Synergistic Effects of 1-MCP Fumigation and ε-Poly-L-Lysine Treatments on Delaying Softening and Enhancing Disease Resistance of Flat Peach Fruit.

Flat peach, a predominant fruit consumed in China, is highly susceptible to softening and perishable. The impact of 1-methylcycloproene (1-MCP) fumigation combined with ε-poly-L-lysine (ε-PL) on softening and postharvest reactive oxygen species (ROS) and phenylpropanoid pathway metabolisms in peaches and its relationship to disease resistance were investigated. Findings revealed that a combination of 1 µL L-1 1-MCP and 300 mg L-1 ε-PL effectively suppressed the activity of cell-wall-degrading enzymes and the disassembly of cell wall structure, thus maintaining higher firmness and lower decay incidence. Compared to the control group, the synergistic approach bolstered enzymatic responses linked to disease resistance and ROS-scavenge system, consistently preserving total phenolics, flavonoids, ascorbic acid, and glutathione levels. Concurrently, the accumulation of hydrogen peroxide and malondialdehyde was significantly diminished post-treatment. These results show that there is good synergistic effect between 1-MCP and ε-PL, which could effectively maintain the quality of flat peach fruit by modulating cell wall metabolism and enhancing the resistance.

Spontaneous resolution of acute gout: mechanisms and therapeutic targets.

Gout is a common inflammatory arthritis that has been increasing in both prevalence and incidence. Consequently, management of refractory and chronic gout has been gaining attention. Onset of gout is related to the deposition of monosodium urate crystals under hyperuricaemia. Interestingly, acute gout attacks often resolve spontaneously within 7-10 days, and many studies have confirmed the notion that gout flares can be self-relieved. However, the underlying mechanism for spontaneous remission of gout requires further elucidation. In this article, we summarise the roles and mechanisms related to spontaneous remission of gout, which are essential for understanding its pathogenesis and developing potential targeted therapies.

Corrigendum: Role of NLRP3 inflammasome in rheumatoid arthritis.

[This corrects the article DOI: 10.3389/fimmu.2022.931690.].

Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication. METHODS: We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. RESULTS: ACLF significantly altered the plasma metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography-mass spectrometry. CONCLUSIONS: Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. CLINICAL TRIAL NUMBER: NCT02457637 and NCT03641872. IMPACT AND IMPLICATIONS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization.

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

The advance of CCN3 in fibrosis.

The extracellular matrix (ECM) is comprised of various extracellular macromolecules, including collagen, enzymes, and glycoproteins, which offer structural and biochemical support to neighboring cells. After tissue injury, extracellular matrix proteins deposit in the damaged tissue to promote tissue healing. However, an imbalance between ECM production and degradation can result in excessive deposition, leading to fibrosis and subsequent organ dysfunction. Acting as a regulatory protein within the extracellular matrix, CCN3 plays a crucial role in numerous biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Many studies have demonstrated that CCN3 can reduce the production of ECM in tissues through diverse mechanisms thereby exerting an inhibitory effect on fibrosis. Consequently, CCN3 emerges as a promising therapeutic target for ameliorating fibrosis.

Increased SEMA6B expression as a potential prognostic and immune cell infiltration biomarker in thyroid cancer patients.

BACKGROUND: Even today, thyroid cancer (THCA) remains an important threat to global health. For THCA patients, differentiated thyroid cancer is the most commonly identified pathological subtype, and those diagnosed with papillary thyroid cancer generally have good overall prognosis. For poorly differentiated subtype THCA, patients have aggressive disease course, higher risk of distant organ metastasis and inferior overall prognosis. METHODS: RNA-seq data from TCGA and GTEx databases are collected and analyzed via R. The correlation between SEMA6B expression level and pathological as well as clinical parameters of THCA patients was respectively investigated. Gene expression profiling and subsequent functional clustering analysis was the performed utilizing GSEA. The receiver operating characteristic (ROC) curve was utilized to evaluate the diagnostic value of SEMA6B expression. RESULTS: Increased SEMA6B expression was characteristic in THCA tumor samples and was associated with specific pathologic and clinical features for TCHA patients. Univariate and multivariate analysis indicated that SEMA6B was independent predictive marker for THCA patients' prognosis. Gene expression profiling and functional clustering analysis suggested that SEMA6B high-expression was related with increased expression of multiple signal pathways and signatures of multiple immune cell infiltration. CONCLUSIONS: In this study, through bioinformatic analysis and clinical data investigation, we demonstrated the potential value of SEMA6B as diagnostic and prognostic marker in THCA patient treatment.

LRBmat: A novel gut microbial interaction and individual heterogeneity inference method for colorectal cancer.

The gut microbial community has been shown to play a significant role in various diseases, including colorectal cancer (CRC), which is a major public health concern worldwide. The accurate diagnosis and etiological analysis of CRC are crucial issues. Numerous methods have utilized gut microbiota to address these challenges; however, few have considered the complex interactions and individual heterogeneity of the gut microbiota, which are important issues in genetics and intestinal microbiology, particularly in high-dimensional cases. This paper presents a novel method called Binary matrix based on Logistic Regression (LRBmat) to address these concerns. The binary matrix in LRBmat can directly mitigate or eliminate the influence of heterogeneity, while also capturing information on gut microbial interactions with any order. LRBmat is highly adaptable and can be combined with any machine learning method to enhance its capabilities. The proposed method was evaluated using real CRC data and demonstrated superior classification performance compared to state-of-the-art methods. Furthermore, the association rules extracted from the binary matrix of the real data align well with biological properties and existing literature, thereby aiding in the etiological analysis of CRC.

Prediction of coronary heart disease in gout patients using machine learning models.

Growing evidence shows that there is an increased risk of cardiovascular diseases among gout patients, especially coronary heart disease (CHD). Screening for CHD in gout patients based on simple clinical factors is still challenging. Here we aim to build a diagnostic model based on machine learning so as to avoid missed diagnoses or over exaggerated examinations as much as possible. Over 300 patient samples collected from Jiangxi Provincial People's Hospital were divided into two groups (gout and gout+CHD). The prediction of CHD in gout patients has thus been modeled as a binary classification problem. A total of eight clinical indicators were selected as features for machine learning classifiers. A combined sampling technique was used to overcome the imbalanced problem in the training dataset. Eight machine learning models were used including logistic regression, decision tree, ensemble learning models (random forest, XGBoost, LightGBM, GBDT), support vector machine (SVM) and neural networks. Our results showed that stepwise logistic regression and SVM achieved more excellent AUC values, while the random forest and XGBoost models achieved more excellent performances in terms of recall and accuracy. Furthermore, several high-risk factors were found to be effective indices in predicting CHD in gout patients, which provide insights into the clinical diagnosis.

Identification of Tregs-Related Genes with Molecular Patterns in Patients with Systemic Sclerosis Related to ILD.

BACKGROUND: Systemic Sclerosis (SSc) is an autoimmune disease that is characterized by vasculopathy, digital ulcers, Raynaud's phenomenon, renal failure, pulmonary arterial hypertension, and fibrosis. Regulatory T (Treg) cell subsets have recently been found to play crucial roles in SSc with interstitial lung disease (ILD) pathogenesis. This study investigates the molecular mechanism of Treg-related genes in SSc patients through bioinformatic analyses. METHODS: The GSE181228 dataset of SSc was used in this study. CIBERSORT was used for assessing the category and proportions of immune cells in SSc. Random forest and least absolute shrinkage and selection operator (LASSO) regression analysis were used to select the hub Treg-related genes. RESULTS: Through bioinformatic analyses, LIPN and CLEC4D were selected as hub Treg-regulated genes. The diagnostic power of the two genes separately for SSc was 0.824 and 0.826. LIPN was associated with the pathway of aminoacyl-tRNA biosynthesis, Primary immunodeficiency, DNA replication, etc. The expression of CLEC4D was associated with the pathway of Neutrophil extracellular trap formation, PPAR signaling pathway, Staphylococcus aureus infection, Systemic lupus erythematosus, TNF signaling pathway, and Toll-like receptor signaling pathway. CONCLUSION: Through bioinformatic analyses, we identified two Treg-related hub genes (LIPN, CLEC4D) that are mainly involved in the immune response and metabolism of Tregs in SSc with ILD. Moreover, our findings may provide the potential for studying the molecular mechanism of SSc with ILD.

Innovative natural antimicrobial natamycin incorporated titanium dioxide (nano-TiO2)/ poly (butylene adipate-co-terephthalate) (PBAT) /poly (lactic acid) (PLA) biodegradable active film (NTP@PLA) and application in grape preservation.

Poly (butylene adipate-co-terephthalate) (PBAT)/polylactic acid (PLA) blended with compatibilizers (polycaprolactone, PCL; poly (ethylene glycol), PEG; titanium dioxide, nano-TiO2) (TP@PLA composites) were developed by melt processing. Natamycin incorporated into TP@PLA blend composites formed NTP@PLA films, which exhibited high tensile strength (24.1-43.5 MPa) and elongation at break (85.8-258.2 %), and exhibited good oxygen permeability, water vapor permeability, surface hydrophobicity and biodegradability. The in vitro results revealed that inhibition of Penicillium expansum cell growth of the NTP@PLA films with addition of 1.0 wt% natamycin reached 95.72 %. The NTP@PLA film with natamycin effectively reduced incidence of decay (1.52 %) on grapes, maintained their quality, and inhibited the growth of pathogenic fungi to up to 0.42 log cfu·g-1. This study generates new insights into the preservation properties of antimicrobial NTP@PLA film, which endow it with great application potential as a novel and eco-friendly packaging material for the food industry.

Corrigendum: Relationship between c-reactive protein/serum albumin ratio, neutrophil/lymphocyte ratio, and ANCA-associated vasculitis activity: A retrospective single center cohort study.

[This corrects the article DOI: 10.3389/fmed.2022.855869.].

Role of NLRP3 Inflammasome in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by multi-articular, symmetrical and invasive arthritis resulting from immune system abnormalities involving T and B lymphocytes. Although significant progress has been made in the understanding of RA pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest that NLRP3 inflammasome, a regulator of inflammation, might play an important role in the development of RA. There have been increasing clinical and pre-clinical evidence showing the treatment of NLRP3/IL-1ß in inflammatory diseases. To provide a foundation for the development of therapeutic strategies, we will briefly summarize the roles of NLRP3 inflammasome in RA and explore its potential clinical treatment.

Histone deacetylase 3 facilitates TNFα-mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection.

BACKGROUND: As important enzymes regulating acetylation, histone deacetylases (HDACs) participate in a series of cell physiological process. However, the mechanisms responsible for individual HDAC family members in regulating innate immunity remained to be elucidated. Here we sought to reveal the mechanism of HDAC3 in regulating the inflammatory response of macrophages. METHODS: RNAseq was done to detect the transcriptional influence of HDAC3 on macrophages. Kyoto Encyclopedia of Genes and Genomes was used to reveal the change of signaling pathways after HDAC3 knockout. CHIPseq was done to detect the deacetylation modification of HDAC3 on chromosome. Western blot, immunofluorescence, and real-time quantitative PCR were used to measure the change of genes and proteins' levels. Mice were intratracheal instillation with lipopolysaccharide or Pseudomonas aeruginosa to determine the influence of HDAC3 on inflammatory response in vivo. RESULTS: HDAC3-deficient macrophages had increased expression of cathepsins resulting from elevated histone acetylation. Over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which reduced TNFα mediated NF-κB activation and inflammatory response. Consistently, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and thereby susceptible to Pseudomonas aeruginosa infection. CONCLUSION: HDAC3 was required for protecting RIP1 from degrading by CTSB in macrophages. Decreased RIP1 in HDAC3 knockout macrophages impaired TNFα mediated NF-κB activation. Our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.

Metabolomics Analysis of the Prefrontal Cortex in a Rat Chronic Unpredictable Mild Stress Model of Depression.

Background: Depressive disorder is the leading cause of disability and suicidality worldwide. Metabolites are considered indicators and regulators of depression. However, the pathophysiology of the prefrontal cortex (PFC) in depression remains unclear. Methods: A chronic unpredictable mild stress (CUMS) model and a maturation rodent model of depression was used to investigate metabolic changes in the PFC. Eighteen male Sprague-Dawley rats were randomly divided into CUMS and control groups. The sucrose preference test (SPT) and forced swimming test (FST) were employed to evaluate and record depression-associated behaviors and changes in body weight (BW). High-performance liquid chromatography-tandem mass spectrometry was applied to test metabolites in rat PFC. Furthermore, principal component analysis and orthogonal partial least-squares discriminant analysis were employed to identify differentially abundant metabolites. Metabolic pathways were analyzed using MetaboAnalyst. Finally, a metabolite-protein interaction network was established to illustrate the function of differential metabolites. Results: SPT and FST results confirmed successful establishment of the CUMS-induced depression-like behavior model in rats. Five metabolites, including 1-methylnicotinamide, 3-methylhistidine, acetylcholine, glycerophospho-N-palmitoyl ethanolamine, α-D-mannose 1-phosphate, were identified as potential biomarkers of depression. Four pathways changed in the CUMS group. Metabolite-protein interaction analysis revealed that 10 pathways play roles in the metabolism of depression. Conclusion: Five potential biomarkers were identified in the PFC and metabolite-protein interactions associated with metabolic pathophysiological processes were explored using the CUMS model. The results of this study will assist physicians and scientists in discovering potential diagnostic markers and novel therapeutic targets for depression.

Relationship Between C-Reactive Protein/Serum Albumin Ratio, Neutrophil/Lymphocyte Ratio, and ANCA-Associated Vasculitis Activity: A Retrospective Single Center Cohort Study.

Objectives: To evaluate the role of C-reactive protein/albumin ratio (CAR), neutrophil/lymphocyte ratio (NLR), and mean platelet volume (MPV) in newly diagnosed AAV patients and examine their clinical significance. Methods: Data from 79 untreated newly diagnosed AAV patients were collected and 76 health examination subjects were included in the healthy control group. All clinical characteristics of AAV patients were extracted from their medical records. The NLR, CAR, and MPV levels of AAV patients and the healthy controls were compared and the correlation between these markers and clinical characteristics was analyzed. Patients were then divided into two groups based on the 2003 Birmingham Vasculitis Activity Score (BVAS). The correlation between NLR, CAR, and MPV and disease activity was analyzed and their effects on the cumulative survival rate were analyzed. Results: Compared with the healthy control group, elevated CAR, NLR, and MPV were observed in AAV patients. CAR (r = 0.701, P < 0.0001) and NLR (r = 0.369, P < 0.05) were positively correlated with the BVAS while MPV did not show any significant correlation (P = 0.85). The optimal cutoff value for disease activity evaluation using CAR was 0.80 (sensitivity: 85% and specificity: 82%, P < 0.05). The optimal cutoff value for disease activity evaluation using NLR was 5.15 (sensitivity: 66% and specificity: 72%, P < 0.05). Kaplan-Meier survival analysis revealed that the all-cause mortality rate was higher in patients with CAR ≥ 0.8 than in patients with CAR < 0.8 (P < 0.05). Patients with low NLR also showed a lower cumulative survival rate (P < 0.05). Conclusions: NLR and CAR can reflect the inflammatory response and disease activity in AAV patients, while MPV is not significantly correlated with disease activity in AAV patients. The all-cause mortality rate was higher in patients with high CAR and NLR than in patients with low CAR and NLR.

Corrigendum: Glucagon-Like Peptide-1 Receptor Regulates Macrophage Migration in Monosodium Urate-Induced Peritoneal Inflammation.

[This corrects the article DOI: 10.3389/fimmu.2022.772446.].