Exploration of potential biomarkers for prurigo nodularis based on plasma-metabolome analysis.

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.

New insight into prurigo nodularis: Proadrenomedullin N-terminal 20 peptide mediates mouse mast cell activation via Mrgprb2.

BACKGROUND: Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N-terminal 20 (PAMP) activates mast cell degranulation via Mas-related G protein-coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear. OBJECTIVE: To determine the role of PAMP-induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN. METHODS: The expression of PAMP and the number of MRGPRX2-expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9-20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT-PCR, ELISA, flow cytometry, and siRNA techniques. RESULTS: PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9-20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and ß-hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF-α, and GM-CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE-FcεRI activation. CONCLUSIONS: The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN.

RNA sequencing reveals the transcriptome profile of the atopic prurigo nodularis with severe itching.

Prurigo nodularis (PN), characterized by inevitable chronicity and severe pruritus, is most frequently associated with atopy compared with other origins. However, the skin transcriptomic profiling of PN arising from atopic dermatitis (AD), so-called atopic PN (APN), remains unclear. We sought to explore the cutaneous transcriptome of APN with severe pruritus and compare it with classic AD. RNA sequencing was performed on the lesional skin from 13 APN to 11 AD patients with severe pruritus (itch numerical rating scale score ≥ 7) and normal skin from 11 healthy subjects. Quantitative real-time polymerase chain reaction and immunochemistry were used for validation. We detected 1085 and 1984 differentially expressed genes (DEGs) in lesional APN skin and lesional AD skin versus normal skin, respectively. In total, 142 itch/inflammation-related DEGs were identified. Itch/inflammation-related DEGs, such as IL-6, IL-10, IL-13, oncostatin M, and IL-4 receptor, had elevated gene transcript levels in both diseases. The itch/inflammation-related DEGs that increased only in APN were mainly neuroactive molecules, while many inflammatory mediators such as T helper 22-related genes were found to be increased only in AD. Both disorders showed mixed Th1/Th2/Th17 polarisation and impaired skin barrier. In contrast to AD, M1/M2 macrophage activation, tumor necrosis factor production, fibrosis, revascularization and neural dysregulation are unique features of APN. The study findings broaden our understanding of the pathogenesis underlying APN, which provides insights into novel pathogenesis with potential therapeutic implications.

Finite-time synchronization for coupled neural networks with time-delay jumping coupling.

The finite-time synchronization problem is studied for coupled neural networks (CNNs) with time-delay jumping coupling. Markovian switching topologies, imprecise delay models, uncertain parameters and the unavailable of topology modes are considered in this work. A mode-dependent delay with pre-known conditional probability is built to handle the imprecise delay model problem. A hidden Markov model with uncertain parameters is introduced to describe the mode mismatch problem, and an asynchronous controller is designed. Besides, a set of Bernoulli processes models the random packet dropouts during data communication. Based on Markovian switching topologies, mode-dependent delays, uncertain probabilities and packet dropout, a sufficient condition that guarantees the CNNs reach finite-time synchronization (FTS) is derived. Finally, a numerical example is derived to demonstrate the efficiency of the proposed synchronous technique.

[µ2-N (2),N (2')-Bis(3-meth-oxy-2-oxido-benzyl-idene)benzene-1,3-dicarbo-hydrazi-dato]bis-[pyridine-copper(II)].

In the centrosymmetric dinuclear title complex, [Cu2(C24H18N4O6)(C5H5N)2], the Cu(II) ions is tetra-coordinated by two O-atoms and one N-donor of the bridging terephthalo-hydra-zonate ligand and by one pyridine N atom, resulting in a nearly square-planar N2O2 coordination geometry with the Cu(II) ion 0.044 (2) Šout of the mean plane (r.m.s. deviation of 0.0675 Å) of the coordinating atoms.

Molecular mechanisms of pruritus in prurigo nodularis.

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune network; however, the underlying mechanism remains undetermined. Itch mediators play a key role in pruritus amplification in PN and understanding their action mechanism will undoubtedly lead to the development of novel targeted antipruritic agents. In this review, we describe a series of pruritogens and receptors involved in mediating itching in PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways. Moreover, we provide a prospective outlook on potential therapies based on existing findings.

Gut microbiota and risk of five common cancers: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Previous studies have linked gut microbiota with cancer etiology, but the associations for specific gut microbiota are causal or owing to bias remain to be elucidated. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effect of gut microbiota on cancer risk. Five common cancers, including breast, endometrial, lung, ovarian, and prostate cancer as well as their subtypes (sample sizes ranging from 27,209 to 228,951) were included as the outcomes. Genetic information for gut microbiota was obtained from a genome-wide association study (GWAS) comprising 18,340 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the robust adjusted profile scores, weighted median, and MR Egger used as supplementary methods for causal inference. Sensitivity analyses including the Cochran Q test, Egger intercept test, and leave-one-out analysis were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers. RESULTS: UVMR detected a higher abundance of genus Sellimonas predicted a higher risk of estrogen receptor-positive breast cancer (OR = 1.09, 95% CI 1.05-1.14, p = 2.01 × 10-5 ), and a higher abundance of class Alphaproteobacteria was associated with a lower risk of prostate cancer (OR = 0.84, 95% CI 0.75-0.93, p = 1.11 × 10-3 ). Sensitivity analysis found little evidence of bias in the current study. MVMR further confirmed that genus Sellimonas exerted a direct effect on breast cancer, while the effect of class Alphaproteobacteria on prostate cancer was driven by the common risk factors of prostate cancer. CONCLUSION: Our study implies the involvement of gut microbiota in cancer development, which provides a novel potential target for cancer screening and prevention, and might have an implication for future functional analysis.

2-Amino-pyridinium 2-meth-oxy-carbonyl-4,6-dinitro-phenolate.

In the title mol-ecular salt, C(5)H(7)N(2) (+)·C(8)H(5)N(2)O(7) (-), the 2-amino-pyridinium cation is essentially planar, with a maximium deviation of 0.015 (1) Å, while the 2-meth-oxy-carbonyl-4,6-dinitro-phenolate anion is slightly twisted away from planarity, with a maximium deviation of 0.187 (1) Å. Deprotonation of the hy-droxy O atom was observed. The cation and anion are connected by four bifurcated N-H⋯(O,O) hydrogen bonds, forming a mol-ecular proton-transfer adduct. The dihedral angle between the pyridinium ring in the cation and the benzene ring in the anion is 3.65 (6)°. Every adduct connects to six neighboring adducts by N-H⋯O and C-H⋯O hydrogen bonds, yielding extended layers parallel to the bc plane. There is a weak π-π inter-action between the benzene rings of two neighboring anions; the inter-planar spacing and the centroid-centroid separation are 3.309 (1) and 3.69 (1) Å, respectively.

[2,2'-Dihy-droxy-N,N-(3-hy-droxy-imino-pentane-2,4-di-yl)dibenzo-hydra-zid-ato]copper(II).

The Cu(II) atom in the title complex, [Cu(C(19)H(17)N(5)O(5))], is coordinated by two N atoms and two O atoms of one 2,2'-dihy-droxy-N(2),N(2)'-(3-hy-droxy-imino-pentane-2,4-di-yl)dibenzo-hydrazidate ligand, exhibiting a distorted square-planar geometry. The dihedral angle between the two benzene rings in the oxime hydrazone is 7.62 (15)°. The molecular configuration is stabilized by intramolecular O-H⋯N hydrogen bonds. Pairs of centrosymmetrically related molecules are linked into dimers by two inter-molecular C-H⋯O hydrogen bonds. Each dimer is further connected to four neighboring dimers via four O-H⋯O hydrogen bonds, forming an extended two-dimensional structure. The oxime O atom is disordered over two orientations in a 2:1 ratio.

(Acetyl-acetonato-κO,O')aqua-[2-(2-nitro-phen-oxy)-N'-(2-oxidobenzyl-idene-κO)acetohydrazidato-κO,N']manganese(III).

In the title complex, [Mn(C(15)H(11)N(3)O(5))(C(5)H(7)O(2))(H(2)O)], the Mn(III) ion has a distorted octa-hedral coordination geometry. It is coordinated by a phen-oxy O atom, a hydrazine N atom and a carbonyl O atom of the 2-(2-nitro-phen-oxy)-N'-(2-oxidobenzyl-idene-κO)acetohydrazidate dianion, by two O atoms of the acetyl-acetonate anion and by the O atom of a coordinated water mol-ecule. In the crystal structure, complex mol-ecules are linked into centrosymmetric dimeric units through four inter-molecular O-H⋯O hydrogen bonds involving both H atoms of the coordinated water mol-ecule.