Keratins play critical roles in intermediate filament formation, inflammatory responses and cellular signaling in epithelium. While keratins is a major epidermal fluorophore, the mechanisms underlying the autofluorescence (AF) of keratins and its biomedical implications have remained unknown. Our study used mouse skin as a model to study these topics,showing that UV dose-dependently induced increases in green AF at the spinous layer of the epidermis of mouse within 6 hr of the UV exposures, which may be used for non-invasive prediction of UV-induced skin damage. The UV-induced AF appears to be induced by cysteine protease-mediated keratin 1 proteolysis: 1) UV rapidly induced significant keratin 1 degradation; 2) administration of keratin 1 siRNA largely decreased the UV-induced AF; and 3) administration of E-64, a cysteine protease inhibitor, significantly attenuated the UV-induced AF and keratin 1 degradation. Our study has also suggested that the UV-induced keratin 1 proteolysis may be a novel crucial pathological factor in UV-induced skin damage, which is supported by both the findings that indicate critical biological roles of keratin 1 in epithelium and our observation that prevention of UV-induced keratin 1 proteolysis can lead to decreased UV-induced skin damage. Collectively, our study has suggested that UV-induced keratin 1 proteolysis may be a novel and valuable target for diagnosis, prevention and treatment of UV-induced skin damage.
Human autofluorescence (AF) has shown significant potential for non-invasive diagnosis, while information regarding the pathological implications of the changes of epidermal AF is deficient. Our study has suggested that epidermal green AF may become the first endogenous indicator of the levels of inflammatory and reactive oxygen species (ROS) factors to which the skin is exposed: The AF intensity has virtually linear relationships with the dosages of UV, LPS and ROS in mouse models or skin cell culture studies; and the green AF intensity in skin is also highly correlated with the risk of cerebral small vessel disease patients to develop acute ischemic stroke. Since ROS and inflammatory factors to which healthy skin is exposed should come from such pathways as the blood circulation, epidermal green AF may also become the first biomarker of the levels of oxidative stress and inflammation in the body.We further found that keratin 1 degradation mediates the UV-induced increases in green AF intensity, and that decreased keratin 1 levels can lead to cell death. These findings have collectively suggested that organ damage-produced ROS and inflammatory factors may be transported along the body, producing increased epidermal green AF, which may become a common biomarker for organ injury as well as the levels of inflammation and oxidative stress in the body. Our study has also highlighted an essential relationship between skin's changes and organ damage, as well as critical roles of epidermal keratins in both UV-induced skin damage and non-invasive evaluation of organ injury.
Our recent study has reported that UV-induced epidermal autofluorescence (AF) can be used as a novel biomarker for predicting UV-induced skin damage, which is originated from UV-induced, cysteine protease-mediated keratin 1 degradation. A key question regarding these findings is: Does oxidative stress play a significant role in the UV-induced epidermal AF and keratin 1 proteolysis? In our current study, we administered the widely used antioxidant N-acetyl cysteine (NAC) into the skin of mouse ears to test our hypothesis that oxidative stress mediates UV-induced increases in the epidermal AF and keratin 1 degradation. Our study has shown that NAC administration can significantly attenuate the UVC-induced AF increases. The NAC administration can also significantly decrease the UVC-induced keratin 1 degradation.Collectively, our findings have indicated that the oxidative stress induced by UVC is causative to the UVC-induced increases in epidermal AF and keratin 1 proteolysis.Moreover, since oxidative stress is significantly increased in multiple regions of the body in several major diseases, the oxidative stress-induced increases in epidermal AF may become a novel biomarker for diagnosis of major diseases.
Testosterone’s role in female depression is not well understood, with studies reporting conflicting results. Here, we use meta-analytical and Mendelian randomization techniques to determine whether serum testosterone levels differ between depressed and healthy women and whether such a relationship is casual. Our meta-analysis shows a significant association between absolute serum testosterone levels and female depression, which remains true for the premenopausal group while achieving borderline significance in the postmenopausal group. The results from our Mendelian randomization analysis failed to show any causal relationship between testosterone and depression. Our results show that women with depression do indeed display significantly different serum levels of testosterone. However, the directions of the effect of this relationship are conflicting and may be due to menopausal status. Since our Mendelian randomization analysis was insignificant, the difference in testosterone levels between healthy and depressed women is most likely a manifestation of the disease itself. Further studies could be carried out to leverage this newfound insight into better diagnostic capabilities culminating in early intervention in female depression.
Schizophrenia (SCZ) is a severe mental disorder that may result in hallucinations, delusions, and extremely disordered thinking. How each cell type in the brain contributes to SCZ occurrence is still unclear. Here, we leveraged the human dorsolateral prefrontal cortex bulk RNA-seq data, then used the RNA-seq deconvolution algorithm CIBERSORTx to generate SCZ brain single-cell RNA-seq data for a comprehensive analysis to understand SCZ-associated brain cell types and gene expression changes. Firstly, we observed that the proportions of brain cell types in SCZ differed from normal samples. Among these cell types, astrocyte, pericyte, and PAX6 cells were found to have a higher proportion in SCZ patients (astrocyte: SCZ = 0.163, control = 0.145, P.adj = 4.9 × 10−4, effect size = 0.478; pericyte: SCZ = 0.057, control = 0.066, P.adj = 1.1 × 10−4, effect size = 0.519; PAX6: SCZ = 0.014, control = 0.011, P.adj = 0.014, effect size = 0.377), while the L5/6_IT_CAR3 cells and LAMP5 cells are the exact opposite (L5/6_IT_Car3: SCZ = 0.102, control = 0.108, P.adj = 0.016, effect size = 0.369; LAMP5: SCZ = 0.057, control = 0.066, P.adj = 2.2 × 10−6, effect size = 0.617). Next, we investigated gene expression in cell types and functional pathways in SCZ. We observed chemical synaptic transmission dysregulation in two types of GABAergic neurons (PVALB and LAMP5), and immune reaction involvement in GABAergic neurons (SST) and non-neuronal cell types (endothelial and oligodendrocyte). Furthermore, we observed that some differential expression genes from bulk RNA-seq displayed cell-type-specific abnormalities in the expression of molecules in SCZ. Finally, the cell types with the SCZ-related transcriptomic changes could be considered to belong to the same module since we observed two major similar coordinated transcriptomic changes across these cell types. Together, our results offer novel insights into cellular heterogeneity and the molecular mechanisms underlying SCZ.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.