LFQ-Based Peptide and Protein Intensity Differential Expression Analysis.

Testing for significant differences in quantities at the protein level is a common goal of many LFQ-based mass spectrometry proteomics experiments. Starting from a table of protein and/or peptide quantities from a given proteomics quantification software, many tools and R packages exist to perform the final tasks of imputation, summarization, normalization, and statistical testing. To evaluate the effects of packages and settings in their substeps on the final list of significant proteins, we studied several packages on three public data sets with known expected protein fold changes. We found that the results between packages and even across different parameters of the same package can vary significantly. In addition to usability aspects and feature/compatibility lists of different packages, this paper highlights sensitivity and specificity trade-offs that come with specific packages and settings.

Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma.

Liver cancer accounts for 6% of all malignancies causing death worldwide, and hepatocellular carcinoma (HCC) is the most common histological type. HCC is a heterogeneous cancer, but how the tumour microenvironment (TME) of HCC contributes to the progression of HCC remains unclear. In this study, we investigated the immune microenvironment by multiomics analysis. The tumour immune infiltration characteristics of HCC were determined at the genomic, epigenetic, bulk transcriptome and single-cell levels by data from The Cancer Genome Atlas portal and the Gene Expression Omnibus (GEO). An epigenetic immune-related scoring system (EIRS) was developed to stratify patients with poor prognosis. SPP1, one gene in the EIRS system, was identified as an immune-related predictor of poor survival in HCC patients. Through receptor-ligand pair analysis in single-cell RNA-seq, SPP1 was indicated to mediate the crosstalk between HCC cells and macrophages via SPP1-CD44 and SPP1-PTGER4 association. In vitro experiments further validate SPP1 can trigger the polarization of macrophages to M2-phenotype tumour-associated macrophages (TAMs).

Two-atomic-layered optoelectronic device enabled by charge separation on graphene/semiconductor interface.

The Fermi level of graphene on different substrates usually changes significantly due to the interface difference between graphene and two-dimensional semiconductors. This feature opens many possibilities of manipulating optoelectronic devices by constructing graphene heterostructures through interface modification. Herein, we report the fabrication and optoelectronic response of an unconventional heterojunction device based on a graphene-MoSe2 hybrid interface. Different from the traditional three or more layered structure where the semiconductor is sandwiched between two electrodes, this device contains only two atomic layers: the MoSe2 layer serving as the photon absorber and the graphene layer functioning as the charge acceptor and both electrodes. This structure looks like short-circuited but shows an obvious photoelectric response, which is aided by electron transfers from MoSe2 to graphene. The photocurrent generation is explored quantitatively with electronic dynamics of graphene aided with ultrafast measurements. The two-layered architecture simplifies the fabrication of atomic-thick optoelectronic devices, allowing the as-grown semiconductors to be directly used and eliminating the damage-prone transfer process.

Second-harmonic generation divergence-a method for domain size evaluation of 2D materials.

Single-atomic-layered materials are important for future electronics. They allow optoelectronic devices to be fabricated at the single-atomic layer level. A single-atomic-layered two-dimensional (2D) transition metal dichalcogenide (TMD) film is usually composed of randomly orientated single-crystalline domains, and the size distribution of the domains on a large-area film has a significant impact on the applications of the film, but the impact is difficult to characterize. We report an approach to evaluate the size of the single-crystalline domains by measuring the second-harmonic generation divergence caused by the domains of different orientations. Using this method, domain size mapping on an 8×8mm2 region of a continuous MoS2 film is achieved. This method provides a fast and efficient way of domain size characterization across a large area in a non-destructive and transfer-free manner for single-atomic-layered TMD films.

Prognostic biomarker SMARCC1 and its association with immune infiltrates in hepatocellular carcinoma.

BACKGROUND: Epigenetic alterations contribute greatly to metastasis and dissemination in hepatocellular carcinoma (HCC). SMARCC1, as a SWI/SNF chromatin remodeling factor, has been reported to play important roles in many cancers. For the first time, with the bioinformatics analysis and wet-bench experiments, we explored the biological significance of SMARCC1 and its potential as putative therapeutic target in HCC. METHODS: The mRNA expression profiles and prognostic value of SMARCC1 were analyzed in the Oncomine, UALCAN and Kaplan-Meier Plotter databases. The expression of SMARCC1 and associated clinicopathological factors were further evaluated using a tissue microarray. Differentially expressed genes associated with SMARCC1 in HCC were obtained and analyzed via the LinkedOmics and GEPIA databases and Cytoscape software. To verify the important role of SMARCC1 in HCC, we knocked down and overexpressed SMARCC1 in different hepatic cell lines and conducted several functional experiments. Then, we evaluated the mutation profiles and transcriptional regulators of SMARCC1 using the cBioPortal, COSMIC, CistromeDB and TCGA databases. Finally, we addressed the relationship of SMARCC1 expression with immune cell infiltration via TIMER database analysis. RESULTS: Through data mining and tissue microarray verification, we found that the protein and mRNA levels of SMARCC1 are high in tumor tissues, which has remarkable diagnostic value in HCC patients. SMARCC1 and its hub genes showed prognostic value in HCC. Furthermore, we confirmed that SMARCC1 influenced the proliferation, migration, and invasion of HCC cells. Moreover, correlation analyses revealed that SMARCC1 expression was positively correlated with ZBTB40 transcription factors and negatively correlated with the DNA methylation level. Overall, we found that SMARCC1 affects immune infiltration and plays a tumor-promoting role in HCC. CONCLUSIONS: SMARCC1 is overexpressed and is a putative prognostic predictor in HCC. Due to the tumor-promoting role of SMARCC1, treatments inhibiting DNA methyltransferases and transcription factors or weakening the role of SMARCC1 in immune infiltration might improve the survival of HCC patients.

Cyclin-dependent kinase 19 upregulation correlates with an unfavorable prognosis in hepatocellular carcinoma.

OBJECTIVES: Cyclin-dependent kinase 19 (CDK19) is a component of the mediator coactivator complex, which is required for transcriptional activation. In this study, we utilized public databases and wet-bench hepatic cell line experiments to elucidate the potential roles of CDK19 in hepatocellular cancer (HCC). MATERIALS AND METHODS: We studied the relationships between CDK19 expression and several clinical features related to HCC via the Oncomine and UALCAN databases. The prognostic value of CDK19 was tested using the Kaplan-Meier Plotter database. We presented the mutations of CDK19 and addressed the relation of CDK19 expression with immune cell infiltration by means of the cBioPortal, Catalogue of Somatic Mutations in Cancer (COSMIC) and Tumor IMmune Estimation Resource (TIMER) databases. Hub genes were obtained and further analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. To test the in silico findings, we knocked down CDK19 with short hairpin RNA (shRNA) technology in two hepatic cell lines and conducted several functional characterization experiments. RESULTS: Marked CDK19 upregulation was found in HCC tissues versus normal liver tissues, and CDK19 mRNA expression had high diagnostic value in HCC patients. Subgroup analysis showed that CDK19 overexpression was associated with sex, tumor stage and TP53 mutation status. The prognostic value of CDK19 upregulation for overall survival (OS) was significant in patients with stage 2-3, stage 3-4, and grade 2 disease. One percent of the patients had CDK19 mutations, but no relationship between CDK19 mutation and prognosis was observed. CDK19 was positively correlated with the abundances of CD4 + T cells, macrophages and dendritic cells. We identified 10 genes correlated with CDK19, 8 of which presented excellent prognostic value in HCC. These hub genes were directly involved in cell division and regulation of the G2/M cell cycle transition. Protein-protein interaction (PPI) and pathway predictions indicated that CDK19 is highly likely to be involved in several cellular functions, such as proliferation, migration, and invasion. These functions were strongly interfered from two independent hepatic cell lines after CDK19 knockdown. CONCLUSIONS: CDK19 could be a prognostic marker in HCC, and its therapeutic potential in HCC needs further study.

Photoluminescence of monolayer MoS2 modulated by water/O2/laser irradiation.

The low photoluminescence (PL) quantum yields of transition metal dichalcogenide monolayers have been a limiting factor for their optoelectronic applications. Various and even inconsistent mechanisms have been proposed to modulate their PL efficiencies. Herein, we use PL/Raman microspectroscopy and the corresponding in situ mapping, atomic force microscopy, and field-effect transistor (FET) characterization to investigate the changes in the structural and optical properties of monolayer MoS2. Relatively low power density (<4.08 × 105 W cm-2) of laser irradiation in ambient air can cause a slight PL suppression effect on monolayer MoS2, whereas relatively high power density (∼1.02 × 106 W cm-2) of laser irradiation brings significant PL enhancement. Experiments under different atmospheres reveal that the laser-irradiation-induced enhancement only occurs in the atmosphere containing O2 and is more remarkable in pure O2. In addition, physically adsorbed water can also induce PL enhancement of monolayer MoS2. FET devices suggest that the adsorbed water produces a p-doping effect on MoS2, and the laser irradiation in ambient air generates an n-doping effect, and both types of doping can enhance the PL intensity. The island-shaped defects caused by laser irradiation can be stabilized by oxygen atoms and act as trapping centers for excited trions or electrons, thus reducing the non-radiative recombination ratio and enhancing the PL intensity. The physically adsorbed water works in a similar way. A low power density of laser irradiation can sweep away the originally adsorbed H2O on the surface, thus reducing the PL.

miRNA miR-17-92 cluster is differentially regulated in the imiqumod-treated skin but is not required for imiqumod-induced psoriasis-like dermatitis in mice.

MicroRNAs (miRNAs) play very important roles in the control of immune cell and keratinocyte development and function and are implicated in skin inflammatory diseases, including psoriasis. miRNA miR-17-92 was reported to promote the differentiation of Th1 and Th1 cells and to regulate cell proliferation and apoptosis. Here we showed that imiquimod (IMQ) differentially regulates the expression of miR-17-92 cluster in the mouse skin, upregulating miR-17 and miR-19 families and downregulating miR-92. To investigate whether miR-17-92 cluster is functionally involved in the psoriasis, we have generated three mutant mice with specific deletion or overexpression of miR-17-92 cluster in keratinocytes, or with deletion of miR-17-92 cluster in T cells. Interestingly, deletion or overexpression of miR-17-92 cluster in keratinocytes, or deletion of miR-17-92 in T cells did not significantly affect IMQ-induced psoriasis-like dermatitis development in the mutant mice compared with wild-type littermates. Thus, miRNA miR-17-92 cluster may not be a key factor regulating imiqumod-induced psoriasis-like dermatitis.

Roles of microRNAs in psoriasis: Immunological functions and potential biomarkers.

MicroRNAs (miRNAs) are small non-coding RNA molecules, which function in RNA silencing and post-transcriptional regulation of gene expression. Psoriasis is an inflammatory skin disease characterized by the dysfunction of keratinocytes, with the immune dysregulation. We reviewed the recent studies on the roles of miRNAs in psoriasis and showed that miRNAs play key roles in psoriasis, including the regulation of hyperproliferation, cytokine and chemokine production in keratinocyte, as well as mediating immune dysfunction in psoriasis. Furthermore, miRNAs, particularly, circulating miRNAs may serve as novel biomarkers for diagnosis, monitoring therapy response and reflecting the disease severity. Thus, targeting specific miRNAs may be used to develop new therapeutic methods for psoriasis.

Application of metabolomics on diagnosis and treatment of patients with psoriasis in traditional Chinese medicine.

Traditional Chinese medicine (TCM) is one of the oldest forms of medical system. With syndrome as the core of diagnosis and therapy in TCM, it has the advantage of collecting macroscopic information of patients for diagnosis. To understand the in vivo mechanism of TCM, a metabolomics approach was used to investigate the global biological characterization of the urine of psoriasis patients with Blood Stasis Syndrome and the therapeutic metabolomics mechanism of the Optimized Yinxieling formula. A total of 41 cases of psoriasis patients with Blood Stasis Syndrome and 19 healthy volunteers were enrolled in this study. Fasting urine samples from patients with consecutive Optimized Yinxieling intake after 0, 4, 8 and 12 weeks and from healthy volunteers were analyzed by Orthogonal Projection on Latent Structures Discriminant Analysis (OPLS-DA), which was utilized for High Performance Liquid Chromatography (HPLC) analysis and temporal metabolic changes identification. For psoriasis group, the scores of PASI of patients decreased after 12 weeks of Optimized Yinxieling treating. The metabolic variations visualized not only in the healthy group and psoriasis group, but also in the psoriasis group before and after Optimized Yinxieling treatment, demonstrated that the metabolic characteristics of the two groups were significantly different. The optimized complex structure of the target proteins from Protein Data Bank was analyzed by software package Discovery Studio. With docking score of original inhibitor and the receptor as the threshold values, two compounds from Chinese medicinal chemical database were predicted to have good interactions with the target proteins. The Metabolomics technique combining molecular docking analysis enhanced our current understanding of the metabolic response to Blood Stasis Syndrome of Psoriasis and the action mechanism of Optimized Yinxieling. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.

Monitoring response to neoadjuvant therapy for breast cancer in all treatment phases using an ultrasound deep learning model.

Purpose: The aim of this study was to investigate the value of a deep learning model (DLM) based on breast tumor ultrasound image segmentation in predicting pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. Methods: The dataset contains a total of 1393 ultrasound images of 913 patients from Renmin Hospital of Wuhan University, of which 956 ultrasound images of 856 patients were used as the training set, and 437 ultrasound images of 57 patients underwent NAC were used as the test set. A U-Net-based end-to-end DLM was developed for automatically tumor segmentation and area calculation. The predictive abilities of the DLM, manual segmentation model (MSM), and two traditional ultrasound measurement methods (longest axis model [LAM] and dual-axis model [DAM]) for pathological complete response (pCR) were compared using changes in tumor size ratios to develop receiver operating characteristic curves. Results: The average intersection over union value of the DLM was 0.856. The early-stage ultrasound-predicted area under curve (AUC) values of pCR were not significantly different from those of the intermediate and late stages (p< 0.05). The AUCs for MSM, DLM, LAM and DAM were 0.840, 0.756, 0.778 and 0.796, respectively. There was no significant difference in AUC values of the predictive ability of the four models. Conclusion: Ultrasonography was predictive of pCR in the early stages of NAC. DLM have a similar predictive value to conventional ultrasound for pCR, with an add benefit in effectively improving workflow.

Comprehensive analysis of cuproptosis-related genes involved in immune infiltration and their use in the diagnosis of hepatic ischemia‒reperfusion injury: an experimental Study.

BACKGROUND: Hepatic ischemia reperfusion injury (HIRI) is a common injury not only during liver transplantation but also during major hepatic surgery. HIRI causes severe complications and affects the prognosis and survival of patients. Cuproptosis, a newly identified form of cell death, plays an important role in a variety of illnesses. However, its role in HIRI remains unknown. MATERIALS AND METHODS: The GSE151648 dataset was mined from the Gene Expression Omnibus (GEO) database, and differences were analyzed for intersections. Based on the differentially expressed genes (DEGs), functional annotation, differentially expressed cuproptosis-related genes (DE-CRGs) identification and lasso logistic regression were conducted. Correlation analysis of DE-CRGs and immune infiltration was further conducted, and DE-CRGs were applied to construct an HIRI diagnostic model. The hierarchical clustering method was used to classify the specimens of HIRI, and functional annotation was conducted to verify the accuracy of these DE-CRGs in predicting HIRI progression. The GSE14951 microarray dataset and GSE171539 single-cell sequencing dataset were chosen as validation datasets. At the same time, the significance of DE-CRGs was verified using a mouse model of HIRI with cuproptosis inhibitors and inducers. Finally, a network of transcription-factor-DE-CRGs and miRNA-DE-CRGs was constructed to reveal the regulation mechanisms. And potential drugs for DE-CRGs were predicted using Drug Gene Interaction Database (DGIdb). RESULTS: Overall, 2390 DEGs and 19 DE-CRGs were identified. Through machine learning algorithms, 8 featured DE-CRGs (GNL3, ALAS1, TSC22D2, KLF5, GTF2B, DNTTIP2, SLFN11 and HNRNPU) were screened, and 2 cuproptosis-related subclusters were defined. Based on the 8 DE-CRGs obtained from the HIRI model (AUC=0.97), the nomogram model demonstrated accuracy in predicting HIRI. Eight DE-CRGs were highly expressed in HIRI samples and were negatively related to immune cell infiltration. A higher level of immune infiltration and expression of CRG group B was found in the HIRI population. Differences in cell death and immune regulation were found between the 2 groups. The diagnostic value of the 8 DE-CRGs was confirmed in the validation of two datasets. The identification of 7 DE-CRGs (SLFN11 excluded) by HIRI animal model experiments was also confirmed. Using hTFtarget, miRWalk and DGIDB database, we predicted that 17 transcription factors, 192 miRNAs and 10 drugs might interact with the DE-CRGs. CONCLUSION: This study shows that cuproptosis may occur in HIRI and is correlated with immune infiltration. Additionally, a cuproptosis-related predictive model was constructed for studying the causes of HIRI and developing targeted treatment options for HIRI.

Predicting life span of type 2 diabetes patients through alkaline phosphatase and vitamin D: Results from NHANES 1999-2018.

BACKGROUND AND AIMS: Disparities in serum biomarker levels related to mortality persist within the US diabetic population. We conducted a study to explore the impact of alkaline phosphatase (ALP) on all-cause mortality and cardiovascular disease (CVD) mortality in type 2 diabetes patients. METHODS: We analyzed a nationally representative sample of individuals aged 20 years and above from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States between 1999 and 2018. Baseline demographic information and biochemical markers, including blood glucose, γ-glutamyltranspeptidase, vitamin D and albumin, were collected. Participants were divided into four groups based on ALP levels and linked to the National Death Index to assess mortality. Follow-up continued until December 2019, and multiple mediation analyses were performed to assess the combined impact of different indicators on ALP differences in all-cause mortality and cardiovascular mortality risk. RESULTS: Our analysis included 6481 NHANES participants, categorized as follows: 1626 (21.9%) had ALP levels below 58 U/L, 1674 in the second quartile (58-72 U/L), 1569 in the third quartile (72-88.3 U/L), and 1612 in the fourth quartile (above 88.3U/L). Significantly higher all-cause mortality and cardiovascular mortality rates were observed among participants in the 4th ALP quartile compared to other levels. The all-cause mortality rate was 38.06 per 1000 person-years (95% CI 34.89-41.51), and the cardiovascular mortality rate was 10.67 (9.06-12.57). Mediation analysis indicated that Vitamin D and albumin played a mediating role in the association between all-cause mortality, cardiovascular mortality, and ALP levels, with mediation proportions ranging from 10.33% to 27.64%. CONCLUSIONS: Our study suggests that ALP levels have clinical value in predicting all-cause and CVD mortality risk in T2DM patients. The upregulation of Vitamin D and albumin might play a significant role in improving risk prediction and enable targeted interventions for reducing mortality risk in this population.

Potential biomarkers for psoriasis topical treatment by in-depth serum proteomics.

BACKGROUND: Psoriasis is a chronic skin disease, and topical sequential therapy with a combination of calcipotriol and calcipotriol betamethasone is currently approved topical treatment. However, the exact mechanism by which this treatment regimen relieves psoriasis is unknown. METHOD: We assembled a cohort of 65 psoriasis patients and divided post-treatment cohort into responder group and non-responder group according to the Psoriasis Area Severity Index (PASI) score after 12-week treatment. We measured the expression levels of proteins in collected 130 serum samples using our in-depth proteomics platform with a data-independent acquisition mass spectrometer and antibody microarray. We performed bioinformatics analyses of the biologic processes and signaling pathways that were changed in the responder group and constructed a proteomics landscape of psoriasis pathogenesis response to treatment. We then validated the biomarkers of disease severity in an independent cohort of 88 samples using an enzyme-linked immunosorbent assay. RESULTS: We first identified 174 differentially expressed proteins (DEPs) for comparative analysis of proteins between responders and non-responders at baseline (p < 0.05). Then pathway analysis showed that the responders focused more on signaling molecules and interaction, complement and coagulation cascades, whereas the non-responders more on signal transduction and IL-17 signaling pathways. We further identified four candidate biomarkers (COLEC11, C1QA, BNC2, ITIH4) response to treatment. We also found 125 DEPs (p < 0.05) after treatment compared with before treatment in responder group. Pathway analysis showed an enrichment in pathways related to complement and coagulation cascades, phagosome, ECM-receptor interaction, cholesterol metabolism, vitamin digestion and absorption. CD14 was validated as potential biomarkers for the disease severity of psoriasis and treatment targets. CONCLUSION: In this work, we analyzed the response to topical sequential therapy and finally identified four biomarkers. Additionally, we found that topical sequential therapy may alleviate psoriasis by regulating lipid metabolism and modulating the immune response by affecting the complement activation process.

Efficacy, cardiotoxicity and factors affecting pathologic complete response of neoadjuvant chemotherapy with anthracycline-containing verses anthracycline-free regimens plus dual HER2 blockade for HER2-positive early-stage breast cancer: a retrospective study.

Background: The aim of this study was to compare the efficacy, cardiotoxicity and factors affecting pathologic complete response (pCR) of neoadjuvant chemotherapy (NACT) regimen TCbHP (docetaxel/nab-paclitaxel, carboplatin, trastuzumab and pertuzumab) and AC-THP (doxorubicin, cyclophosphamide followed by docetaxel/nab-paclitaxel, trastuzumab and pertuzumab) for human epidermal growth factor receptor 2-positive (HER2+) early-stage breast cancer at a retrospective cohort. Methods: This retrospective study included the patients with HER2+ early-stage breast cancer who received NACT with the regimen TCbHP or AC-THP and then underwent surgery from 2019 to 2022. pCR rate and breast-conserving rate were calculated to evaluate the efficacy of the regimens. Left ventricular ejection fraction (LVEF) from echocardiograms and abnormal electrocardiographs (ECGs) were collected to evaluate the cardiotoxicity of the two regimens. Association between the characteristics of the breast cancer lesions by magnetic resonance imaging (MRI) and the pCR rate were also explored. Results: A total of 159 patients were enrolled, including 48 patients in the AC-THP group and 111 patients in the TCbHP group. The pCR rate of the TCbHP group 64.0% (71/111) was significantly higher than that of for the the AC-THP group 37.5% (18/48) (P=0.002). Estrogen receptor (ER) status (P=0.011, OR: 0.437, 95% CI: 0.231-0.829), progesterone receptor (PR) status (P=0.001, OR: 0.309, 95% CI: 0.157-0.608) and IHC HER2 status (P=0.003, OR: 7.167, 95% CI: 1.970-26.076) were significantly correlated with the pCR rate. LVEF decreased at 6 and 12 months after treatment in the AC-THP group (P=0.024 and 0.040), which only decreased after 6 months of treatment in the TCbHP group (P=0.048). Post-NACT MRI characteristics including mass features (P<0.001) and enhancement type (P<0.001) were significantly associated with pCR rate. Conclusions: Early-stage HER2+ breast cancer treated with the TCbHP regimen has a higher pCR rate than the AC-THP group. The TCbHP regimen appears to have lower cardiotoxicity than the AC-THP regimen in terms of LVEF. Mass features and enhancement type at post-NACT MRI significantly associated with the pCR rate of breast cancer patients.

AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis.

The crosstalk between ferroptosis and cancer metastasis remains unclear. Here, we identify AMER1 as a key regulator of ferroptosis. AMER1 loss causes resistance to ferroptosis in colorectal cancer (CRC) cells. Interestingly, AMER1-deficient CRC cells preferentially form distant metastases, while AMER1-naive CRC cells mainly invade lymph nodes. Moreover, the ferroptosis inhibitor liproxstatin-1 effectively promotes hematogenous transfer of AMER1-naive cells. Mechanistically, AMER1 binds to SLC7A11 and ferritin light chain (FTL) and recruits ß-TrCP1/2, which degrade SLC7A11 and FTL by ubiquitination. Therefore, AMER1 deficiency increases cellular cystine levels but decreases the pool of labile free iron, thereby enhancing resistance to ferroptosis in CRC cells. Thus, AMER1 deficiency increases the survival of CRC cells in the blood under conditions of high oxidative stress and then promotes hematogenous metastasis of CRC. In conclusion, AMER1 mediates the crosstalk between ferroptosis and cancer metastasis, which provides a window of opportunity for treating metastatic colorectal cancer patients with AMER1 mutations.

Celastrol inhibits store operated calcium entry and suppresses psoriasis.

Introduction: Psoriasis is an inflammatory autoimmune skin disease that is hard to cure and prone to relapse. Currently available global immunosuppressive agents for psoriasis may cause severe side effects, thus it is crucial to identify new therapeutic reagents and druggable signaling pathways for psoriasis. Methods: To check the effects of SOCE inhibitors on psoriasis, we used animal models, biochemical approaches, together with various imaging techniques, including calcium, confocal and FRET imaging. Results and discussion: Store operated calcium (Ca2+) entry (SOCE), mediated by STIM1 and Orai1, is crucial for the function of keratinocytes and immune cells, the two major players in psoriasis. Here we showed that a natural compound celastrol is a novel SOCE inhibitor, and it ameliorated the skin lesion and reduced PASI scores in imiquimod-induced psoriasis-like mice. Celastrol dose- and time-dependently inhibited SOCE in HEK cells and HaCaT cells, a keratinocyte cell line. Mechanistically, celastrol inhibited SOCE via its actions both on STIM1 and Orai1. It inhibited Ca2+ entry through constitutively-active Orai1 mutants independent of STIM1. Rather than blocking the conformational switch and oligomerization of STIM1 during SOCE activation, celastrol diminished the transition from oligomerized STIM1 into aggregates, thus locking STIM1 in a partially active state. As a result, it abolished the functional coupling between STIM1 and Orai1, diminishing SOCE signals. Overall, our findings identified a new SOCE inhibitor celastrol that suppresses psoriasis, suggesting that SOCE pathway may serve as a new druggable target for treating psoriasis.

Corrigendum: Deep sequencing of plasma exosomal microRNA level in psoriasis vulgaris patients.

[This corrects the article DOI: 10.3389/fmed.2022.895564.].

Multi-omics approach identifies PI3 as a biomarker for disease severity and hyper-keratinization in psoriasis.

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis. OBJECTIVE: To define and compare biomarkers of disease severity and progression in psoriatic skin. METHODS: We performed proteome profiling to study the proteins circulating in the serum from patients with psoriasis, psoriatic arthritis and ankylosing spondylitis, and transcriptome sequencing to investigate the gene expression in skin from the same cohort. We then used machine learning approaches to evaluate different biomarker candidates across several independent cohorts. In order to reveal the cell-type specificity of different biomarkers, we also analyzed a single-cell dataset of skin samples. In-situ staining was applied for the validation of biomarker expression. RESULTS: We identified that the peptidase inhibitor 3 (PI3) was significantly correlated with the corresponding local skin gene expression, and was associated with disease severity. We applied machine learning methods to confirm that PI3 was an effective psoriasis classifier, Finally, we validated PI3 as psoriasis biomarker using in-situ staining and public datasets. Single-cell data and in-situ staining indicated that PI3 was specifically highly expressed in keratinocytes from psoriatic lesions. CONCLUSION: Our results suggest that PI3 may be a psoriasis-specific biomarker for disease severity and hyper-keratinization.

Synthetic Antibacterial Quaternary Phosphorus Salts Promote Methicillin-Resistant Staphylococcus aureus-Infected Wound Healing.

Background: Drug-resistant microbes pose a global health concern, requiring the urgent development of effective antibacterial agents and strategies in clinical practice. Therefore, there is an urgent need to explore novel antibacterial materials to effectively eliminate bacteria. The synthesis of quaternary phosphonium salt in haloargentate systems, wherein the phosphorus atom is represented in a cationic form, is a possible strategy for the development of antibacterial materials. Methods: Using (triphenyl)phosphonium-based quaternary phosphorus salts with different spacer lengths (n=2, 4, 6) as a template, we designed three kinds of quaternary phosphorus salts as effective antibacterial agents against drug-resistant bacteria. Results: The synthesized quaternary phosphorus salt of (1,4-DBTPP)Br2 effectively prevented the formation of the bacterial biofilms, and degraded bacterial membranes and cell walls by promoting the production of reactive oxygen species, which exhibited effective therapeutic effects in a rat model of a superficial wound infected with methicillin-resistant Staphylococcus aureus. Conclusion: The quaternary phosphorus salt (1,4-DBTPP)Br2 demonstrated hemocompatibility and low toxicity, revealing its potential in the treatment of clinical infections.