The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing. Wounding of human keratinocyte monolayers in vitro led to the rapid activation of the eIF2 kinase GCN2. We determined that deletion or pharmacological inhibition of GCN2 significantly delayed collective cell migration and wound closure. Global transcriptomic, biochemical, and cellular analyses indicated that GCN2 is necessary for maintenance of intracellular free amino acids, particularly cysteine, as well as coordination of RAC1-GTP-driven reactive oxygen species (ROS) generation, lamellipodia formation, and focal adhesion dynamics following keratinocyte wounding. In vivo experiments using mice deficient for GCN2 validated the role of the eIF2 kinase during wound healing in intact skin. These results indicate that GCN2 is critical for appropriate induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds.

The psychological consequences of androgenetic alopecia: A systematic review.

INTRODUCTION: Androgenetic alopecia is the most common cause of hair loss in both males and females. In a society that places significant value on hair and associates it with attractiveness, a lack there of can have damaging psychological consequences. The psychosocial impact of hair loss is often overlooked due to the medically benign nature of offending conditions. Addressing the psychological aspects of androgenetic alopecia can improve holistic patient care and patient outcomes. METHODS: A search was conducted in PubMed using the following search strategy: androgenetic alopecia AND anxiety OR depression OR psychological OR psychosocial OR self-esteem. Studies were excluded if they focused on any other type of alopecia or were published in a language other than English. RESULTS: A total of 13 studies were retained after the initial search process. The included studies date from 1992 to 2021. They all conclude that androgenetic alopecia serves as a significant psychosocial stressor in the lives of those affected. It impairs quality of life according to multiple measures. CONCLUSION: The data examined from these studies shed light on the increased need to attend to the psychosocial comorbidity associated with androgenetic alopecia. These hair-loss patients often present to dermatology clinics to seek treatment but would also benefit from psychological support.

Circumscribed Palmar Hypokeratosis With Superimposed Actinic Keratosis.

A man in his late 70s with a history of psoriasis and non-melanoma skin cancer presented with a progressive rash on his right thenar eminence. He first noticed it about one year ago. He denied any pruritus in the affected region but did note some overlying skin breakdown. He had used topical betamethasone and calcipotriene cream in the past with minimal improvement. Physical examination revealed a pink atrophic plaque with linear hyperkeratotic borders and central fissuring on the right thenar eminence extending into the first webspace. A shave biopsy revealed hypokeratosis with a rim of surrounding hyperkeratosis and associated parakeratosis, basal keratinocyte atypia, and lichenoid inflammation. These histopathological features were consistent with circumscribed palmar hypokeratosis and central actinic keratosis. Circumscribed palmar hypokeratosis is often considered a benign entity, but there have been reports suggesting an association with premalignancy. The decision was made to treat with 5-fluorouracil and calcipotriene cream twice daily for six weeks. At his two-month follow-up, he endorsed a robust reaction, which was further suggestive of premalignant change. He had a near-complete resolution of the rash. This case features circumscribed palmar hypokeratosis and suggests a novel treatment option for patients who develop concomitant actinic keratosis.