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1. Hydrogen isotope separation using graphene-based membranes in liquid water

Author

Zhang, Xiangrui, Wang, Hequn, Xiao, Tiantian, Chen, Xiaoyi, Li, Wen, Xu, Yihan, Lin, Jianlong, Wang, Zhe, Peng, Hailin, and Zhang, Sheng

Subjects
Physics - Chemical Physics, Condensed Matter - Materials Science
Abstract

Hydrogen isotope separation has been effectively achieved using gaseous H2/D2 filtered through graphene/Nafion composite membranes. Nevertheless, deuteron nearly does not exist in the form of gaseous D2 in nature but in liquid water. Thus, it is a more feasible way to separate and enrich deuterium from water. Herein we have successfully transferred monolayer graphene to a rigid and porous polymer substrate PITEM (polyimide tracked film), which could avoid the swelling problem of the Nafion substrate, as well as keep the integrity of graphene. Meanwhile, defects in large area of CVD graphene could be successfully repaired by interfacial polymerization resulting in high separation factor. Moreover, a new model was proposed for the proton transport mechanism through monolayer graphene based on the kinetic isotope effect (KIE). In this model, graphene plays the significant role in the H/D separation process by completely breaking the O-H/O-D bond, which can maximize the KIE leading to prompted H/D separation performance. This work suggests a promising application of using monolayer graphene in industry and proposes a pronounced understanding of proton transport in graphene, Comment: 10 pages, 4 figures (6pages, 6figures for SI)

Published
2022

4. DFT Study on the Second-Order NLO Responses of 2-Phenyl Benzoquinoline Ir(III) Complexes by Substituents and Redox Effects

Author

Wang, Hequn, Sun, Liting, Zhao, Yuanyuan, and Qiu, Yongqing

Abstract

Metal complexes have received extensive attention in nonlinear optical (NLO) materials because of their advantages, such as shorter response times and more flexible structural properties. Density functional theory is used in investigating the geometric structures, electronic structures, charge centroid, and first hyperpolarizability (βtot) of a series of selected 15 coordinated Ir(III) complexes. The substitute effect and one-electron redox process effects on the structures and properties of 15 coordinated Ir(III) complexes are considered. When the electron-withdrawing group is introduced into the ligand, the HOMO–LUMO energy gap decreases and the βtotvalue increases, positively correlating with the electron-withdrawing ability. The single electron redox process can also improve the NLO responses of complexes, especially the reduction process. The βtotvalue of complex 4–is the largest, 2078 times higher than that of complex 4. The analysis shows that the variation of NLO responses of complexes is ascribed to the change of electronic structures and the charge transfer modes induced by the ligand modification and redox process, which are considered to be two effective methods in enhancing the NLO responses of 2-phenyl benzoquinoline Ir(III) complexes. This study aims to offer design insights into high-performance nonlinear optical materials.

Published
2024
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8. Where do I stand in the EU? Income comparisons and perceptions

Author

Bublitz, Elisabeth, Jäger, Julian, Wang, Hequn, Beblo, Miriam, and Lohmann, Henning

Subjects
Inequality, H24, C91, ddc:330, Perceptions, European Union, D31, Survey Experiment
Abstract

With a survey experiment conducted in Germany, Italy, Poland, and Sweden, we investigate how EU citizens rank themselves within the EU. In all four countries, (mis-)perceptions of EU income positions result primarily from respondents' (incomplete) information about their national position and their perceived country ranking within the EU. Low-income respondents tend to place themselves higher and richer respondents lower in both the national and EU income distribution. Respondents who are informed about their income position estimate their EU ranking more accurately in a follow-up survey. Our findings show that concepts of inequality at the EU level are empirically meaningful and that EU citizens have a reference frame beyond their own country.

Published
2022

9. Perceived income positions and attitudes towards EU inequality: A cross-country survey experiment

Author

Bublitz, Elisabeth, Wang, Hequn, Jäger, Julian, Beblo, Miriam, and Lohmann, Henning

Subjects
Misperceptions, Inequality, ddc:330, Income, F55, European Union, EU Minimum Wage, D63, D31, Survey Experiment
Abstract

We examine the relationship between perceived income positions and attitudes towards inequality at a supranational-level. Conducting a survey in four EU Member States (Germany, Italy, Poland, and Sweden), we confirm that their citizens misperceive their own income position in the EU. Once we account for these misperceptions, we find that those with a lower income rank assess EU income differences as more unjust and are more supportive of an EU minimum wage. When we inform a randomized subsample about their actual income position in the EU, those who learn to be richer than they initially thought assess EU income differences as less unjust. Respondents in Italy, Poland, and to a lesser extent Sweden drive these results whereas income misperceptions of German respondents have opposing effects.

Published
2022

10. A unique gel matrix moisturizer delivers deep hydration resulting in significant clinical improvement in radiance and texture

Author

Bianchini,Julie M, Zhang,Qihong, Hanna,Gabriel, Flach,Carol R, Wang,Hequn, Southall,Michael D., Mendelsohn,Richard, and Randhawa,Manpreet

Subjects
moisturization, Clinical, Cosmetic and Investigational Dermatology, integumentary system, confocal Raman microscopy, dynamic skin barrier, skin hydration, skin radiance, Original Research
Abstract

Julie M Bianchini,1 Qihong Zhang,2 Gabriel Hanna,2 Carol R Flach,2 Hequn Wang,1 Michael D Southall,1 Richard Mendelsohn,2 Manpreet Randhawa11Johnson and Johnson Consumer Companies, Inc., Skillman, NJ, USA; 2Department of Chemistry, Rutgers University, Newark, NJ, USAIntroduction: As skin ages, it loses its ability to retain moisture and becomes rough and dry. This results in a clinically dull appearance with a loss of radiance, firmness, and suppleness. Symptoms can be improved with use of a moisturizer that builds and maintains skin hydration over time; however, most moisturizers that occlude the skin surface are perceived as heavy and greasy and are not consumer preferred.Methods: A unique, consumer-preferred gel matrix formula was developed by combining liquid crystal structures, which mimic skin barrier lipid assembly, with specific emulsifiers that deliver water deep into skin. Ex vivo studies were conducted to investigate the superior hydrating effects of the gel matrix formula. Confocal Raman microscopy studies assessed the spatial distribution of water in ex vivo skin after application of the gel matrix formula. To determine the effects of the gel matrix formula on dry facial skin, a 12-week clinical study was conducted with subjects with self-perceived skin dryness and dullness.Results: The formulation significantly increased the relative water content throughout epidermal regions, which was not observed with the application of a competitive gel formula. Instrumental measurements assessed improvements in skin surface moisturization and barrier function. Clinical grading showed significant improvements in hydration-related endpoints including radiance, clarity, and texture. Subject self-agree assessment demonstrated that subjects observed improvements in the appearance of their facial skin.Conclusion: These studies demonstrated that the gel matrix formula increased skin water content in deeper layers, and resulted in significant clinical improvements in hydration, barrier function, and clinical appearance of radiance.Keywords: confocal Raman microscopy, skin radiance, moisturization, dynamic skin barrier, skin hydration

Published
2019

11. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Author

Allouche, Jennifer, primary, Rachmin, Inbal, additional, Adhikari, Kaustubh, additional, Pardo, Luba M., additional, Lee, Ju Hee, additional, McConnell, Alicia M., additional, Kato, Shinichiro, additional, Fan, Shaohua, additional, Kawakami, Akinori, additional, Suita, Yusuke, additional, Wakamatsu, Kazumasa, additional, Igras, Vivien, additional, Zhang, Jianming, additional, Navarro, Paula P., additional, Lugo, Camila Makhlouta, additional, Noonan, Haley R., additional, Christie, Kathleen A., additional, Itin, Kaspar, additional, Mujahid, Nisma, additional, Lo, Jennifer A., additional, Won, Chong Hyun, additional, Evans, Conor L., additional, Weng, Qing Yu, additional, Wang, Hequn, additional, Osseiran, Sam, additional, Lovas, Alyssa, additional, Németh, István, additional, Cozzio, Antonio, additional, Navarini, Alexander A., additional, Hsiao, Jennifer J., additional, Nguyen, Nhu, additional, Kemény, Lajos V., additional, Iliopoulos, Othon, additional, Berking, Carola, additional, Ruzicka, Thomas, additional, Gonzalez-José, Rolando, additional, Bortolini, Maria-Cátira, additional, Canizales-Quinteros, Samuel, additional, Acuna-Alonso, Victor, additional, Gallo, Carla, additional, Poletti, Giovanni, additional, Bedoya, Gabriel, additional, Rothhammer, Francisco, additional, Ito, Shosuke, additional, Schiaffino, Maria Vittoria, additional, Chao, Luke H., additional, Kleinstiver, Benjamin P., additional, Tishkoff, Sarah, additional, Zon, Leonard I., additional, Nijsten, Tamar, additional, Ruiz-Linares, Andrés, additional, Fisher, David E., additional, and Roider, Elisabeth, additional

Published
2021
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12. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Author

Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., Roider, Elisabeth, Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., and Roider, Elisabeth

Abstract

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

Published
2021

16. In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin

Author

Harvard University--MIT Division of Health Sciences and Technology, Osseiran, Sam, Nichols, Alexander J., Tsao, Hensin, Wang, Hequn, Igras, Vivien, Roider, Elisabeth M., Pruessner, Joachim, Fisher, David E., Evans, Conor L., Harvard University--MIT Division of Health Sciences and Technology, Osseiran, Sam, Nichols, Alexander J., Tsao, Hensin, Wang, Hequn, Igras, Vivien, Roider, Elisabeth M., Pruessner, Joachim, Fisher, David E., and Evans, Conor L.

Abstract

Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1re/e, red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1re/e; Tyrc/c (“albino-red-haired”) mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas., BRIDGE (Project) (Grant 222700), Canadian Institutes of Health Research, Frances Keany Rickard Fund Fellowship, National Institutes of Health (U.S.) (5P01 CA163222-03), National Institutes of Health (U.S.) (5R01 AR043369-19), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation

Published
2017

17. In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin

Author

Wang, Hequn, Osseiran, Sam, Igras, Vivien, Nichols, Alexander J, Roider, Elisabeth M, Pruessner, Joachim, Tsao, Hensin, Fisher, David E, Evans, Conor L, Wang, Hequn, Osseiran, Sam, Igras, Vivien, Nichols, Alexander J, Roider, Elisabeth M, Pruessner, Joachim, Tsao, Hensin, Fisher, David E, and Evans, Conor L

Abstract

Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1r(e/e), red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1r(e/e); Tyr(c/c) ("albino-red-haired") mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas.

Published
2016

30. Holistic investigation of the anti‐wrinkle and repair efficacy of a facial cream enriched with C‐xyloside.

Author

Zang, Shanshan, Chen, Juanjuan, Chevalier, Cyril, Zhang, Ji, Li, Shumei, Wang, Hequn, Li, Jing, Chen, Yangdong, Xu, Hongling, Sheng, Le, Zhang, Zhiming, and Qiu, Jie

Subjects
*FACIAL creams (Cosmetics), *WRINKLES (Skin), *SKIN aging, *PROTEIN expression, *CELL proliferation
Abstract

Objective Methods Results Conclusion To investigate the repairing and anti‐wrinkle efficacy of the facial cream enriched with C‐xyloside, aiming at comprehensively evaluating its skin anti‐ aging effect and clarify its potential mechanism of action.The repairing efficacy was studied on 3D epidermis skin model and the antiaging efficacy was studied on ex‐vivo human skin. Two clinical studies were conducted with Chinese females. In the first study, 49 subjects aged between 30 and 50 with wrinkle concerns were recruited and instructed to apply the investigational cream containing C‐xyloside for 8 weeks. Wrinkles attributes were assessed by dermatologist. Instrumental measurements on skin hydration, trans‐epidermal water loss (TEWL), and skin elasticity were also conducted. In the second study, 30 subjects aged between 25 and 60 with self‐declared sensitive skin and facial redness were recruited and instructed to apply the cream for 4 weeks. Biomarker analysis of the stratum corneum was conducted through facial tape strips.The cream improved the histomorphology of the 3D epidermis skin model after SLS stimulation, and significantly increase the expression of LOR and FLG. On human skin, the cream improved the histopathology induced by UV, and significantly increased the protein content of COL I and COL III, collagen density and the number of Ki‐67 positive cell of skin compared with model group (n = 3, p < 0.01). The results from the first clinical study demonstrate a significant increased the skin hydration and elasticity by 21.90%, 13.08% (R2) and 12.30% (R5), respectively (n = 49, p < 0.05), and the TEWL values decreased by 33.94% (n = 49, p < 0.05), after 8 weeks application of the cream. In addition, the scores for nasolabial folds, glabellar wrinkle, underneath eye wrinkles, crow's feet wrinkle and forehead wrinkle in the volunteers exhibited a significant reduction of 34.02%, 43.34%, 50.03%, 33.64% and 55.81% respectively (n = 49, p < 0.05). The (rCE)/(fCE) ratio of volunteers based on tape stripping significant increased after using the sample cream (n = 30, p < 0.05).The cream containing C‐xyloside showed improvement of skin wrinkles and enhancement of skin barrier function. These efficacies may be attributed to the fact that the sample cream can increase the expression of skin barrier related proteins LOR and FLG, promote the maturation of cornified envelope, enhance collagen I and III protein expression and stimulate skin cell proliferation, to provide sufficient evidence supporting its antiaging efficacy of skin. [ABSTRACT FROM AUTHOR]

Published
2024
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31. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Author

Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., Roider, Elisabeth, Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., and Roider, Elisabeth

Abstract

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

32. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

Author

Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., Roider, Elisabeth, Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., and Roider, Elisabeth

Abstract

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

33. Using elongated microparticles to enhance tailorable nanoemulsion delivery in excised human skin and volunteers

Author

Miko Yamada, Tarl W. Prow, Hequn Wang, Nhung Dang, Conor L. Evans, Frank Sainsbury, Michael S. Roberts, Sam Osseiran, Yousuf H. Mohammed, Paul J. Belt, Hossam H. Tayeb, Yamada, Miko, Tayeb, Hossam, Wang, Hequn, Dang, Nhung, Mohammed, Yousuf H, Osseiran, Sam, Belt, Paul J, Roberts, Michael, Evans, Conor L, Sainsbury, Frank, and Prow, Tarl W

Subjects
Pharmaceutical Science, Human skin, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Imaging data, Article, Drug Delivery Systems, Microscopy, Image acquisition, Humans, Skin, Chemistry, Hydrophobic drug, 021001 nanoscience & nanotechnology, Silicon Dioxide, Controlled release, Fluorescence, Healthy Volunteers, 0104 chemical sciences, 3. Good health, Drug delivery, Nanoparticles, Emulsions, 0210 nano-technology, Peptides, Biomedical engineering
Abstract

This study demonstrates, for the first time, clinical testing of elongated silica microparticles (EMP) combined with tailorable nanoemulsions (TNE) to enhance topical delivery of hydrophobic drug surrogates. Likewise, this is the first report of 6-carboxyfluorescein (a model molecule for topically delivered hydrophobic drugs) AM1 & DAMP4 (novel short peptide surfactants) used in volunteers. The EMP penetrates through the epidermis and stop at the dermal-epidermal junction (DEJ). TNE are unusually stable and useful because the oil core allows high drug loading levels and the surface properties can be easily controlled. At first, we chose alginate as a crosslinking agent between EMP and TNE. We initially incorporated a fluorescent lipophilic dye, DiI, as a hydrophobic drug surrogate into TNE for visualization with microscopy. We compared four different coating approaches to combine EMP and TNE and tested these formulations in freshly excised human skin. The delivery profile characterisation was imaged by dye- free coherent anti-Stoke Raman scattering (CARS) microscopy to detect the core droplet of TNE that was packed with pharmaceutical grade lipid (glycerol) instead of DiI. These data show the EMP penetrating to the DEJ followed by controlled release of the TNE. Freeze-dried formulations with crosslinking resulted in a sustained release profile, whereas a freeze-dried formulation without crosslinking showed an immediate burst-type release profile. Finally, we tested the crosslinked TNE coated EMP formulation in volunteers using multiphoton microscopy (MPM) and fluorescence-lifetime imaging microscopy (FLIM) to document the penetration depth characteristics. These forms of microscopy have limitations in terms of image acquisition speed and imaging area coverage but can detect fluorescent drug delivery through the superficial skin in volunteers. 6-Carboxyfluorescein was selected as the fluorescent drug surrogate for the volunteer study based on the similarity of size, charge and hydrophobicity characteristics to small therapeutic drugs that are difficult to deliver through skin. The imaging data showed a 6-carboxyfluorescein signal deep in volunteer skin supporting the hypothesis that EMP can indeed enhance the delivery of TNE in human skin. There were no adverse events recorded at the time of the study or after the study, supporting the use of 6-carboxyfluorescein as a safe and detectable drug surrogate for topical drug research. In conclusion, dry formulations, with controllable release profiles can be obtained with TNE coated EMP that can effectively enhance hydrophobic payload delivery deep into the human epidermis Refereed/Peer-reviewed

Published
2018

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