Exploring the roles and potential therapeutic strategies of inflammation and metabolism in the pathogenesis of vitiligo: a mendelian randomization and bioinformatics-based investigation.

Introduction: Vitiligo, a common autoimmune acquired pigmentary skin disorder, poses challenges due to its unclear pathogenesis. Evidence suggests inflammation and metabolism's pivotal roles in its onset and progression. This study aims to elucidate the causal relationships between vitiligo and inflammatory proteins, immune cells, and metabolites, exploring bidirectional associations and potential drug targets. Methods: Mendelian Randomization (MR) analysis encompassed 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell features, and 1400 metabolites. Bioinformatics analysis included Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and hub protein identification utilized the Molecular Complex Detection (MCODE) plugin. Colocalization analysis and drug target exploration, including molecular docking validation, were performed. Results: MR analysis identified 49 proteins, 39 immune cell features, and 59 metabolites causally related to vitiligo. Bioinformatics analysis revealed significant involvement in PPI, GO enrichment, and KEGG pathways. Subnetwork analysis identified six central proteins, with Interferon Regulatory Factor 3 (IRF3) exhibiting strong colocalization evidence. Molecular docking validated Piceatannol's binding to IRF3, indicating a stable interaction. Conclusion: This study comprehensively elucidates inflammation, immune response, and metabolism's intricate involvement in vitiligo pathogenesis. Identified proteins and pathways offer potential therapeutic targets, with IRF3 emerging as a promising candidate. These findings deepen our understanding of vitiligo's etiology, informing future research and drug development endeavors.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

An updated meta-analysis investigating the association between DNMTs gene polymorphism andgastric cancer risk.

Gastric cancer (GC) is a prominent global health issue, as it ranks as the fifth most prevalent type of cancer and the fourth most significant cause of cancer-related mortality worldwide. Although H. pylori is known to play a role in the development of GC, genetic factors also play a role in its onset and progression. Recent studies have shown that genetic polymorphisms are strongly associated with the development of GC and that certain single nucleotide polymorphisms (SNPs) can be used as biomarkers for early diagnosis and prevention. Epigenetic disturbances, such as DNA methylation, are involved in the development of GC, and mutations in the DNA methyltransferase (DNMT) gene have been found to increase the risk of GC. However, previous findings on the association between DNMTs SNPs and GC risk have been inconsistent. In this study, an updated meta-analysis of three well-studied and controversial DNMTs polymorphic loci, DNMT1 rs16999593, DNMT3A rs1550117 and DNMT3B rs1569686, was performed to provide more reliable results. It was found that DNMT1 rs16999593 was not associated with GC, DNMT3A rs1550117 may have a positive association with GC risk, and DNMT3B rs1569686 may be a protective factor for GC. These findings may provide valuable information for early diagnosis and prevention of GC, but further studies are needed to confirm these results.

AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake.

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA.

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.

Coding-Sequence Identification and Transcriptional Profiling of Nine AMTs and Four NRTs From Tobacco Revealed Their Differential Regulation by Developmental Stages, Nitrogen Nutrition, and Photoperiod.

Although many members encoding different ammonium- and nitrate-transporters (AMTs, NRTs) were identified and functionally characterized from several plant species, little is known about molecular components for [Formula: see text]- and [Formula: see text] acquisition/transport in tobacco, which is often used as a plant model for biological studies besides its agricultural and industrial interest. We reported here the first molecular identification in tobacco (Nicotiana tabacum) of nine AMTs and four NRTs, which are respectively divided into four (AMT1/2/3/4) and two (NRT1/2) clusters and whose functionalities were preliminarily evidenced by heterologous functional-complementation in yeast or Arabidopsis. Tissue-specific transcriptional profiling by qPCR revealed that NtAMT1.1/NRT1.1 mRNA occurred widely in leaves, flower organs and roots; only NtAMT1.1/1.3/2.1NRT1.2/2.2 were strongly transcribed in the aged leaves, implying their dominant roles in N-remobilization from source/senescent tissues. N-dependent expression analysis showed a marked upregulation of NtAMT1.1 in the roots by N-starvation and resupply with N including [Formula: see text], suggesting a predominant action of NtAMT1.1 in [Formula: see text] uptake/transport whenever required. The obvious leaf-expression of other NtAMTs e.g., AMT1.2 responsive to N indicates a major place, where they may play transport roles associated with plant N-status and ([Formula: see text]-)N movement within aerial-parts. The preferentially root-specific transcription of NtNRT1.1/1.2/2.1 responsive to N argues their importance for root [Formula: see text] uptake and even sensing in root systems. Moreover, of all NtAMTs/NRTs, only NtAMT1.1/NRT1.1/1.2 showed their root-expression alteration in a typical diurnal-oscillation pattern, reflecting likely their significant roles in root N-acquisition regulated by internal N-demand influenced by diurnal-dependent assimilation and translocation of carbohydrates from shoots. This suggestion could be supported at least in part by sucrose- and MSX-affected transcriptional-regulation of NtNRT1.1/1.2. Thus, present data provide valuable molecular bases for the existence of AMTs/NRTs in tobacco, promoting a deeper understanding of their biological functions.

Molecular identification of tobacco NtAMT1.3 that mediated ammonium root-influx with high affinity and improved plant growth on ammonium when overexpressed in Arabidopsis and tobacco.

Although biological functions of ammonium (NH4+) transporters (AMTs) have been intensively studied in many plant species, little is known about molecular bases responsible for NH4+ movement in tobacco. Here, we reported the identification and functional characterization of a putative NH4+ transporter NtAMT1.3 from tobacco (Nicotiana tabacum). Analysis in silico showed that NtAMT1.3 encoded an integral membrane protein containing 464 amino acid residues and exhibiting 10 predicted transmembrane α-helices. Heterologous functionality study demonstrated that NtAMT1.3 expression facilitated NH4+ entry across plasma membrane of NH4+-uptake defective yeast and Arabidopsis qko mutant, allowing a restored growth of both yeast and Arabidopsis mutant on low NH4+. qPCR assay revealed that NtAMT1.3 was expressed in both roots and leaves and significantly up-regulated by nitrogen starvation and resupply of its putative substrate NH4+ and even nitrate, suggesting that NtAMT1.3 should represent a nitrogen-responsive gene. Critically, constitutive overexpression of NtAMT1.3 in tobacco per se improved obviously the growth of transgenic plants on NH4+ and enhanced leaf nitrogen (15% more) accumulation, consistent with observation of 35% more NH4+ uptake by the roots of transgenic lines in 20min root-influx test. Together with data showing its plasma membrane localization and saturated transport nature with Km of about 50µM for NH4+, we suggest that NtAMT1.3 acts an active NH4+ transporter that plays a significant role in NH4+ acquisition and utilization in tobacco.