HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.

Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

Summary of Outpatient Visits for Characteristic Nursing in Traditional Chinese Medicine.

The aim of this study was to investigate the practical outcomes of traditional Chinese medicine specialty nursing clinics in the clinical setting. Outpatient services have become increasingly popular for seeking medical care. Establishing traditional Chinese medicine specialty nursing clinics can meet the medical needs of the general public, and provide patients with convenient and efficient medical services. This study employed a retrospective cross-sectional observational design to analyze the medical service status of all patients who attended the clinic since its opening. Five qualified traditional Chinese medicine nursing experts identified and implemented 5 categories of traditional Chinese medicine characteristic nursing techniques, including cupping, moxibustion, needle acupuncture, and massage. Nurses and patients evaluated the treatment outcomes for various diseases. Since the establishment of the nursing outpatient department 2 years ago, there have been over 7046 visits, with a satisfaction rate of 97.1%. Currently, 5 nursing experts are nurturing a total of 11 graduate students, conducting 5 free clinics in the nursing outpatient department, and organizing 3 visits by overseas experts. The traditional Chinese medicine specialty nursing outpatient service effectively meets the diverse medical needs of patients, alleviates the outpatient pressure on hospitals, enhances the specialized development of nurses, increases the prominence of traditional Chinese medicine specialty nursing techniques, and promotes traditional Chinese medicine culture.

Identifying the Spatial Architecture That Restricts the Proximity of CD8+ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma.

The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC.

The application of ferritin in transporting and binding diverse metal ions.

The ferritin cage can not only load iron ions in its inner cavity, but also has the capacity to carry other metal ions, thus constructing a new biological nano-transport system. The nanoparticles formed by ferritin and minerals can be used as ingredients of mineral supplements, which overcome the shortcomings of traditional mineral ingredients such as low bioavailability. Moreover, ferritin can be used to remove heavy metal ions from contaminated food. Silver and palladium nanoparticles formed by ferritin are also applied as anticancer agents. Ferritin combined with metal ions can be also used to detect harmful substances. This review aims to provide a comprehensive overview of ferritin's function in transporting and binding metal ions, and discusses the limitations and future prospects, which offers valuable insights for the application of ferritin in mineral supplements, food detoxifiers, anticancer agents, and food detections.

Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC.

Inflammasome activity is important for the immune response and is instrumental in numerous clinical conditions. Here we identify a mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that the function of ASC in assembling the inflammasome is controlled by its modification with SUMO (small ubiquitin-like modifier) and identify that the nuclear ZBTB16 (zinc-finger and BTB domain-containing protein 16) promotes this SUMOylation. The physiological significance of this activity is demonstrated through the reduction of acute inflammatory pathogenesis caused by a constitutive hyperactive inflammasome by ablating ZBTB16 in a mouse model of Muckle-Wells syndrome. Together our findings identify an further mechanism by which ZBTB16-dependent control of ASC SUMOylation assembles the inflammasome to promote this pro-inflammatory response.

Multifaceted Applications of Ferritin Nanocages in Delivering Metal Ions, Bioactive Compounds, and Enzymes: A Comprehensive Review.

Ferritin, a distinctive iron-storage protein, possesses a unique cage-like nanoscale structure that enables it to encapsulate and deliver a wide range of biomolecules. Recent advances prove that ferritin can serve as an efficient 8 nm diameter carrier for various bioinorganic nutrients, such as minerals, bioactive polyphenols, and enzymes. This review offers a comprehensive summary of ferritin's structural features from different sources and emphasizes its functions in iron supplementation, calcium delivery, single- and coencapsulation of polyphenols, and enzyme package. Additionally, the influence of innovative food processing technologies, including manothermosonication, pulsed electric field, and atmospheric cold plasma, on the structure and function of ferritin are examined. Furthermore, the limitations and prospects of ferritin in food and nutritional applications are discussed. The exploration of ferritin as a multifunctional protein with the capacity to load various biomolecules is crucial to fully harnessing its potential in food applications.

Genetic profile of Chinese patients with small bowel cancer categorized by anatomic location.

BACKGROUND: Small bowel cancer (SBC) is a very rare solid malignancy. Consequently, compared with other malignant gastrointestinal tumors, our knowledge regarding SBC, specifically its molecular attributes, remains limited. Herein, we aim to provide an overview of the gene characteristics of Chinese patients with SBC, We particularly focus on elucidating the genetic intricacies that differentiate SBC patients whose primary tumors originate in distinct anatomical regions within the small bowel. METHODS: During the period ranging from February 2018 to December 2022, a total of 298 tumor samples were consecutively collected from Chinese patients diagnosed with small bowel cancer.. Next-generation sequencing (NGS) was performed to detect gene mutation, assess microsatellite instability (MSI), and evaluate tumor mutational burden (TMB). Additionally,, IHC was used to analyze the level of PD-L1 expression within the samples. RESULTS: The outcomes of the next-generation sequencing (NGS) unveiled the predominant gene mutations observed in Chinese patients with small bowel cancer (SBC). The top ten gene mutations identified were as follows: TP53 (53%), KRAS (51%), APC (31%), SMAD4 (19%), VEGFA (15%), CDKN2A (15%), RAC1 (15%), LRP1B (14%), MGMT (14%, CD74 (13%). Subsequent analysis revealed disparities in the gene landscape between the cohort in this study and that of the Memorial Sloan Kettering Cancer Center (MSKCC), Notably, distinguishable mutational frequencies were identified in several genes, including ERBB2, FBXW7, PIK3CA, etc. which exhibited contrasting presence in both this cohort and the MSKCC cohort.. Furthermore, we noticed variations in the frequency of gene mutations among SBC patients depending on the specific anatomical site where the tumors originated within the small bowel. In addition, the distribution of patients with high microsatellite instability (MSI-H) and tumor mutational burden (TMB) levels varied among SBC patients with tumors originating from the duodenum, jejunum, and ileum. CONCLUSION: Chinese patients with small bowel cancer exhibited a distinct genetic profile in comparison to other populations, highlighting a unique genetic landscape. Furthermore, noticeable disparities in the genetic landscape were observed between patients with cancer situated in the duodenum and those with cancer affecting other regions of the small bowel, this suggests that these patients should be treated differently.

SUMOylation of the ubiquitin ligase component KEAP1 at K39 upregulates NRF2 and its target function in lung cancer cell proliferation.

Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is important for the expression of genes associated with oxidative stress. The levels of NRF2 are controlled by Kelch-like ECH-associated protein 1 (KEAP1)-dependent degradation. Although oxidative stress is known to suppress KEAP1 activity to stabilize the levels of NRF2, the mechanism for this control is unclear. Here, we identify that KEAP1 is modified by SUMO1 at the lysine residue position 39 (K39). Arginine replacement of this lysine (K39R) in KEAP1 did not affect its stability, subcellular localization, or dimerization but promoted the formation of the Cullin 3 ubiquitin ligase and increased NRF2 ubiquitination. This was accompanied by decreased NRF2 expression. Gene reporter assays showed that the transcription of antioxidant response elements was heightened in KEAP1-WT cells compared to cells expressing the KEAP1-K39R SUMO1 substrate mutant. Consistent with this, chromatin immunoprecipitation assays revealed higher NRF2 binding to the promoter regions of antioxidant genes in cells expressing the KEAP1-WT compared to the KEAP1-K39R mutant protein in H1299 lung cancer cell. The significance of this suppression of KEAP1 activity by its SUMOylation was tested in a subcutaneous tumor model of H1299 lung cancer cell lines that differentially expressed the WT and K39R KEAP1 constructs. This model showed that mutating the SUMOylation site on KEAP1 altered the production of reactive oxygen species and suppressed tumor growth. Taken together, our study recognizes that NRF2-dependent redox control is regulated by the SUMOylation of KEAP1. These findings identify a potential new therapeutic option to counteract oxidative stress.

Phytoferritin functions in two interface-loading of natural pigment betanin and caffeic acid with enhanced color stability and the sustained release of betanin.

Betanin, a natural red pigment, is sensitive and prone to fading and discoloration, affecting its stability and bioavailability. Phytoferritin is a nano-diameter protein with unique interior-/exterior-interfaces. By the unique interfaces and pH-induced self-assembly of ferritin, a ferritin-betanin complex (FB) with an encapsulation efficiency of 17.66 ± 1.24% was prepared. The caffeic acid-FB (CFB) was further fabricated by attaching ferritin with caffeic acid, and the binding number n of caffeic acid was 88.47 ± 9.49, with a binding constant K of (1.63 ± 0.33) × 104 M-1. Fluorescence and Fourier transform infrared analysis indicated that the encapsulation of betanin and the binding of caffeic acid influenced the ferritin structure. The interaction between caffeic acid and ferritin was mainly through van der Waals forces and hydrogen bonds. TEM and DLS showed that the globular structure and diameter (12 nm) remained in CFB. Furthermore, the ferritin and caffeic acid exhibited a synergistic effect in enhancing thermal, light, and ferric ion stabilities, and controlled the betanin release in a more sustained manner in the simulated gastrointestinal tract. In addition, the antioxidant capacity of CFB was enhanced compared with free betanin. This study promotes the bioavailability of betanin by two interface-loading of ferritin, and guides the use of ferritin nanoparticles as a nanocarrier for pigment stabilization.

The Hydrolysis of Pigment-Protein Phycoerythrin by Bromelain Enhances the Color Stability.

Phycoerythrin (PE) is a natural protein-pigment complex with a strong pink color, but it is sensitive to thermal and light variations. In this study, PE was extracted from Porphyra haitanensis in a yield of 0.2% (w/w). The phycoerythrin hydrolysates (PEH) (3-10 kDa) were prepared by enzymatic hydrolysis of PE with bromelain (8000 U/g) at 47 °C for 30 min, with a degree of hydrolysis (DH) of 11.57 ± 0.39% and a color degradation rate of 7.98 ± 0.39%. The physicochemical properties of PEH were evaluated. The UV and fluorescence spectra indicated that bromelain changed the microenvironment around phycoerythrobilin (PEB). The infrared spectrum revealed that the bromelain hydrolysis increased the α-helix content of PEH. The scanning electron microscope showed that bromelain destroyed the dense and smooth structure of PE, resulting in irregular porous structures. The radical scavenging activities of DPPH and ABTS of PEH were increased relative to that of PE (p < 0.05). The thermal (50-80 °C)-, UV (0.5-3 h)-, visible light irradiation (2-8 h)-, and metal ion exposing stabilities of PEH were significantly improved (p < 0.05). This study provides a potential scheme for overcoming the sensitivity of PE to thermal and light variations and facilitates PEH as a natural colorant ingredient in food and pigment applications.

Identification of calcium and integrin-binding protein 1 as a reprogrammed glucose metabolism mediator to restrict immune cell infiltration in the stromal compartment of pancreatic ductal adenocarcinoma.

An increasing body of evidence has suggested that reprogrammed metabolism plays a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC) by affecting the tumor and stromal cellular components in the tumor microenvironment (TME). By analyzing the KRAS pathway and metabolic pathways, we found that calcium and integrin-binding protein 1 (CIB1) corresponded with upregulation of glucose metabolism pathways and was associated with poor prognosis in patients with PDAC from The Cancer Genome Atlas (TCGA). Elevated CIB1 expression combined with upregulated glycolysis, oxidative phosphorylation (Oxphos), hypoxia pathway activation, and cell cycle promoted PDAC tumor growth and increased tumor cellular com-ponents. Furthermore, we confirmed the mRNA overexpression of CIB1 and co-expression of CIB1 and KRAS mutation in cell lines from the Expression Atlas. Subsequently, immunohistochemistry staining from the Human Protein Atlas (HPA) showed that high expression of CIB1 in tumor cells was associated with an increased tumor compartment and reduced stromal cellular abundance. Furthermore, using multiplexed immunohistochemistry (mIHC), we verified that low stromal abundance was correlated with low infiltration of CD8+ PD-1- T cells which led to suppressed anti-tumor immunity. Overall, our findings identify CIB1 as a metabolic pathway-mediated factor for the restriction of immune cell infiltration in the stromal compartment of PDAC and highlight the potential value of CIB1 as a prognostic biomarker involved in metabolic reprogramming and immune modulation.

A Novel and Validated 8-Pyroptosis-Related Genes Based Risk Prediction Model for Diffuse Large B Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin's Lymphoma (NHL), has a lethal nature. Thus, the establishment of a novel model to predict the prognosis of DLBCL and guide its therapy is an urgency. Meanwhile, pyroptosis is engaged in the progression of DLBCL with further investigations required to reveal the underlying mechanism. METHODS: LASSO regression was conducted to establish a risk model based on those PRGs. External datasets, RT-qPCR and IHC images from The Human Protein Alta (HPA) database were utilized to validate the model. ssGSEA was utilized to estimate the score of immune components in DLBCL. RESULTS: A model based on 8 PRGs was established to generate a risk score. Validation of the model confirmed its robust performance. The risk score was associated with advanced clinical stages and shorter overall survivals. Two novel second-line chemotherapies were found to be potential treatments for high-risk patients. The risk score was also found to be correlated with immune components in DLBCL. CONCLUSION: This novel model can be utilized in clinical practices to predict the prognosis of DLBCL and guide the treatment of patients at high risk, providing an overview of immune regulatory program via pyroptosis in DLBCL.

Phycobiliproteins, the pigment-protein complex form of natural food colorants and bioactive ingredients.

Currently, the use of synthetic pigments in foods is restricted since synthetic pigments are proven and suspected to be harmful to human health. Phycobiliproteins (PBPs), existed in phycobilisomes (PBSs) of algae, are a kind of pigment-proteins with intense color. The specific color of PBPs (red and blue) is given by the water-soluble open-chained tetrapyrrole chromophore (phycobilin) that covalently attaches to the apo-protein via thioether linkages to cysteine residues. According to the spectral characteristics of PBPs, they can be categorized as phycoerythrins (PEs), phycocyanins (PCs), allophycocyanins (APCs), and phycoerythrocyanins (PECs). PBPs can be used as natural food colorants, fluorescent substances, and bioactive ingredients in food applications owing to their color characteristics and physiological activities. This paper mainly summarizes the extraction and purification methods of the PBPs and reviews their characteristics and applications. Moreover, the use of several strategies such as additives, microencapsulation, electrospray, and cross-linking to improve the stability and bioavailability of PBPs as well as the future outlooks of PBPs as natural colorants in food commercialization are elucidated.

Preliminary Interpretations of Epigenetic Profiling of Cord Blood in Preeclampsia.

Preeclampsia (PE) is characterized by new-onset hypertension after 20 weeks of pregnancy and results in high maternal and fetal mortality worldwide. It has been reported that PE is associated with abnormalities in the umbilical cord and cord blood. However, previous studies were focused primarily on the transcriptomics level, while the underlying gene regulatory landscapes are still unclear. Thus, we performed the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) using the umbilical cord blood samples collected from a patient with superimposed PE and three healthy donors to uncover the chromatin accessibility changes attributed to PE. We have identified genes associated with immunomodulation and hypoxia response that have higher chromatin accessibility close to their transcription start sites. Motif analysis indicated that the GATA family transcription factor binding was enriched in PE and may play an essential regulatory role in the disease progression. Overall, our findings provide an overview of gene regulatory programs and the corresponding downstream pathways associated with PE that may influence the placenta function and fetal growth.

Immune Microenvironment: New Insight for Familial Adenomatous Polyposis.

Currently, the main treatment for familial adenomatous polyposis (FAP) is surgery, however, surgery is far from ideal as there are many complications such as uncontrollable bowel movements, pouch inflammation, anastomotic stricture, and secondary fibroids. Therefore, it is necessary to further expand the understanding of FAP and develop new treatments for FAP. The immune microenvironment including immune cells and cytokines, plays an important role in FAP and the progression of FAP to adenocarcinoma, thus it may be a promising treatment for FAP. In the current review, we summarized the recent progress in the immune microenvironment of FAP.

Early menarche and its relationship to paternal migrant work among middle-school-aged students in China.

Associations have been shown between father's absence and menarcheal age, but most studies have focused on absence resulting from divorce, abandonment or death. Little research has been conducted to evaluate the effect on menarcheal age of paternal absence through migrant work. In a sample of 400 middle school students, this study examined the association between paternal migrant work and menarcheal age against a backdrop of extensive rural-to-urban migration in China. Data were collected through a self-reported questionnaire, including social-demographic characteristics, aspects of family relationships, information about father's migrant work and age at menarche. After adjusting for BMI, parent marital status and perceived relationship with mother, lower self-perceived quality of father-daughter relationship (both 'father present, relationship poor' and 'father absent, relationship poor') and lower frequency of contact with the father were associated with higher odds for early menarche. These findings suggest that the assumption that father's absence for work influences the timing of menarche needs to be examined in the context of the quality of the father-daughter relationship and paternal care, which appear to play a critical role in the timing of menarche. These findings also emphasize the importance of enhancing paternal involvement and improving father-daughter relationships in the development of appropriate reproductive strategy in daughters.

A high density SLAF-seq SNP genetic map and QTL for seed size, oil and protein content in upland cotton.

BACKGROUND: Cotton is a leading natural fiber crop. Beyond its fiber, cottonseed is a valuable source of plant protein and oil. Due to the much higher value of cotton fiber, there is less consideration of cottonseed quality despite its potential value. Though some QTL controlling cottonseed quality have been identified, few of them that warrant further study are known. Identifying stable QTL controlling seed size, oil and protein content is necessary for improvement of cottonseed quality. RESULTS: In this study, a recombinant inbred line (RIL) population was developed from a cross between upland cotton cultivars/lines Yumian 1 and M11. Specific locus amplified fragment sequencing (SLAF-seq) technology was used to construct a genetic map that covered 3353.15 cM with an average distance between consecutive markers of 0.48 cM. The seed index, together with kernel size, oil and protein content were further used to identify QTL. In total, 58 QTL associated with six traits were detected, including 13 stable QTL detected in all three environments and 11 in two environments. CONCLUSION: A high resolution genetic map including 7033 SNP loci was constructed through specific locus amplified fragment sequencing technology. A total of 13 stable QTL associated with six cottonseed quality traits were detected. These stable QTL have the potential for fine mapping, identifying candidate genes, elaborating molecular mechanisms of cottonseed development, and application in cotton breeding programs.

Transition-Metal-Free Coupling Annulation of Arynes with Ketones and Alkynoates: Assembly of Functionalized Naphthalenes.

A transition-metal-free coupling annulation reaction of arynes, ketones, and alkynoates has been demonstrated. Using this formal [2 + 2 + 2] cycloaddition reaction, a wide variety of naphthalene derivatives were conveniently constructed in one pot with high efficiency. In addition, this novel and valid annulation has been successfully applied to the synthesis of 1-phenanthrenol derivatives.

Acid-Mediated N-H/α,ß-C(sp(3))-H Trifunctionalization of Pyrrolidine: Intermolecular [3 + 2] Cycloaddition for the Construction of 2,3-Dihydro-1H-Pyrrolizine Derivatives.

A one-pot acid-mediated reaction has been developed for the N-H/α,ß-C(sp(3))-H trifunctionalization of pyrrolidine without any metallic reagents or external oxidants. This reaction involves the intermolecular [3 + 2] cycloaddition of in situ-generated azomethine ylides with acrylic esters to provide facile access to 2,3-dihydro-1H-pyrrolizine derivatives in high yields under mild conditions.