The multifaceted role of autophagy in skin autoimmune disorders: a guardian or culprit?

Autophagy is a cellular process that functions to maintain intracellular homeostasis via the degradation and recycling of defective organelles or damaged proteins. This dynamic mechanism participates in various biological processes, such as the regulation of cellular differentiation, proliferation, survival, and the modulation of inflammation and immune responses. Recent evidence has demonstrated the involvement of polymorphisms in autophagy-related genes in various skin autoimmune diseases. In addition, autophagy, along with autophagy-related proteins, also contributes to homeostasis maintenance and immune regulation in the skin, which is associated with skin autoimmune disorders. This review aims to provide an overview of the multifaceted role of autophagy in skin autoimmune diseases and shed light on the potential of autophagy-targeting therapeutic strategies in dermatology

Genetic susceptibility to vitiligo: Recent progress from genome-wide association studies

Generalized vitiligo (GV) is a complicated disease in which patchy depigmentation results from the autoimmune loss of melanocytes from affected regions. It may follow a pattern of polygenetic or multifactorial inheritance. Previously, a number of genetic susceptibility factors have been identified through linkage and candidate gene studies, such as HLA, PTPN22, NALP1, and XBP1. Recently, a series of genome-wide association studies have been carried out in different populations to further explore the susceptibility variants for GV. More than 30 robust susceptibility loci have been identified and confirmed. Most of these associated genes encode components of biological pathways reaching from the immune cell to the melanocytes. In this review, we summarize the advances of vitiligo epidemiology and genetics, and highlight recent findings from genome-wide association studies, emphasizing susceptibility loci and comparing the susceptibility loci between Chinese people and Caucasians. These genetic studies may help in providing an insight into the pathogenesis of this disease and initiating the feasibility of genetic diagnosis and personalized treatment for patients with GV in the future

Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes

Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of functional melanocytes from the epidermis and follicular reservoir. Among multiple hypotheses which have been proposed in the pathogenesis of vitiligo, autoimmunity and oxidative stress-mediated toxicity in melanocytes remain most widely accepted. Macroautophagy is a lysosome-dependent degradation pathway which widely exists in eukaryotic cells. Autophagy participates in the oxidative stress response in many cells, which plays a protective role in preventing damage caused by oxidative stress. Recent studies have enrolled autophagy as an important regulator in limiting damage caused by UV light and lipid oxidation, keeping oxidative stress in a steady state in epidermal keratinocytes and maintaining normal proliferation and aging of melanocytes. Impairment of autophagy might disrupt the antioxidant defense system which renders melanocytes to oxidative insults. These findings provide supportive evidence to explore new ideas of the pathogenesis of vitiligo and other pigmentation disorders

Identification and Validation of Autophagy-Related Genes in Vitiligo

Vitiligo is a common depigmented disease with unclear pathogenesis. Autophagy is crucial for maintaining cellular homeostasis and has been linked to a variety of autoimmune disorders; however, there have been no reports exploring the involvement of autophagy-related genes (ARGs) in vitiligo using bioinformatics methodologies. In this study, RNA-sequencing technology was used to identify the differentially expressed genes (DEGs) and the Human Autophagy Database (HADb) was overlapped to identify differentially expressed autophagy-related genes (DEARGs) in stable non-segmental vitiligo (NSV). Bioinformatics analyses were conducted with R packages and Ingenuity Pathways Analysis (IPA). DEARGs were further confirmed with qRT-PCR. Critical autophagy markers were detected with Western blotting analysis. We identified a total of 39 DEARGs in vitiligo lesions. DEARGs-enriched canonical pathways, diseases and bio functions, upstream regulators, and networks were discovered. qRT-PCR confirmed the significant increases in FOS and RGS19 in vitiligo lesions. Lower microtubule-associated protein 1 light chain (LC3) II/LC3I ratio and higher sequestosome 1 (SQSTM1, p62) expression were found in vitiligo lesions. In conclusion, this study provided a new insight that autophagy dysregulation appeared in stable vitiligo lesions and might be involved in the etiology of vitiligo by taking part in multiple pathways and bio functions

Identification and Validation of Autophagy-Related Genes in Vitiligo

Vitiligo is a common depigmented disease with unclear pathogenesis. Autophagy is crucial for maintaining cellular homeostasis and has been linked to a variety of autoimmune disorders; however, there have been no reports exploring the involvement of autophagy-related genes (ARGs) in vitiligo using bioinformatics methodologies. In this study, RNA-sequencing technology was used to identify the differentially expressed genes (DEGs) and the Human Autophagy Database (HADb) was overlapped to identify differentially expressed autophagy-related genes (DEARGs) in stable non-segmental vitiligo (NSV). Bioinformatics analyses were conducted with R packages and Ingenuity Pathways Analysis (IPA). DEARGs were further confirmed with qRT-PCR. Critical autophagy markers were detected with Western blotting analysis. We identified a total of 39 DEARGs in vitiligo lesions. DEARGs-enriched canonical pathways, diseases and bio functions, upstream regulators, and networks were discovered. qRT-PCR confirmed the significant increases in FOS and RGS19 in vitiligo lesions. Lower microtubule-associated protein 1 light chain (LC3) II/LC3I ratio and higher sequestosome 1 (SQSTM1, p62) expression were found in vitiligo lesions. In conclusion, this study provided a new insight that autophagy dysregulation appeared in stable vitiligo lesions and might be involved in the etiology of vitiligo by taking part in multiple pathways and bio functions

A network pharmacology study of Chinese medicine QiShenYiQi to reveal its underlying multi-compound, multi-target, multi-pathway mode of action.

Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine, QiShenYiQi (QSYQ), on myocardial infarction. QSYQ is composed of Astragalus membranaceus (Huangqi), Salvia miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and Dalbergia odorifera (Jiangxiang). Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched in ArrayTrack. 55 potential targets of QSYQ were identified, of which 14 were confirmed in CVD-related literatures with experimental supporting evidences. Furthermore, three sesquiterpene components of QSYQ, Trans-nerolidol, (3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol and (3S,6R,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol from Dalbergia odorifera T. Chen, were validated experimentally in this study. Their anti-inflammatory effects and potential targets including extracellular signal-regulated kinase-1/2, peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 were identified. Finally, through a three-level compound-target-pathway network with experimental analysis, our study depicts a complex MOA of QSYQ on myocardial infarction