Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 46
Filter
1.
Mol Pharm ; 19(3): 974-984, 2022 03 07.
Article in English | MEDLINE | ID: mdl-35179903

ABSTRACT

Surgical site infections represent a significant clinical problem. Herein, we report a nanofiber dressing for topical codelivery of immunomodulating compounds including 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and VID400, a CYP24A1 inhibitor in a sustained manner, for inducing the expression of the endogenous cathelicidin antimicrobial peptide (CAMP) gene encoding the hCAP18 protein, which is processed into the LL-37 peptide. Nanofiber wound dressings with coencapsulation of 1,25(OH)2D3 and VID400 were generated by electrospinning. Both 1,25(OH)2D3 and VID400 were coencapsulated into nanofibers with loading efficiencies higher than 90% and exhibited a prolonged release from nanofiber membranes longer than 28 days. Incubation with 1,25(OH)2D3/VID400-coencapsulated poly(ϵ-caprolactone) nanofiber membranes greatly induced the hCAP18/LL-37 gene expression in monocytes, neutrophils, and keratinocytes in vitro. Moreover, the administration of 1,25(OH)2D3/VID400-coencapsulated nanofiber membranes dramatically promoted the hCAP18/LL-37 expression in dermal wounds created in both human CAMP transgenic mice and human skin tissues. The 1,25(OH)2D3- and VID400-coencapsulated nanofiber dressings enhanced innate immunity via the more effective induction of antimicrobial peptide than the free drug alone or 1,25(OH)2D3-loaded nanofibers. Together, 1,25(OH)2D3/VID400-embedded nanofiber dressings presented in this study show potential in preventing surgical site infections.


Subject(s)
Nanofibers , Animals , Antimicrobial Peptides , Bandages , Imidazoles , Mice , Nanofibers/chemistry , Surgical Wound Infection , Vitamin D/analogs & derivatives , Vitamin D3 24-Hydroxylase
2.
Expert Rev Proteomics ; 18(11): 1009-1017, 2021 11.
Article in English | MEDLINE | ID: mdl-34739354

ABSTRACT

INTRODUCTION: COUP-TF INTERACTING PROTEIN 2 (CTIP2) is a crucial transcription factor exhibiting its control through coupled modulation of epigenetic modification and transcriptional regulation of key genes related to skin, immune, and nervous system development. Previous studies have validated the essential role of CTIP2 in skin development and maintenance, propagating its effects in epidermal permeability barrier (EPB) homeostasis, wound healing, inflammatory diseases, and epithelial cancers. Lipid metabolism dysregulation, on the other hand, has also established its independent emerging role over the years in normal skin development and various skin-associated ailments. This review focuses on the relatively unexplored connections between CTIP2-mediated control of lipid metabolism and alteration of EPB homeostasis, delayed wound healing, inflammatory diseases exacerbation, and cancer promotion and progression. AREAS COVERED: Here we have discussed the intricate interplay of various endogenous lipids and lipoproteins accompanying skin development and associated disease processes and the possible link to CTIP2-mediated regulation of lipid metabolism. EXPERT OPINION: Establishing the link between CTIP2 and lipid metabolism alterations in the context of skin morphogenesis and diverse types of skin diseases including cancer can help us identify novel targets for effective therapeutic intervention.


Subject(s)
Lipid Metabolism , Repressor Proteins , Epidermis/metabolism , Humans , Repressor Proteins/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism
3.
Mol Carcinog ; 58(9): 1680-1690, 2019 09.
Article in English | MEDLINE | ID: mdl-31211467

ABSTRACT

Treatment with vemurafenib, a potent and selective inhibitor of mitogen-activated protein kinase signaling downstream of the BRAFV600E oncogene, elicits dramatic clinical responses in patients with metastatic melanoma. Unfortunately, the clinical utility of this drug is limited by a high incidence of drug resistance. Thus, there is an unmet need for alternative therapeutic strategies to treat vemurafenib-resistant metastatic melanomas. We have conducted high-throughput screening of two bioactive compound libraries (Siga and Spectrum libraries) against a metastatic melanoma cell line (A2058) and identified two structurally analogous compounds, deguelin and rotenone, from a cell viability assay. Vemurafenib-resistant melanoma cell lines, A2058R and A375R (containing the BRAFV600E mutation), also showed reduced proliferation when treated with these two compounds. Deguelin, a mitochondrial complex I inhibitor, was noted to significantly inhibit oxygen consumption in cellular metabolism assays. Mechanistically, deguelin treatment rapidly activates AMPK signaling, which results in inhibition of mTORC1 signaling and differential phosphorylation of mTORC1's downstream effectors, 4E-BP1 and p70S6 kinase. Deguelin also significantly inhibited ERK activation and Ki67 expression without altering Akt activation in the same timeframe in the vemurafenib-resistant melanoma cells. These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug-resistant melanomas harboring BRAF V600E mutations.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Electron Transport Complex I/antagonists & inhibitors , Melanoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Rotenone/analogs & derivatives , Vemurafenib/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/genetics , Humans , MAP Kinase Signaling System/drug effects , Mechanistic Target of Rapamycin Complex 1/metabolism , Melanoma/genetics , Mitogen-Activated Protein Kinases/metabolism , Mutation/drug effects , Rotenone/pharmacology , Signal Transduction/drug effects
4.
Expert Rev Proteomics ; 16(8): 627-645, 2019 08.
Article in English | MEDLINE | ID: mdl-31322970

ABSTRACT

Introduction: Atopic dermatitis (AD) is a multifactorial ailment associated with barrier breach and intense systemic inflammation. Several studies over the years have shown the complex interplay of a large number of factors in governing the progression and outcome of AD. In addition to the diverse types of AD resulting due to variation in the intrinsic mechanisms giving rise to AD such as single nucleotide polymorphisms (SNPs), epigenetic alterations or transcriptional changes, extrinsic factors such as age, ancestry, ethnicity, immunological background of the subject, the interactions of the subject with environmental stimuli and existing microbiome in the periphery surrounding the subject account for further heterogeneity in the clinical manifestations of the disease. Areas covered: Here we have selectively discussed transcriptional regulation of genes associated with skin lipid metabolism in the context of AD. Transcriptional control and transcriptomic changes are just one face of this multifaceted disease known to affect humans and a detailed study concerning those will enable us to develop targeted therapies to deal with the disease. Expert opinion: Large-scale integration of different omics approaches (genomics, epigenomics, transcriptomics, lipidomics, proteomics, metabolomics, effect of exposome) will help identify the potential candidate gene(s) associated with the development of various endotypes of AD.


Subject(s)
Dermatitis, Atopic/genetics , Lipid Metabolism/physiology , Transcriptome/genetics , Humans , Lipid Metabolism/genetics , Polymorphism, Single Nucleotide/genetics , Skin/metabolism , Skin/pathology
5.
BMC Cancer ; 17(1): 736, 2017 Nov 09.
Article in English | MEDLINE | ID: mdl-29121869

ABSTRACT

BACKGROUND: Understanding the underlying molecular mechanisms involved in the formation of cutaneous malignant melanoma is critical for improved diagnosis and treatment. Keratinocytic nuclear receptor Retinoid X Receptor α (RXRα) has a protective role against melanomagenesis and is involved in the regulation of keratinocyte and melanocyte homeostasis subsequent acute ultraviolet (UV) irradiation. METHODS: We generated a trigenic mouse model system (RXRα ep-/- | Tyr-NRAS Q61K | CDK4 R24C/R24C ) harboring an epidermal knockout of Retinoid X Receptor α (RXRα ep-/- ), combined with oncogenic NRAS Q61K (constitutively active RAS) and activated CDK4 R24C/R24C (constitutively active CDK4). Those mice were subjected to a single neonatal dose of UVB treatment and the role of RXR α was evaluated by characterizing the molecular and cellular changes that took place in the untreated and UVB treated trigenic RXRα ep-/- mice compared to the control mice with functional RXRα. RESULTS: Here we report that the trigenic mice develops spontaneous melanoma and exposure to a single neonatal UVB treatment reduces the tumor latency in those mice compared to control mice with functional RXRα. Melanomas from the trigenic RXRα ep-/- mice are substantial in size, show increased proliferation, exhibit increased expression of malignant melanoma markers and exhibit enhanced vascularization. Altered expression of several biomarkers including increased expression of activated AKT, p21 and cyclin D1 and reduced expression of pro-apoptotic marker BAX was observed in the tumor adjacent normal (TAN) skin of acute ultraviolet B treated trigenic RXRα ep-/- mice. Interestingly, we observed a significant increase in p21 and Cyclin D1 in the TAN skin of un-irradiated trigenic RXRα ep-/- mice, suggesting that those changes might be consequences of loss of functional RXRα in the melanoma microenvironment. Loss of RXRα in the epidermal keratinocytes in combination with oncogenic NRAS Q61K and CDK4 R24C/R24C mutations in trigenic mice led to significant melanoma invasion into the draining lymph nodes as compared to controls with functional RXRα. CONCLUSIONS: Our study demonstrates the protective role of keratinocytic RxRα in (1) suppressing spontaneous and acute UVB-induced melanoma, and (2) preventing progression of the melanoma to malignancy in the presence of driver mutations like activated CDK4 R24C/R24C and oncogenic NRAS Q61K .


Subject(s)
Ablation Techniques/methods , Cyclin-Dependent Kinase 4/metabolism , GTP Phosphohydrolases/metabolism , Melanoma/metabolism , Membrane Proteins/metabolism , Retinoid X Receptor alpha/deficiency , Skin Neoplasms/metabolism , Ultraviolet Rays/adverse effects , Acute Disease , Animals , Animals, Newborn , Carcinogenesis/pathology , Carcinogenesis/radiation effects , Male , Melanoma/etiology , Melanoma/pathology , Mice , Mice, Knockout , Mice, Transgenic , Skin Neoplasms/etiology , Skin Neoplasms/pathology , Melanoma, Cutaneous Malignant
6.
PLoS Genet ; 10(5): e1004321, 2014 May.
Article in English | MEDLINE | ID: mdl-24810760

ABSTRACT

Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRß, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/ß. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/ß. Loss of RXRs α/ß specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.


Subject(s)
Cell Cycle/radiation effects , Immunity, Innate/physiology , Melanocytes/physiology , Retinoid X Receptor alpha/physiology , Retinoid X Receptor beta/physiology , Ultraviolet Rays , Animals , Melanocytes/radiation effects , Mice , Mice, Transgenic , Retinoid X Receptor alpha/genetics , Retinoid X Receptor beta/genetics
7.
Expert Rev Proteomics ; 13(5): 451-6, 2016 05.
Article in English | MEDLINE | ID: mdl-27121756

ABSTRACT

INTRODUCTION: Lipidomics is the large-scale profiling and characterization of lipid species in a biological system using mass spectrometry. The skin barrier is mainly comprised of corneocytes and a lipid-enriched extracellular matrix. The major skin lipids are ceramides, cholesterol and free fatty acids (FFA). Lipid compositions are altered in inflammatory skin disorders with disrupted skin barrier such as atopic dermatitis (AD). AREAS COVERED: Here we discuss some of the recent applications of lipidomics in human skin biology and in inflammatory skin diseases such as AD, psoriasis and Netherton syndrome. We also review applications of lipidomics in human skin equivalent and in pre-clinical animal models of skin diseases to gain insight into the pathogenesis of the skin disease. Expert commentary: Skin lipidomics analysis could be a fast, reliable and noninvasive tool to characterize the skin lipid profile and to monitor the progression of inflammatory skin diseases such as AD.


Subject(s)
Dermatitis/diagnosis , Epidermis/metabolism , Lipids/analysis , Animals , Dermatitis/metabolism , Dermatitis/pathology , Disease Progression , Early Diagnosis , Epidermis/chemistry , Humans , Mass Spectrometry , Netherton Syndrome/diagnosis , Netherton Syndrome/metabolism , Netherton Syndrome/pathology , Psoriasis/diagnosis , Psoriasis/metabolism , Psoriasis/pathology
8.
Invest New Drugs ; 34(1): 24-40, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26563191

ABSTRACT

Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2). We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28 days in response to 0.3 mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy signaling in HUVECs raise the possibility that both cyanobacterial natural products share a common mechanism of action.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Depsipeptides/pharmacology , Glioblastoma/drug therapy , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Female , Glioblastoma/pathology , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Nude , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Xenograft Model Antitumor Assays
9.
J Cell Sci ; 125(Pt 23): 5733-44, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23015591

ABSTRACT

Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and positively regulating EGFR transcription in proliferating cells and Notch1 transcription in differentiating cells. In proliferative cells, the EGFR promoter is occupied by Ctip2, whereas Ctip2 is only recruited to the Notch1 promoter under differentiating conditions. Activation of EGFR signaling downregulates Ctip2 at the transcript level, whereas high calcium signaling triggers SUMOylation, ubiquitination and proteasomal degradation of Ctip2 at the protein level. Together, our findings demonstrate a novel mechanism(s) of Ctip2-mediated, coordinated control of epidermal proliferation and terminal differentiation, and identify a pathway of negative feedback regulation of Ctip2 during epidermal development.


Subject(s)
Epidermal Cells , Epidermis/metabolism , ErbB Receptors/metabolism , Receptors, Notch/metabolism , Repressor Proteins/metabolism , Signal Transduction/physiology , Tumor Suppressor Proteins/metabolism , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Cell Proliferation , Cells, Cultured , Chromatin Immunoprecipitation , ErbB Receptors/genetics , Immunoblotting , Immunohistochemistry , Immunoprecipitation , In Situ Nick-End Labeling , In Vitro Techniques , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Mice, Knockout , Receptors, Notch/genetics , Repressor Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Tumor Suppressor Proteins/genetics
10.
Photochem Photobiol Sci ; 13(3): 531-40, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24407555

ABSTRACT

Grp1-associated scaffold protein (Grasp), the product of a retinoic acid-induced gene in P19 embryonal carcinoma cells, is expressed primarily in brain, heart, and lung of the mouse. We report herein that Grasp transcripts are also found in mouse skin in which the Grasp gene is robustly induced following acute ultraviolet-B (UVB) exposure. Grasp(-/-) mice were found to exhibit delayed epidermal proliferation and a blunted apoptotic response after acute UVB exposure. Immunohistochemical analyses revealed that the nuclear residence time of the tumor suppressor protein p53 was reduced in Grasp(-/-) mice after UVB exposure. Taken together, our results suggest that a physiological role of Grasp may be to regulate skin homeostasis after UVB exposure, potentially by influencing p53-mediated apoptotic responses in skin.


Subject(s)
Carrier Proteins/metabolism , Membrane Proteins/metabolism , Skin Physiological Phenomena/radiation effects , Skin/radiation effects , Animals , Apoptosis/physiology , Apoptosis/radiation effects , Carrier Proteins/genetics , Cell Nucleus/physiology , Cell Nucleus/radiation effects , Cell Proliferation/radiation effects , Cells, Cultured , Dermis/physiology , Dermis/radiation effects , Epidermis/pathology , Epidermis/physiology , Epidermis/radiation effects , Fibroblasts/physiology , Fibroblasts/radiation effects , Homeostasis/physiology , Homeostasis/radiation effects , Intracellular Signaling Peptides and Proteins , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Tumor Suppressor Protein p53/metabolism , Ultraviolet Rays
11.
J Invest Dermatol ; 144(10): 2145-2161, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39001720

ABSTRACT

Novel pathways of vitamin D3, lumisterol 3 (L3), and tachysterol 3 (T3) activation have been discovered, initiated by CYP11A1 and/or CYP27A1 in the case of L3 and T3. The resulting hydroxymetabolites enhance protection of skin against DNA damage and oxidative stress; stimulate keratinocyte differentiation; exert anti-inflammatory, antifibrogenic, and anticancer activities; and inhibit cell proliferation in a structure-dependent manner. They act on nuclear receptors, including vitamin D receptor, aryl hydrocarbon receptor, LXRα/ß, RAR-related orphan receptor α/γ, and peroxisome proliferator-activated receptor-γ, with selectivity defined by their core structure and distribution of hydroxyl groups. They can activate NRF2 and p53 and inhibit NF-κB, IL-17, Shh, and Wnt/ß-catenin signaling. Thus, they protect skin integrity and physiology.


Subject(s)
Skin , Humans , Skin/metabolism , Skin/drug effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Animals , Cholestanetriol 26-Monooxygenase/metabolism , Cholestanetriol 26-Monooxygenase/genetics , Vitamin D/metabolism , Vitamin D/pharmacology , Vitamin D/analogs & derivatives , Cell Proliferation/drug effects , Cholecalciferol/pharmacology , Cholecalciferol/metabolism , Oxidative Stress/drug effects , Signal Transduction/drug effects
12.
Cancers (Basel) ; 16(12)2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38927967

ABSTRACT

Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.

13.
Cancers (Basel) ; 15(11)2023 Jun 02.
Article in English | MEDLINE | ID: mdl-37297001

ABSTRACT

Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.

14.
Cells ; 11(13)2022 07 03.
Article in English | MEDLINE | ID: mdl-35805190

ABSTRACT

Transcriptional regulator BCL11A plays a crucial role in coordinating a suite of developmental processes including skin morphogenesis, barrier functions and lipid metabolism. There is little or no reports so far documenting the role of BCL11A in postnatal adult skin homeostasis and in the physiological process of tissue repair and regeneration. The current study establishes for the first time the In Vivo role of epidermal BCL11A in maintaining adult epidermal homeostasis and as a negative regulator of cutaneous wound healing. Conditional ablation of Bcl11a in skin epidermal keratinocytes (Bcl11aep-/-mice) enhances the keratinocyte proliferation and differentiation program, suggesting its critical role in epidermal homeostasis of adult murine skin. Further, loss of keratinocytic BCL11A promotes rapid closure of excisional wounds both in a cell autonomous manner likely via accelerating wound re-epithelialization and in a non-cell autonomous manner by enhancing angiogenesis. The epidermis specific Bcl11a knockout mouse serves as a prototype to gain mechanistic understanding of various downstream pathways converging towards the manifestation of an accelerated healing phenotype upon its deletion.


Subject(s)
Epidermis , Keratinocytes , Repressor Proteins/metabolism , Animals , Homeostasis , Keratinocytes/metabolism , Mice , Skin/metabolism , Transcription Factors/metabolism , Wound Healing
15.
Cancers (Basel) ; 14(6)2022 Mar 16.
Article in English | MEDLINE | ID: mdl-35326683

ABSTRACT

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases.

16.
Adv Healthc Mater ; 11(20): e2200849, 2022 10.
Article in English | MEDLINE | ID: mdl-35930707

ABSTRACT

Exosomes show great potential in diagnostic and therapeutic applications. Inspired by the human innate immune defense, herein, we report engineered exosomes derived from monocytic cells treated with immunomodulating compounds 1α,25-dihydroxyvitamin D3, and CYP24A1 inhibitor VID400 which are slowly released from electrospun nanofiber matrices. These engineered exosomes contain significantly more cathelicidin/LL-37 when compared with exosomes derived from either untreated cells or Cathelicidin Human Tagged ORF Clone transfected cells. In addition, such exosomes exhibit multiple biological functions evidenced by killing bacteria, facilitating human umbilical vein endothelial cell tube formation, and enhancing skin cell proliferation and migration. Taken together, the engineered exosomes developed in this study can be used as therapeutics alone or in combination with other biomaterials for effective infection management, wound healing, and tissue regeneration.


Subject(s)
Exosomes , Humans , Vitamin D3 24-Hydroxylase , Antimicrobial Cationic Peptides/pharmacology , Human Umbilical Vein Endothelial Cells , Biocompatible Materials , Cathelicidins
17.
J Invest Dermatol ; 142(7): 1903-1911.e5, 2022 07.
Article in English | MEDLINE | ID: mdl-35031135

ABSTRACT

Pigment-producing melanocytes overcome frequent oxidative stress in their physiological role of protecting the skin against the deleterious effects of solar UV irradiation. This is accomplished by the activity of several endogenous antioxidant systems, including the thioredoxin antioxidant system, in which thioredoxin reductase 1 (TR1) plays an important part. To determine whether TR1 contributes to the redox regulation of melanocyte homeostasis, we have generated a selective melanocytic Txnrd1-knockout mouse model (Txnrd1mel‒/‒), which exhibits a depigmentation phenotype consisting of variable amelanotic ventral spotting and reduced pigmentation on the extremities (tail tip, ears, and paws). The antioxidant role of TR1 was further probed in the presence of acute neonatal UVB irradiation, which stimulates melanocyte activation and introduces a spike in oxidative stress in the skin microenvironment. Interestingly, we observed a significant reduction in overall melanocyte count and proliferation in the absence of TR1. Furthermore, melanocytes exhibited an elevated level of UV-induced DNA damage in the form of 8-oxo-2'-deoxyguanosine after acute UVB treatment. We also saw an engagement of compensatory antioxidant mechanisms through increased nuclear localization of transcription factor NRF2. Altogether, these data indicate that melanocytic TR1 positively regulates melanocyte homeostasis and pigmentation during development and protects against UVB-induced DNA damage and oxidative stress.


Subject(s)
Photobiology , Thioredoxin Reductase 1 , Animals , Antioxidants/pharmacology , Melanocytes/radiation effects , Mice , Pigmentation , Thioredoxin Reductase 1/genetics , Ultraviolet Rays
18.
Cancers (Basel) ; 14(20)2022 Oct 13.
Article in English | MEDLINE | ID: mdl-36291795

ABSTRACT

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.

19.
Front Oncol ; 11: 743667, 2021.
Article in English | MEDLINE | ID: mdl-34692525

ABSTRACT

Melanoma is the malignant transformation of melanocytes and represents the most lethal form of skin cancer. While early-stage melanoma localized to the skin can be cured with surgical excision, metastatic melanoma often requires a multi-pronged approach and even then can exhibit treatment resistance. Understanding the molecular mechanisms involved in the pathogenesis of melanoma could lead to novel diagnostic, prognostic, and therapeutic strategies to ultimately decrease morbidity and mortality. One emerging candidate that may have value as both a prognostic marker and in a therapeutic context is the vitamin D receptor (VDR). VDR is a nuclear steroid hormone receptor activated by 1,25 dihydroxy-vitamin D3 [calcitriol, 1,25(OH)2D3]. While 1,25 dihydroxy-vitamin D3 is typically thought of in relation to calcium metabolism, it also plays an important role in cell proliferation, differentiation, programmed-cell death as well as photoprotection. This review discusses the role of VDR in the crosstalk between keratinocytes and melanocytes during melanomagenesis and summarizes the clinical data regarding VDR polymorphisms, VDR as a prognostic marker, and potential uses of vitamin D and its analogs as an adjuvant treatment for melanoma.

20.
Methods Mol Biol ; 2155: 115-123, 2020.
Article in English | MEDLINE | ID: mdl-32474872

ABSTRACT

Wound healing process is the outcome of a series of actions and combined with collaborative process involving concerted efforts of multiple cell types. The dynamic series of events constituting each of these overlapping rather than discrete stages of wound healing increases its complexity and the necessity to understand it. The contrasting mechanisms of wound healing employed by mouse (via wound contraction) and humans (via reepithelialization) puts forth the need of a model closely mimicking human wound-healing and hence comes the applicability of the mouse excisional wound splinting model. Use of silicone-based splints has demonstrated their effectiveness in aptly resembling the human reepithelialization mediated wound healing by preventing contraction during healing. The rising popularity of nanofiber-based treatments for wound healing through sustained release of factors/molecules promoting wound closure can be potentially implemented in association with this model to determine its efficacy in wound management in a more humanized way.


Subject(s)
Nanofibers , Re-Epithelialization , Skin Physiological Phenomena , Skin/injuries , Splints , Wound Healing , Animals , Biomarkers , Contracture , Disease Models, Animal , Immunohistochemistry , Mice
SELECTION OF CITATIONS
SEARCH DETAIL