of ingredients able to mitigate skin photodamage. Amino acids and peptides, and A. barbadensis extract were tested for their in vivo efficacy. Nevertheless, all the ingredients were analyzed with in vitro studies as preliminary screening before in vivo, ex vivo and/or clinical studies. In summary, this study provides an overview of the use of active ingredients in commercial aftersun products to understand better the benefits associated with their use in cosmetic formulations and identify opportunities for innovation.

Artificial Dendritic Cells: A New Era of Promising Antitumor Immunotherapy.

The accelerated development of antitumor immunotherapies in recent years has brought immunomodulation into the spotlight. These include immunotherapeutic treatments with dendritic cell (DC)-based vaccines which can elicit tumor-specific immune responses and prolong survival. However, this personalized treatment has several drawbacks, including being costly, labor-intensive, and time consuming. This has sparked interest in producing artificial dendritic cells (aDCs) to open up the possibility of standardized "off-the-shelf" protocols and circumvent the cumbersome and expensive personalized medicine. aDCs take advantage of materials that can be designed and tailored for specific clinical applications. Here, an overview of the immunobiology underlying antigen presentation by DCs is provided in an attempt to select the key features to be mimicked and/or improved through the development of aDCs. The inherent properties of aDCs that greatly impact their performance in vivo and, consequently, the fate of the triggered immune response are also outlined.

Exploiting the Integrated Valorization of Eucalyptus globulus Leaves: Chemical Composition and Biological Potential of the Lipophilic Fraction before and after Hydrodistillation.

E. globulus leaves have been mainly exploited for essential oil recovery or for energy generation in industrial pulp mills, neglecting the abundance of valuable families of extractives, namely, triterpenic acids, that might open new ways for the integrated valorization of this biomass. Therefore, this study highlights the lipophilic characterization of E. globulus leaves before and after hydrodistillation, aiming at the integrated valorization of both essential oils and triterpenic acids. The lipophilic composition of E. globulus leaves after hydrodistillation is reported for the first time. Extracts were obtained by dichloromethane Soxhlet extraction and analyzed by gas chromatography-mass spectrometry. In addition, their cytotoxicity on different cell lines representative of the innate immune system, skin, liver, and intestine were evaluated. Triterpenic acids, such as betulonic, oleanolic, betulinic and ursolic acids, were found to be the main components of these lipophilic extracts, ranging from 30.63-37.14 g kg-1 of dry weight (dw), and representing 87.7-89.0% w/w of the total content of the identified compounds. In particular, ursolic acid was the major constituent of all extracts, representing 46.8-50.7% w/w of the total content of the identified compounds. Other constituents, such as fatty acids, long-chain aliphatic alcohols and ß-sitosterol were also found in smaller amounts in the studied extracts. This study also demonstrates that the hydrodistillation process does not affect the recovery of compounds of greatest interest, namely, triterpenic acids. Therefore, the results establish that this biomass residue can be considered as a promising source of value-added bioactive compounds, opening new strategies for upgrading pulp industry residues within an integrated biorefinery context.

A Hydrophilic Sulfated Resveratrol Derivative for Topical Application: Sensitization and Anti-Allergic Potential.

Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic formulations. RSV-GS is a synthetic hydrophilic sulfated glycosylated derivative inspired by marine natural products that present a lower cytotoxicity than RSV while exhibiting similar levels of bioactivity. Herein, we predict the skin sensitization potential of this new compound using an in vitro approach based on the OECD 442E guideline. Furthermore, the anti-allergic potential of RSV-GS was also disclosed. The monocyte THP-1 cell line was stimulated with RSV and RSV-GS in the presence or absence of the extreme skin allergen 1-fluoro-2,4-dinitrobenzene (DNFB). The results demonstrated that RSV-GS alone (500 µM) evoked a relative fluorescence index (RFI) lower than the thresholds established by the OECD guideline for CD54 (200%) and CD86 (150%), indicating the absence of a skin sensitization potential. Interestingly, in the presence of the skin allergen DNFB, RSV-GS exhibited the ability to rescue the DNFB-induced maturation of THP-1 cells, with RFI values lower than those for RSV, suggesting the potential of RSV-GS to mitigate skin sensitization evoked by allergens and, consequently, allergic contact dermatitis. These results open new avenues for the use of RSV-GS as a safe and anti-allergic active cosmetic ingredient.

ERP evidence of heightened attentional response to visual stimuli in migraine headache disorders.

New findings from migraine studies have indicated that this common headache disorder is associated with anomalies in attentional processing. In tandem with the previous explorations, this study will provide evidence to show that visual attention is impacted by migraine headache disorders. 43 individuals were initially recruited in the migraine group and 33 people with non-migraine headache disorders were in the control group. The event-related potentials (ERP) of the participants were calculated using data from a visual oddball paradigm task. By analyzing the N200 and P300 ERP components, migraineurs, as compared to controls, had an exaggerated oddball response showing increased amplitude in N200 and P300 difference scores for the oddball vs. standard, while the latencies of the two components remained the same in the migraine and control groups. We then looked at two classifications of migraine with and without aura compared to non-migraine controls. One-Way ANOVA analysis of the two migraine groups and the non-migraine control group showed that the different level of N200 and P300 amplitude mean scores was greater between migraineurs without aura and the control group while these components' latency remained the same relatively in the three groups. Our results give more neurophysiological support that people with migraine headaches have altered processing of visual attention.

Inflammation in Bipolar Disorder (BD): Identification of new therapeutic targets.

Bipolar disorder (BD) is a chronic and cyclic mental disorder, characterized by unusual mood swings between mania/hypomania and depression, raising concern in both scientific and medical communities due to its deleterious social and economic impact. Polypharmacy is the rule due to the partial effectiveness of available drugs. Disease course is often unremitting, resulting in frequent cognitive deficits over time. Despite all research efforts in identifying BD-associated molecular mechanisms, current knowledge remains limited. However, the involvement of inflammation in BD pathophysiology is increasingly consensual, with the immune system and neuroinflammation playing a key role in disease course. Evidence includes altered levels of cytokines and acute-phase proteins, pathological microglial activation, deregulation of Nrf2-Keap1 system and changes in biogenic amines neurotransmitters, whose expression is regulated by TNF-α, a pro-inflammatory cytokine highly involved in BD, pointing out inflammation as a novel and attractive therapeutic target for BD. As result, new therapeutic agents including non-steroidal anti-inflammatory drugs, N-acetylcysteine and GSK3 inhibitors have been incorporated in BD treatment. Taking into consideration the latest pre-clinical and clinical trials, in this review we discuss recent data regarding inflammation in BD, unveiling potential therapeutic approaches through direct or indirect modulation of inflammatory response.

Allergic contact dermatitis: From pathophysiology to development of new preventive strategies.

As the body's first line of defense, the skin is the organ most frequently exposed to chemicals present in personal hygiene products, household products, or materials used in the work environment. In this context, skin disorders account for more than 40 % of all occupational and work-related diseases, constituting a significant public health burden. Among skin disorders, allergic contact dermatitis (ACD) is the most prevalent occupational disease and the most common form of immunotoxicity in humans. ACD is a T-cell-mediated skin inflammation resulting from the priming and expansion of allergen-specific CD4+ and CD8+ T cells. The clinical condition is characterized by local skin rash, itchiness, redness, swelling, and lesions, being mainly diagnosed by the patch test. Upon ACD diagnosis, avoiding the exposure to the triggering allergen is the mainstay of treatment to prevent future flares. In cases where avoidance is not possible, the use of a standard of care interim treatments such as steroid creams or ointments, barrier creams, and moisturizers are strongly recommended to alleviate symptoms. In this review, we sought to provide the reader with an overview of the pathophysiology of ACD as well as the currently available pharmacological treatment options. Furthermore, a comprehensive outline of several preventive strategies is also provided.

Evaluating Skin Sensitization Via Soft and Hard Multivariate Modeling.

Allergic contact dermatitis is the most frequent manifestation of immunotoxicity in humans with a prevalence rate of 15% to 20% over general population. Skin sensitization is a complex end point that was for a long time being evaluated using animal testing. Great efforts have been made to completely substitute the use of animals and replace them by integrating data from in vitro and in chemico assays with in silico calculated parameters. However, it remains undefined how to make the best use of the cumulative data in such a way that information gain is maximized and accomplished with the fewest number of tests possible. In this work, 3 skin sensitization prediction models were considered: one to discriminate sensitizers from non-sensitizers, considering a 2-level scale; one according to the GHS, considering a 3-level scale; and the other to categorize potency in a 6-level scale, according to available human data. We used a data set of known human skin allergens for which in vitro, in chemico, and in silico descriptors where available to build classifiers based on soft and hard multivariate modeling. Model building, optimization, and refinement resulted in 100% accuracy in distinguishing between sensitizers and non-sensitizers. The same model was able to perform the characterization, in 3 and 6 levels, respectively, with 98.8 and 97.5% accuracy. Combining data from in vitro and in chemico tests with in silico descriptors is relatively simple to implement and some predictors are fitting the adverse outcome pathway for skin sensitization.

Evidence for abnormal visuospatial attentional processes in the interictal migraineur.

Research shows decreased brain region activity in the right temporo-parietal junction (rTPJ) in people with migraine headache relative to headache-free controls when performing an orienting visuospatial attention task. Functional inactivation of the rTPJ has been associated with rightward performance deviations on laterality-based attention Landmark (LM) and greyscale (GRE) tasks in individuals with unilateral neglect and heightened activation in the rTPJ is associated with leftward deviation, known as pseudoneglect, in controls on these tasks. Given this, we investigated whether migraineurs would lack the leftward deviation found in headache-free controls on visuospatial attention tasks. 36 migraineurs and 38 controls were presented with LM and GRE tasks. Response bias scores showed a significant difference in responses between groups (p = 0.036) on the GRE, a luminance-based task, but not on the LM, a size-based task (p = 0.826). This study is the first to show laterality-based attentional differences in migraineurs, as compared to controls. Specifically, migraineurs were found to have smaller leftward biases on luminance-based visuospatial attention tasks, as compared to controls, aligning with previous research suggesting that migraine may be having an impact on a variety of attention tasks in migraineurs in between headache attacks.

Phlorotannins from Fucus vesiculosus: Modulation of Inflammatory Response by Blocking NF-κB Signaling Pathway.

Due to their large spectrum of bioactive properties, much attention has recently been drawn to phlorotannins-i.e., phenolic compounds characteristic from brown macroalgae. This study aimed to evaluate the antioxidant and anti-inflammatory properties of F. vesiculosus phlorotannin extracts and purified fractions. Overall, the crude extract and its ethyl acetate fraction (EtOAc) showed good radical scavenging activity, particularly towards nitric oxide (NO•). Subsequent subfractions of EtOAc (F1 to F9) with different molecular weights were then shown to inhibit lipopolysaccharide-induced NO• production in macrophages, with stronger effects being observed for fractions of lower MWs. Of the three intracellular markers analyzed, inducible NO• synthase showed the highest sensitivity to almost all the phlorotannin-rich samples, followed by interleukin 1ß and cyclooxygenase 2, which was only inhibited by F2. Furthermore, this subfraction inhibited the phosphorylation and degradation of inhibitory protein κBα, thus preventing the activation of NF-κB and blocking the inflammatory cascade at the transcriptional level. This sample was characterized by the presence of a major compound with a deprotonated molecular ion at m/z 507 with a fragmentation pattern coherent with that of a phlorotannin derivative. Overall, this work unveiled some of the mechanistic aspects behind the anti-inflammatory capacity of phlorotannins from F. vesiculosus, endorsing its use as a possible natural source of anti-inflammatory compounds.

Characterization and Cytotoxicity Assessment of the Lipophilic Fractions of Different Morphological Parts of Acacia dealbata.

Acacia dealbata biomass, either from forest exploitation or from the management of invasive species, can be a strategic topic, namely as a source of high-value compounds. In this sense, the present study aimed at the detailed characterization of the lipophilic components of different morphological parts of A. dealbata and the evaluation of their cytotoxicity in cells representative of different mammals' tissues. The chemical composition of lipophilic extracts from A. dealbata bark, wood and leaves was evaluated using gas chromatography-mass spectrometry (GC-MS). Terpenic compounds (representing 50.2%-68.4% of the total bark and leaves extracts, respectively) and sterols (60.5% of the total wood extract) were the main components of these extracts. Other constituents, such as fatty acids, long-chain aliphatic alcohols, monoglycerides, and aromatic compounds were also detected in the studied extracts. All the extracts showed low or no cytotoxicity in the different cells tested, demonstrating their safety profile and highlighting their potential to be used in nutraceutical or pharmaceutical applications. This study is therefore an important contribution to the valorization of A. dealbata, demonstrating the potential of this species as a source of high value lipophilic compounds.

Lipophilic Fraction of Cultivated Bifurcaria bifurcata R. Ross: Detailed Composition and In Vitro Prospection of Current Challenging Bioactive Properties.

Macroalgae have been seen as an alternative source of molecules with promising bioactivities to use in the prevention and treatment of current lifestyle diseases. In this vein, the lipophilic fraction of short-term (three weeks) cultivated Bifurcaria bifurcata was characterized in detail by gas chromatography-mass spectrometry (GC-MS). B. bifurcata dichloromethane extract was composed mainly by diterpenes (1892.78 ± 133.97 mg kg-1 dry weight (DW)), followed by fatty acids, both saturated (550.35 ± 15.67 mg kg-1 DW) and unsaturated (397.06 ± 18.44 mg kg-1 DW). Considerable amounts of sterols, namely fucosterol (317.68 ± 26.11 mg kg-1 DW) were also found. In vitro tests demonstrated that the B. bifurcata lipophilic extract show antioxidant, anti-inflammatory and antibacterial activities (against both Gram-positive and Gram-negative bacteria), using low extract concentrations (in the order of µg mL-1). Enhancement of antibiotic activity of drug families of major clinical importance was observed by the use of B. bifurcata extract. This enhancement of antibiotic activity depends on the microbial strain and on the antibiotic. This work represents the first detailed phytochemical study of the lipophilic extract of B. bifurcata and is, therefore, an important contribution for the valorization of B. bifurcata macroalgae, with promising applications in functional foods, nutraceutical, cosmetic and biomedical fields.

The Flavone Luteolin Inhibits Liver X Receptor Activation.

Luteolin is a dietary flavonoid with medicinal properties including antioxidant, antimicrobial, anticancer, antiallergic, and anti-inflammatory. However, the effect of luteolin on liver X receptors (LXRs), oxysterol sensors that regulate cholesterol homeostasis, lipogenesis, and inflammation, has yet to be studied. To unveil the potential of luteolin as an LXRα/ß modulator, we investigated by real-time RT-PCR the expression of LXR-target genes, namely, sterol regulatory element binding protein 1c (SREBP-1c) in hepatocytes and ATP-binding cassette transporter (ABC)A1 in macrophages. The lipid content of hepatocytes was evaluated by Oil Red staining. The results demonstrated, for the first time, that luteolin abrogated the LXRα/ß agonist-induced LXRα/ß transcriptional activity and, consequently, inhibited SREBP-1c expression, lipid accumulation, and ABCA1 expression. Therefore, luteolin could abrogate hypertriglyceridemia associated with LXR activation, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism, such as hepatic steatosis, cardiovascular diseases, and diabetes.

Exploring the immunomodulatory properties of glucan particles in human primary cells.

The immunomodulatory properties of ß-glucans have sparked interest among various medical fields. As vaccine adjuvants, glucan particles offer additional advantages as antigen delivery systems. This study reported the immunomodulatory properties of glucan particles with different size and chemical composition. The effect of glucan microparticles (GPs) and glucan nanoparticles (Glu 130 and 355 NPs) was evaluated on human immune cells. While GPs and Glu 355 NPs demonstrated substantial interaction with Dectin-1 receptor on monocytes, Glu 130 NPs exhibited reduced activation of this receptor. This observation was substantiated by blocking Dectin-1, resulting in inhibition of reactive oxygen species production induced by GPs and Glu 355 NPs. Notably, monocyte-derived dendritic cells (moDCs) stimulated by Glu 355 NPs exhibited phenotypic and functional maturation, essential for antigen cross-presentation. The immunomodulatory efficacy was investigated using an autologous mixed lymphocyte reaction (AMLR), resulting in considerable rates of lymphocyte proliferation and an intriguing profile of cytokine and chemokine release. Our findings highlight the importance of meticulously characterizing the size and chemical composition of ß-glucan particles to draw accurate conclusions regarding their immunomodulatory activity. This in vitro model mimics the human cellular immune response, and the results obtained endorse the use of ß-glucan-based delivery systems as future vaccine adjuvants.

The study of galactomannans with different molecular weights and their ability to form microparticles suitable for pulmonary delivery.

The influence of locust bean gum (LBG) galactomannans (GMs) molecular weight (Mw) to assemble microparticulate systems was evaluated, and carriers for deep lung delivery were developed. A commercial batch of LBG with a mannose/galactose (M/G) ratio of 2.4 (batch 1) was used to study the influence of different microwave partial acid hydrolysis conditions on carbohydrate composition, glycosidic linkages, and aqueous solutions viscosity. The microwave treatment did not affect the composition, presenting 4-Man (36-42 %), 4,6-Man (27-35 %), and T-Gal (24-25 %) as the main glycosidic linkages. Depolymerization led to a viscosity reduction (≤0.005 Pa·s) with no major impact on polysaccharide debranching. The structural composition of the LBG galactomannans were further elucidated with sequence-specific proteins using carbohydrate microarray technologies. A second batch of LBG (M/G 3.3) was used to study the impact of GMs with different Mw on microparticle assembling, characteristics, and insulin release kinetics. The low-Mw GMs microparticles led to a faster release (20 min) than the higher-Mw (40 min) ones, impacting the release kinetics. All microparticles exhibited a safety profile to cells of the respiratory tract. However, only the higher-Mw GMs allowed the assembly of microparticles with sizes suitable for this type of administration.

Chronic pruritus: From pathophysiology to drug design.

Pruritus, the most common symptom in dermatology, is an innate response capable of protecting skin against irritants. Nonetheless, when it lasts more than six weeks it is assumed to be a chronic pathology having a negative impact on people's lives. Chronic pruritus (CP) can occur in common and rare skin diseases, having a high prevalence in global population. The existing therapies are unable to counteract CP or are associated with adverse effects, so the development of effective treatments is a pressing issue. The pathophysiological mechanisms underlying CP are not yet completely dissected but, based on current knowledge, involve a wide range of receptors, namely neurokinin 1 receptor (NK1R), Janus kinase (JAK), and transient receptor potential (TRP) ion channels, especially transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1). This review will address the relevance of these molecular targets for the treatment of CP and molecules capable of modulating these receptors that have already been studied clinically or have the potential to possibly alleviate this pathology. According to scientific and clinical literature, there is an increase in the expression of these molecular targets in the lesioned skin of patients experiencing CP when compared with non-lesioned skin, highlighting their importance for the development of potential efficacious drugs through the design of antagonists/inhibitors.

Antioxidants in Sunscreens: Which and What For?

Ultraviolet (UV) radiation promotes the generation of reactive oxygen species (ROS) and nitrogen species (RNS), resulting in skin damage. Cosmetic industries have adopted a strategy to incorporate antioxidants in sunscreen formulations to prevent or minimize UV-induced oxidative damage, boost photoprotection effectiveness, and mitigate skin photoaging. Many antioxidants are naturally derived, mainly from terrestrial plants; however, marine organisms have been increasingly explored as a source of new potent antioxidant molecules. This work aims to characterize the frequency of the use of antioxidants in commercial sunscreens. Photoprotective formulations currently marketed in parapharmacies and pharmacies were analyzed with respect to the composition described on the label. As a result, pure compounds with antioxidant activity were found. The majority of sunscreen formulations contained antioxidants, with vitamin E and its derivatives the most frequent. A more thorough analysis of these antioxidants is also provided, unveiling the top antioxidant ingredients found in sunscreens. A critical appraisal of the scientific evidence regarding their effectiveness is also performed. In conclusion, this work provides an up-to-date overview of the use of antioxidants in commercial sunscreens for a better understanding of the advantages associated with their use in photoprotective formulations.

How to Promote Skin Repair? In-Depth Look at Pharmaceutical and Cosmetic Strategies.

Skin repair encompasses epidermal barrier repair and wound healing which involves multiple cellular and molecular stages. Therefore, many skin repair strategies have been proposed. In order to characterize the usage frequency of skin repair ingredients in cosmetics, medicines, and medical devices, commercialized in Portuguese pharmacies and parapharmacies, a comprehensive analysis of the products' composition was performed. A total of 120 cosmetic products, collected from national pharmacies online platforms, 21 topical medicines, and 46 medical devices, collected from INFARMED database, were included in the study, revealing the top 10 most used skin repair ingredients in these categories. A critical review regarding the effectiveness of the top ingredients was performed and an in-depth analysis focused on the top three skin repair ingredients pursued. Results demonstrated that top three most used cosmetic ingredients were metal salts and oxides (78.3%), vitamin E and its derivatives (54.2%), and Centella asiatica (L.) Urb. extract and actives (35.8%). Regarding medicines, metal salts and oxides were also the most used (47.4%) followed by vitamin B5 and derivatives (23.8%), and vitamin A and derivatives (26.3%). Silicones and derivatives were the most common skin repair ingredients in medical devices (33%), followed by petrolatum and derivatives (22%) and alginate (15%). This work provides an overview of the most used skin repair ingredients, highlighting their different mechanisms of action, aiming to provide an up-to-date tool to support health professionals' decisions.

Polysaccharide-Based Carriers for Pulmonary Insulin Delivery: The Potential of Coffee as an Unconventional Source.

Non-invasive routes for insulin delivery are emerging as alternatives to currently painful subcutaneous injections. For pulmonary delivery, formulations may be in powdered particle form, using carriers such as polysaccharides to stabilise the active principle. Roasted coffee beans and spent coffee grounds (SCG) are rich in polysaccharides, namely galactomannans and arabinogalactans. In this work, the polysaccharides were obtained from roasted coffee and SCG for the preparation of insulin-loaded microparticles. The galactomannan and arabinogalactan-rich fractions of coffee beverages were purified by ultrafiltration and separated by graded ethanol precipitations at 50% and 75%, respectively. For SCG, galactomannan-rich and arabinogalactan-rich fractions were recovered by microwave-assisted extraction at 150 °C and at 180 °C, followed by ultrafiltration. Each extract was spray-dried with insulin 10% (w/w). All microparticles had a raisin-like morphology and average diameters of 1-5 µm, which are appropriate for pulmonary delivery. Galactomannan-based microparticles, independently of their source, released insulin in a gradual manner, while arabinogalactan-based ones presented a burst release. The microparticles were seen to be non-cytotoxic for cells representative of the lung, specifically lung epithelial cells (A549) and macrophages (Raw 264.7) up to 1 mg/mL. This work shows how coffee can be a sustainable source of polysaccharide carriers for insulin delivery via the pulmonary route.

Comparative Studies on the Photoreactivity, Efficacy, and Safety of Depigmenting Agents.

Depigmenting products are increasingly used to counteract skin hyperpigmentation and related psychosocial issues. This study aimed to compare different depigmenting agents-4-butylresorcinol; bakuchiol; tranexamic acid; ascorbyl glucoside; α-arbutin; and ascorbic acid-for photoreactivity; tyrosinase inhibition; and safety. Photoreactivity was assessed using the Reactive Oxygen Species assay. In vitro tyrosinase inhibition was compared, and cell viability was assessed in B-16V melanocytes to evaluate safety. Results showed 4-butylresorcinol, ascorbyl glucoside, and α-arbutin are non-photoreactive, while for ascorbic acid and bakuchiol it was not possible to reach conclusive results due to the lack of specificity of the ROS assay. 4-Butylresorcinol, acting as a competitive inhibitor, displayed potent tyrosinase inhibition, followed by ascorbic acid and bakuchiol. Both 4-butylresorcinol and bakuchiol reduced cell viability in a concentration-dependent manner. The insights obtained in this work support the development of depigmenting products by providing useful scientific guidance on the photostability, tyrosinase inhibitory efficacy, and skin safety of depigmenting agents.