Role of protease-activated receptors in human skin fibrosis and scleroderma

Numerous reports indicate that the platelet glycoprotein (GP) Ib-IX complex (GPIb-IX) binds directly to the potent platelet agonist thrombin and is important for promoting thrombin-induced platelet activation. However, how GPIb-IX contributes to thrombin-induced platelet activation is unclear. It has been suggested that thrombin binding to GPIb facilitates the cleavage, and thus activation, of the protease-activated receptors (PAR). Our data indicate that GPIb-IX promotes thrombin signaling through a GPIb-IX signaling mechanism. Pretreatment of human platelets with MPalphaC, an inhibitory peptide based on a critical 14-3-3 signaling protein binding site on the cytoplasmic domain of the GPIb alpha chain, inhibited thrombin-induced platelet activation. MPalphaC-treatment inhibited thrombin-induced activation of Rac1 and LIMK1, both of which are known to play essential roles in GPIb signaling. To more specifically determine the role of GPIb-IX, we reconstituted GPIb-IX-facilitated thrombin signaling in Chinese Hamster Ovary cells expressing PAR1. Thrombin induced signaling was significantly enhanced by GPIb-expression, and deletion of the cytoplasmic 14-3-3-binding domain of GPIb alpha abolished the stimulatory effect of GPIb on thrombin signaling. Furthermore, the role of GPIb-IX in promoting thrombin signaling requires Rac1, and GPIb-IX-dependent Rac1 activation and LIMK phosphorylation are abolished in delta 605 cells expressing a 14-3-3-binding defective mutant GPIb alpha. Taken together, these data suggest that the stimulatory role of GPIb in thrombin signaling requires a C-terminal 14-3-3-binding region which mediates activation of a Rac1/LIMK1 pathway that promotes thrombin signaling leading to platelet activation.

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5-MOP Induced Protection Against Epidermal DNA Damage by Ultraviolet Radiation in Human Skin: The Role of the Skin Type

Light in Biology and Medicine ◽

10.1007/978-1-4684-5991-3_20 ◽

1991 ◽

pp. 201-209

Author(s):

Antony R. Young ◽

Christopher S. Potten ◽

Caroline A. Chadwick ◽

Gillian M. Murphy ◽

A. Jeffrey Cohen

Keyword(s):

Dna Damage ◽

Ultraviolet Radiation ◽

Human Skin ◽

Skin Type

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Expression of drug transporters in the human skin: comparison in different species and models and its implication for drug development

ADMET & DMPK ◽

10.5599/admet.5.2.390 ◽

2017 ◽

Vol 5 (2) ◽

pp. 75 ◽

Cited By ~ 2

Author(s):

Hanan Osman-Ponchet ◽

Alexandre Gaborit ◽

Jean-Michel Linget ◽

Claire E. Wilson

Keyword(s):

Human Skin ◽

Drug Absorption ◽

Transdermal Delivery ◽

Drug Transporters ◽

Drug Distribution ◽

Skin Surface ◽

Pharmacological Intervention ◽

Novel Targets

<p class="ADMETabstracttext">It is clear that many drug transporters (both ABCs and SLCs) are present in the human skin. Different in vitro skin models can be used to investigate the role of drug transporters in the skin despite quantitative differences in expression profile across species. P-gp was shown to have an important influence on transdermal drug absorption in the skin and to function in “absorptive” transport, carrying substrate drugs from the skin surface to the dermis. This observation might be used to modulate drug distribution inside the skin. If drugs can be retained in the epidermis compartment by inhibition of the transporters, such property of the drug would be beneficial for treatment of dermatological diseases. Therefore, it might be feasible to control transdermal delivery of drugs to specific locations in the skin, by modulating the function of the transporters in the skin. We are at the dawn of an exciting period where drug transporters might be novel targets for improvement of drug delivery to the skin and for pharmacological intervention.</p>

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A critical role of AREG for bleomycin-induced skin fibrosis

10.1101/2021.01.20.427509 ◽

2021 ◽

Author(s):

Mary Yinghua Zhang ◽

Shuyi Fang ◽

Hongyu Gao ◽

Xiaoli Zhang ◽

Dongsheng Gu ◽

...

Keyword(s):

Cell Proliferation ◽

Wound Healing ◽

Oral Mucosa ◽

Healing Process ◽

Critical Role ◽

Skin Fibrosis ◽

Wound Healing Process ◽

Organ Function ◽

Signaling Axis

ABSTRACTWe report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

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Protease-activated receptors are expressed by peptidergic nociceptor neurons, are upregulated in pancreatitis and result in neuronal sensitization: Implications for the role of trypsin in the pathogenes is of pain in pancreatitis

Gastroenterology ◽

10.1016/s0016-5085(00)82744-4 ◽

2000 ◽

Vol 118 (4) ◽

pp. A167 ◽

Cited By ~ 2

Author(s):

Willemijntje A. Hoogerwerf ◽

Maria-Adelaide Micci ◽

Mohan Shenoy ◽

John H. Winston ◽

Helen Lee Hellmich ◽

...

Keyword(s):

Protease Activated Receptors

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The role of TRPV1 channel in aged human skin

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2011.11.003 ◽

2012 ◽

Vol 65 (2) ◽

pp. 81-85 ◽

Cited By ~ 39

Author(s):

Young Mee Lee ◽

So Min Kang ◽

Jin Ho Chung

Keyword(s):

Human Skin ◽

Trpv1 Channel

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Evidence for the involvement of peripheral cold-sensitive TRPM8 channels in human cutaneous hygrosensation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00332.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. R579-R589 ◽

Cited By ~ 1

Author(s):

Oliver Typolt ◽

Davide Filingeri

Keyword(s):

Human Skin ◽

Chemical Activation ◽

The Body ◽

Cold Sensitivity ◽

Trpm8 Channel ◽

Body Regions ◽

Skin Cooling ◽

Cold Sensitive ◽

Skin Wetness

In contrast to other species, humans are believed to lack hygroreceptors for sensing skin wetness. Yet, the molecular basis of human hygrosensation is currently unknown, and it remains unclear whether we possess a receptor-mediated sensing mechanism for skin wetness. The aim of this study was to assess the role of the cutaneous cold-sensitive transient receptor potential melastatin-8 (TRPM8) channel as a molecular mediator of human hygrosensation. To this end, we exploited both the thermal and chemical activation of TRPM8-expressing cutaneous Aδ cold thermoreceptors, and we assessed wetness sensing in healthy young men in response to 1) dry skin cooling in the TRPM8 range of thermosensitivity and 2) application of the TRPM8 agonist menthol. Our results indicate that 1) independently of contact with moisture, a cold-dry stimulus in the TRPM8 range of activation induced wetness perceptions across 12 different body regions and those wetness perceptions varied across the body following regional differences in cold sensitivity; and 2) independently of skin cooling, menthol-induced stimulation of TRPM8 triggered wetness perceptions that were greater than those induced by physical dry cooling and by contact with an aqueous cream containing actual moisture. For the first time, we show that the cutaneous cold-sensing TRPM8 channel plays the dual role of cold and wetness sensor in human skin and that this ion channel is a peripheral mediator of human skin wetness perception.

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