Cis-urocanic Acid Research Articles

Skin Barrier– and Immune Response–Related Biomarkers of Solar UVR Exposure Comparing Indoor and Outdoor Workers

Outdoor workers have increased risk of developing keratinocyte cancer due to accumulated skin damage resulting from chronic and excessive exposure to UVR. This study aims to identify potential noninvasive biomarkers to assess chronic UVR exposure. We analyzed stratum corneum biomarkers collected from 2 skin locations and 2 occupational groups with contrasting solar UVR exposure: the forehead and retroauricular skin among outdoor workers and indoor workers. Using a linear mixed model adjusting for age and skin phototype, we compared biomarkers between both skin sites in indoor and outdoor workers. We measured markers of the immune response and skin barrier, including cytokines, GFs, 15-hydroxyeicosatetraenoic acid, cis- and trans-urocanic acid, and corneocyte topography, indicated by circular nano objects. Differences between the 2 skin sites were found for cis-urocanic acid, total urocanic acid, IL-1α, IL-1RA, IL-1RA/IL-1α, IL-18, 15-hydroxyeicosatetraenoic acid, CCL4, and circular nano objects. The levels of cis-urocanic acid and CCL4 also differed between indoor and outdoor workers. These findings underscore changes in both immune response and skin barrier induced by UVR. They indicate the potential utility of stratum corneum biomarkers in detecting both chronic UVR exposure in occupational setting and aiding in the development of preventive measures.

Natural moisturising factor constituents in South African nursing students.

The majority of South African healthcare workers are Black Africans with dark-pigmented skin. Studies on how the markers of skin barrier function and natural moisturising factor (NMF) compare between dark and light-pigmented skin are limited. Quantifying NMF in a nursing student population during their practical training at university may provide valuable insight into their potential susceptibility to skin conditions associated with low NMF. The objectives of this study were to quantify and compare NMF content of Black African, Mixed Race and White nursing students from their dominant dorsal hand. Forty-nine White, 32 Black African and 5 Mixed Race nursing students participated in this study. Tape strip samples were collected from the participants' dominant dorsal hand and NMF content was measured, including histidine (HIS), pyrrolidone carboxylic acid (PCA), trans-urocanic acid (t-UCA) and cis-urocanic acid (c-UCA), as well as cytokines interleukin-1 alpha (IL-1α) and interleukin-1 receptor antagonist (IL-1RA). No statistically significant differences in PCA, t-UCA, c-UCA, IL-1α or IL-1RA were found between Black African and White nursing students. HIS was significantly (p = 0.001) higher in White nursing students when compared to Black African students. The ratio of tot-UCA/HIS was significantly higher in Black Africans (p = 0.0002) when compared to White nursing students. No significant differences were established in NMF content between White and Black African nursing students, other than HIS which was significantly higher in White students than in Black African students. Different HIS levels between the racial groups suggest variation in histidase activity which may be related to skin pH and pigmentation. This finding may suggest that nursing students at the beginning of their careers may have similar susceptibility to skin diseases related to NMF.

Cis-urocanic acid improves cell viability and suppresses inflammasome activation in human retinal pigment epithelial cells

Age-related macular degeneration (AMD) is a common eye disease among the elderly, which can result in impaired vision and irreversible loss of vision. The majority of patients suffer from the dry (also known as the atrophic) form of the disease, which is completely lacking an effective treatment. In the present study, we evaluated the potential of cis-urocanic acid (cis-UCA) to protect human ARPE-19 cells from cell damage and inflammasome activation induced by UVB light. Urocanic acid is a molecule normally present in human epidermis. Its cis-form has recently been found to alleviate UVB-induced inflammasome activation in human corneal epithelial cells. Here, we observed that cis-UCA is well-tolerated also by human retinal pigment epithelial (RPE) cells at a concentration of 100 μg/ml. Moreover, cis-UCA was cytoprotective and efficiently diminished the levels of mature IL-1β, IL-18, and cleaved caspase-1 in UVB-irradiated ARPE-19 cells. Interestingly, cis-UCA also reduced DNA damage, whereas its effect against ROS production was negligible. Collectively, cis-UCA protected ARPE-19 cells from UVB-induced phototoxicity and inflammasome activation. This study indicates that due to its beneficial properties of preserving cell viability and preventing inflammation, cis-UCA has potential in drug development of chronic ocular diseases, such as AMD.

1052 Urocanase-positive bacteria in the skin regulate the immunomodulatory properties of the UV photoproduct, cis-urocanic acid

1052 Urocanase-positive bacteria in the skin regulate the immunomodulatory properties of the UV photoproduct, cis-urocanic acid

PD-L1 Enhanced by cis-Urocanic Acid on Langerhans Cells Inhibits Vγ4+ γδT17 Cells in Imiquimod-Induced Skin Inflammation

Psoriasis is an IL-23/IL-17-mediated inflammatory autoimmune dermatosis, and UVB may contribute to immunosuppression and ameliorate associated symptoms. One of the pathophysiology underlying UVB therapy is the production of cis-urocanic acid (cis-UCA) by keratinocytes. However, the detailed mechanism is yet to be fully understood. In this study, we found FLG expression and serum cis-UCA levels were significantly lower in patients with psoriasis than in healthy controls. We also noted that cis-UCA application inhibited psoriasiform inflammation through the reduction of Vγ4+ γδT17 cells in murine skin and draining lymph nodes. Meanwhile, CCR6 was downregulated on γδT17 cells, which would suppress the inflammatory reaction at a distal skin site. We revealed that the 5-hydroxytryptamine receptor 2A, the known cis-UCA receptor, was highly expressed on Langerhans cells in the skin. cis-UCA also inhibited IL-23 expression and induced PD-L1 on Langerhans cells, leading to the attenuated proliferation and migration of γδT-cells. Compared to the isotype control, α-PD-L1 treatment invivo could reverse the antipsoriatic effects of cis-UCA. PD-L1 expression on Langerhans cells was sustained through the cis-UCA-induced mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. These findings uncover the cis-UCA-induced PD-L1-mediated immunosuppression on Langerhans cells, which facilitates the resolution of inflammatory dermatoses.

Molecular Mechanisms of Scombroid Food Poisoning.

Scombroid food poisoning (SFP) is a foodborne disease that develops after consumption of fresh fish and, rarely, seafood that has fine organoleptic characteristics but contains a large amount of exogenous histamine. SFP, like other food pseudo-allergic reactions (FPA), is a disorder that is clinically identical to allergic reactions type I, but there are many differences in their pathogenesis. To date, SFP has been widespread throughout the world and is an urgent problem, although exact epidemiological data on incidence varies greatly. The need to distinguish SFP from true IgE-associated allergy to fish and seafood is one of the most difficult examples of the differential diagnosis of allergic conditions. The most important difference is the absence of an IgE response in SFP. The pathogenesis of SFP includes a complex system of interactions between the body and chemical triggers such as exogenous histamine, other biogenic amines, cis-urocanic acid, salicylates, and other histamine liberators. Because of the wide range of molecular pathways involved in this process, it is critical to understand their differences. This may help predict and prevent poor outcomes in patients and contribute to the development of adequate hygienic rules and regulations for seafood product safety. Despite the vast and lengthy history of research on SFP mechanisms, there are still many blank spots in our understanding of this condition. The goals of this review are to differentiate various molecular mechanisms of SFP and describe methods of hygienic regulation of some biogenic amines that influence the concentration of histamine in the human body and play an important role in the mechanism of SFP.

231 cis-urocanic acid mediated cutaneous immune suppression is controlled by microbiome

Urocanic acid (UCA) is one of the key mediators of ultraviolet radiation (UVR)- induced immune suppression in the skin. Skin resident microbes are known to metabolize trans- and cis-UCA, and potentially modulate the subsequent immune response. In the present study we investigated whether skin microbiome can regulate cis-UCA mediated immune suppression. Using 16s rRNA sequencing, we show that cis-UCA application results in significant changes in microbial population, where certain microbes could thrive by utilizing UCA (UCA+).

High pressure Raman investigation on trans-urocanic acid

Trans-urocanic acid (t-UCA) is an important epidermal UV protector predominantly found in human skin. Exposure of UV radiation triggers photoisomerization of t-UCA into its other conformer, cis-urocanic acid (cis-UCA), which has been shown to be a mediator of UV-induced immune-suppression leading to skin cancer. In this report, we present the investigation of molecular changes of t-UCA under high pressures by in-situ high pressure Raman spectroscopy. The study indicates onset of ring opening polymerization of t-UCA at pressure above 1.4 GPa. At pressures beyond 5 GPa, a well discernible characteristic vibrational mode (CC stretch) accompanied by several other spectral features such as δ CO2– and δ NH modes of cis-UCA point towards the isomerization of residual t-UCA monomers into cis-UCA. The content of cis-UCA gradually increased with increase in pressure. On release to ambient conditions, the spectrum of the quenched sample showed Raman modes of polymer and cis-UCA indicating that the changes are irreversible.

Stratum corneum biomarkers after in vivo repeated exposure to sub‐erythemal dosages of ultraviolet radiation in unprotected and sunscreen (SPF 50+) protected skin

There is a need for non-invasive biomarkers to assess in vivo efficacy of protective measures aiming at reducing ultraviolet radiation (UVR) exposure. Stratum corneum (SC) biomarkers showed to be promising markers for internal UVR dose and immune response. To establish a dose-response relationship for SC biomarkers and explore their suitability for in vivo assessment of the blocking effect of two sunscreens with a high sun protection factor (SPF) (50+). Twelve volunteers were exposed to a broad-spectrum UVB (280-320nm), five times a week, during one week. Unprotected back skin was irradiated with 0.24, 0.48, 0.72 and 1.44 standard erythema dose (SED) and sunscreen-protected skin with 3.6 SED. SC samples for determination of the relative amount of cis-urocanic acid (cUCA) and thirteen immunological makers including cytokines and matrix metalloproteinases (MMP) were collected after each irradiation. cUCA sharply increased after the first irradiation in a dose-dependent fashion. However, it levelled-off after subsequent exposures and reached a plateau for the highest UV-dose after the third irradiation. None of the immunological markers showed dose-dependency. However, MMP-9, IL-1β and CCL27 increased gradually from baseline during repetitive exposures to the highest UV-dose. Assessed from cUCA, both sunscreens blocked >98% of the applied UV-dose. cUCA is a sensitive, non-invasive marker of the internal UVR dose enabling in vivo assessment of the blocking effect of high SPF sunscreens in the UVB-region. Immunological SC markers show low sensitivity in detecting immune response at sub-erythemal UVR dosages, suggesting they might be suitable only at higher and/or repetitive UVR exposure.

Ternary Cu(II) Complex with GHK Peptide and Cis-Urocanic Acid as a Potential Physiologically Functional Copper Chelate.

The tripeptide NH2–Gly–His–Lys–COOH (GHK), cis-urocanic acid (cis-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is known as Cu(II)-binding molecule, we found that urocanic acid also coordinates Cu(II) ions. Furthermore, both ligands create ternary Cu(II) complex being probably physiologically functional species. Regarding the natural concentrations of the studied molecules in some human tissues, together with the affinities reported here, we conclude that the ternary complex [GHK][Cu(II)][cis-urocanic acid] may be partly responsible for biological effects of GHK and urocanic acid described in the literature.

UV-B-Induced Inflammasome Activation Can Be Prevented by Cis-Urocanic Acid in Human Corneal Epithelial Cells.

PurposeThe cornea is continually exposed to highly energetic solar UV-B (280-320 nm). Our aim was to investigate whether UV-B triggers the activation of NLRP3 inflammasomes and the production of IL-1β and/or IL-18 in human corneal epithelial (HCE) cells. Additionally, we studied the capability of cis-urocanic acid (cis-UCA) to prevent inflammasome activation or alleviate inflammation through other signaling pathways.MethodsHCE-2 cell line and primary HCE cells were primed using lipopolysaccharide or TNF-α. Thereafter, cells were exposed to UV-B before or after the addition of cis-UCA or caspase-1 inhibitor. Caspase-1 activity was measured from cell lysates by an enzymatic assay. IL-1β, IL-18, IL-6, IL-8, and NLRP3 levels were detected using the ELISA method from cell culture media. Additionally, intracellular NLRP3 levels were determined by the Western blot technique, and cytotoxicity was measured by the LDH assay.ResultsUV-B exposure significantly increased caspase-1 activity in TNF-α-primed HCE cells. This result was consistent with the concurrently induced IL-1β secretion. Both caspase-1 activity and release of IL-1β were reduced by cis-UCA. Additionally, UV-B stimulated the caspase-1-independent production of IL-18, an effect also reduced by cis-UCA. Cis-UCA decreased the release of IL-6, IL-8, and LDH in a time-dependent manner when administered to HCE-2 cells after UV-B exposure.ConclusionsOur findings demonstrate that UV-B activates inflammasomes in HCE cells. Cis-UCA can prevent the secretion of IL-1β and IL-18 and therapeutically reduces the levels of IL-6, IL-8, and LDH in UV-B-stressed HCE cells.

Exposure to cold airflow alters skin pH and epidermal filaggrin degradation products in children with atopic dermatitis

BackgroundWe aimed to evaluate the influence of cold airflow from the air conditioner on skin barrier function and filaggrin degradation products (FDPs) in children with atopic deramtitis (AD). MethodsIn a case-control study, 28 children with AD and 12 normal children without AD were exposed to one of two air conditioner modes (conventional or wind-free) for 2 h. Skin temperature, transepidermal water loss (TEWL), and skin pH were measured on right cheek and forearm at pre- and post-exposure time points. We also measured filaggrin and FDPs from the volar surface of the forearm. ResultsIn AD patients, skin temperature on the forearm decreased after exposure to the conventional and wind-free modes (P < 0.001 and P = 0.026), and TEWL on the cheek and the forearm decreased in the wind-free mode (P = 0.037 and 0.002). Skin pH on the cheek increased only after exposure to the conventional mode in AD group (P = 0.002). However, no changes in TEWL and skin pH were found after exposure to either the conventional or the wind-free mode in the control group. In AD children, the levels of pyrrolidone carboxylic acid (PCA) and cis-urocanic acid (UCA) were reduced only after exposure to the conventional mode (all P = 0.033). The percent changes of PCA and cis-UCA were higher in the AD group than those in the control group after exposure to conventional mode (P = 0.029 and 0.046). ConclusionsSkin barrier function in children with AD may be altered by the exposure to cold airflow from a conventional air conditioner.

355 Insights into effects of topical application of cis-urocanic acid on skin microbiome and immune modulation

355 Insights into effects of topical application of cis-urocanic acid on skin microbiome and immune modulation

Topical cis-urocanic acid prevents ocular surface irritation in both IgE -independent and -mediated rat model

Our purpose was to investigate the effect of locally administered cis-urocanic (cis-UCA) in two experimental models of allergic conjunctivitis. The compound 48/80 (C48/80)-induced ocular irritation model (IgE-independent) and the ovalbumin (OA)-induced ocular allergy model (IgE-mediated) were used to test and compare the effect of cis-UCA on dexamethasone, ketotifen and olopatadine. In the C48/80 model, clinical severity scoring from photographs, immunohistochemical analysis of nuclear Ki-67 antigen to quantify actively proliferating epithelial cells and of caspase-3 enzyme to identify apoptotic activity in the conjunctival tissue were used. In the OA model, an Evans Blue stain concentration of conjunctival tissue was used to evaluate vascular leakage due to allergic reaction. The cis-UCA was well tolerated and effective in both the IgE-independent and -mediated rat models. Treatment with C48/80 caused conjunctival hyperaemia, which was significantly inhibited by ketotifen at the 6h time point (p=0.014) and by dexamethasone and cis-UCA 0.5% at 12 (p=0.004) and 24 (p=0.004) hour time points. In a comparison between the active drug treatments, only ketotifen showed a significant difference (p=0.023) to cis-UCA treatment at the 1h time point, otherwise there were no statistically significant differences between the active drugs. Ketotifen, dexamethasone and cis-UCA 0.5% significantly inhibited the C48/80-induced nuclear accumulation of Ki-67, without differences between the active treatment groups. In the OA model, cis-UCA 0.5% did not inhibit the vascular leakage of conjunctiva, whereas cis-UCA 2.5% of was at least equally effective compared to olopatadine, abolishing the allergic vascular leakage response almost completely. The present findings in the two AC models suggest that cis-UCA might have anti-allergic potency both in immediate and delayed-type allergic reactions in the eye.

Suppression of experimental autoimmune encephalomyelitis by ultraviolet light is not mediated by isomerization of urocanic acid

BackgroundUltraviolet B irradiation confers strong resistance against experimental autoimmune encephalomyelitis, a model of multiple sclerosis. This protection by ultraviolet B is independent of vitamin D production but causes isomerization of urocanic acid, a naturally occurring immunosuppressant.MethodsTo determine whether UCA isomerization from trans to cis is responsible for the protection against experimental autoimmune encephalomyelitis afforded by ultraviolet B, trans- or cis-urocanic acid was administered to animals and their disease progression was monitored.ResultsDisease incidence was reduced by 74% in animals exposed to ultraviolet B, and skin cis-urocanic acid levels increased greater than 30%. However, increasing skin cis-urocanic acid levels independent of ultraviolet B was unable to alter disease onset or progression.ConclusionsIt is unlikely that urocanic acid isomerization is responsible for the ultraviolet B-mediated suppression of experimental autoimmune encephalomyelitis. Additional work is needed to investigate alternative mechanisms by which UVB suppresses disease.

PH Gradient Reversal: An Emerging Hallmark of Cancers.

Several tumors exhibit pH gradient reversal, with acidification of extracellular pH (pHe) and alkalinization of intracellular pH (pHi). The pH gradient reversal is evident even during the preliminary stages of tumorigenesis and is crucial for survival and propagation of tumors, irrespective of their pathology, genetics and origins. Moreover, this hallmark seems to be present ubiquitously in all malignant tumors. Based on these facts, we propose a new emerging hallmark of cancer "pH gradient reversal". Normalizing pH gradient reversal through inhibition of various proton transporters such as Na(+)-H(+) exchanger (NHE), Vacuolar-type H(+)-ATPase (V-ATPase), H(+)/K(+)-ATPases and carbonic anhydrases (CAs) has demonstrated substantial therapeutic benefits. Indeed, inhibition of NHE1 is now being regarded as the latest concept in cancer treatment. A recent patent deals with the utilization of cis-Urocanic acid to acidify the pHi and induce apoptosis in tumors. Another patent reports therapeutic benefit by inhibiting Lactate Dehydrogenase - 5 (LDH-5) in various cancers. Several patents have been formulated by designing drugs activated through acidic pHe providing a cancer specific action. The purpose of this review is to analyze the available literature and help design selective therapies that could be a valuable adjunct to the conventional therapies or even replace them.

Intravesical treatment with cis-urocanic acid improves bladder function in rat model of acute bladder inflammation.

The aim was to study the effect of intravesically instilled cis-urocanic acid (cis-UCA) on bladder function in an experimental rat model of acute bladder inflammation. Hyaluronic acid (HA) was used as a comparator compound. Bladder irritation was induced in female rats by intravesical hydrochloric acid (HCl) infusion. Vehicle, 0.5% HA, or 2% cis-UCA solutions were infused intravesically twice a day for three consequent days. On the fourth day, urodynamical measurements were performed, the animals were sacrificed, and the bladders were removed for histopathological assessment. HCl treatment caused significant impairment of bladder function indicated by decreased micturition intervals and voided urine volumes and induced severe voiding dysfunction observed as occurrence of overflow incontinence. These functional changes were accompanied by increased bladder weight, hemorrhage, and infiltration of inflammatory cells into the urothelium. Intravesical cis-UCA treatment recovered bladder function by significantly prolonging the micturition interval, increasing the voided volume, and reducing the occurrence of overflow incontinence. All these changes were comparable to the effects of HA. Intravesical administration of cis-UCA was able to partially recover bladder function impaired by chemical irritation. Cis-UCA may offer a novel intravesical treatment option in some inflammatory conditions of the bladder. Neurourol. Urodynam. 35:786-791, 2016. © 2015 Wiley Periodicals, Inc.

The mastocyte: the off switch of UV itch.

The mastocyte: the off switch of UV itch.

Prevention of Photocarcinogenesis by Agonists of 5-HT1A and Antagonists of 5-HT2A Receptors.

Exposure to UV radiation is the principal cause of nonmelanoma skin cancer, a process in which serotonin (5-HT) is intimately involved. This review focuses on the potential of serotonin receptors, namely 5-HT1/2A, as therapeutic targets for prevention of photocarcinogenesis. UV-induced immunosuppression is triggered by a cascade of events initiated when cis-urocanic acid, a UV photoreceptor present in the skin, binds to the serotonin receptor. Serotonin receptor antagonists will therefore attempt to block this association, and in turn, prevent skin cancer induction. In addition, 5-HT2A receptor antagonists are also capable of regulating DNA repair, including the acceleration of nucleotide excision repair. At the same time, UV-induced formation of reactive oxygen species is also reduced by these agents. Since the involvement of serotonin in photocarcinogenesis process is somewhat underexplored as a pertinent therapeutic effect, this review intends to reveal the use of serotonergic drugs as an important strategy to prevent and/or inhibit photocarcinogenesis. Considering the emergency of developing novel therapeutic strategies for skin cancer management, the use of these agents, whose benefits have partially been studied, may be crucial especially if topically applied. Topical nanoformulations containing serotonin receptor agonists and/or antagonists also represent a pioneer concept in this area. Graphical Abstract ᅟ.

Determination of trans- and cis-urocanic acid in relation to histamine, putrescine, and cadaverine contents in tuna (Auxis Thazard) at different storage temperatures.

Scombroid fish poisoning is usually associated with consumption of fish containing high levels of histamine. However, reports indicate that some cases have responded to antihistamine therapy while ingested histamine levels in these cases were low. Potentiation of histamine toxicity by some biogenic amines, and release of endogenous histamine by other compounds such as cis-urocanic acid (UCA) are some hypotheses that have been put forth to explain this anomaly. Very little is known about the effects of storage conditions on the production of both UCA isomers and biogenic amines in tuna. Thus, the production of trans- and cis-UCA, histamine, putrescine, and cadaverine in tuna during 15 d of storage at 0, 3, and 10°C and 2 d storage at ambient temperature were monitored. The initial trans- and cis-UCA contents in fresh tuna were 2.90 and 1.47 mg/kg, respectively, whereas the levels of putrescine and cadaverine were less than 2 mg/kg, and histamine was not detected. The highest levels of trans- and cis-UCA were obtained during 15 d storage at 3°C (23.74 and 21.79 mg/kg, respectively) while the highest concentrations of histamine (2796 mg/kg), putrescine (220.32 mg/kg) and cadaverine (1045.20 mg/kg) were obtained during storage at room temperature, 10 and 10°C, respectively. Histamine content increased considerably during storage at 10°C whereas trans- and cis-UCA contents changed slightly. The initial trans-UCA content decreased during storage at ambient temperature. Thus, unlike histamine, concentrations of trans- and cis-UCA did not result in elevated levels during storage of tuna.