Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia.

The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown. Using a Pseudomonas aeruginosa-induced pneumonia model, we reported that IL-10-producing B cells (IL-10+ B cells) play a key role in spontaneously resolving infection-mediated inflammation. Accumulated cytosolic reactive oxygen species (ROS) during inflammation were shown to drive IL-10+ B-cell generation by remodeling one-carbon metabolism. Depletion of the enzyme serine hydroxymethyltransferase 1 (Shmt1) led to inadequate one-carbon metabolism and decreased IL-10+ B-cell production. Furthermore, increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine (SAM), altering histone H3 lysine 4 methylation (H3K4me) at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells. Therefore, the one-carbon metabolism-associated compound ethacrynic acid (EA) was screened and found to potentially treat infectious pneumonia by boosting IL-10+ B-cell generation. Overall, these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.

New Insights into the TIFY Gene Family of Brassica napus and Its Involvement in the Regulation of Shoot Branching.

As plant-specific transcription factors, the TIFY family genes are involved in the responses to a series of biotic and abiotic stresses and the regulation of the development of multiple organs. To explore the potential roles of the TIFY gene family in shoot branching, which can shape plant architecture and finally determine seed yield, we conducted comprehensive genome-wide analyses of the TIFY gene family in Brassica napus. Here, HMMER search and BLASTp were used to identify the TIFY members. A total of 70 TIFY members were identified and divided into four subfamilies based on the conserved domains and motifs. These TIFY genes were distributed across 19 chromosomes. The predicted subcellular localizations revealed that most TIFY proteins were located in the nucleus. The tissue expression profile analyses indicated that TIFY genes were highly expressed in the stem, flower bud, and silique at the transcriptional level. High-proportioned activation of the dormant axillary buds on stems determined the branch numbers of rapeseed plants. Here, transcriptome analyses were conducted on axillary buds in four sequential developing stages, that is, dormant, temporarily dormant, being activated, and elongating (already activated). Surprisingly, the transcription of the majority of TIFY genes (65 of the 70) significantly decreased on the activation of buds. GO enrichment analysis and hormone treatments indicated that the transcription of TIFY family genes can be strongly induced by jasmonic acid, implying that the TIFY family genes may be involved in the regulation of jasmonic acid-mediated branch development. These results shed light on the roles of TIFY family genes in plant architecture.

NPRA promotes fatty acid metabolism and proliferation of gastric cancer cells by binding to PPARα.

Among cancers, gastric cancer (GC) ranks third globally in morbidity and mortality, particularly in East Asia. Natriuretic peptide receptor A (NPRA), a receptor for guanylate cyclase, plays important roles in regulating water and sodium balance. Recent studies have suggested that NPRA is involved in tumorigenesis, but its role in GC development remains unclear. Herein, we showed that the expression level of NPRA was positively correlated with gastric tumor size and clinical stage. Patients with high NPRA expression had a lower five-year survival rate than those with low expression, and NPRA was identified as an independent predictor of GC prognosis. NPRA knockdown suppressed GC cell proliferation, migration and invasion. NPRA overexpression enhanced cell malignant behavior. Immunohistochemistry of collected tumor samples showed that tumors with high NPRA expression had higher peroxisome proliferator-activated receptor α (PPARα) levels. In vivo and in vitro studies showed that NPRA promotes fatty acid oxidation and tumor cell metastasis. Co-IP showed that NPRA binds to PPARα and prevents PPARα degradation. PPARα upregulation under NPRA protection activates arnitine palmitoyl transferase 1B (CPT1B) to promote fatty acid oxidation. In this study, new mechanisms by which NPRA promotes the development of GC and new regulatory mechanisms of PPARα were identified.

JAC4 Alleviates Rotenone-Induced Parkinson's Disease through the Inactivation of the NLRP3 Signal Pathway.

Parkinson's disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in the substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) is a common and widely used pesticide which can directly inhibit mitochondrial complex I, leading to a loss of dopaminergic neurons. Our previous studies proved that the JWA gene (arl6ip5) may play a prominent role in resisting aging, oxidative stress and inflammation, and JWA knockout in astrocytes increases the susceptibility of mice to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. JWA-activating compound 4 (JAC4) is a small-molecule activator of the JWA gene, but its role in and mechanism against PD have not yet been clarified. In the present study, we showed that the JWA expression level is strongly related to tyrosine hydroxylase (TH) in different growth periods of mice. Additionally, we constructed models with Rot in vivo and in vitro to observe the neuroprotective effects of JAC4. Our results demonstrated that JAC4 prophylactic intervention improved motor dysfunction and dopaminergic neuron loss in mice. Mechanistically, JAC4 reduced oxidative stress damage by reversing mitochondrial complex I damage, reducing nuclear factor kappa-B (NF-κB) translocation and repressing nucleotide-binding domain, leucine-rich-containing family and pyrin domain-containing-3 (NLRP3) inflammasome activation. Overall, our results provide proof that JAC4 could serve as a novel effective agent for PD prevention.

Interleukin-35 -producing B cells rescues inflammatory bowel disease in a mouse model via STAT3 phosphorylation and intestinal microbiota modification.

Interleukin-35 (IL-35)-producing B cells (IL-35+B cells) play an important role in diseases, and the expansion of IL-35+ immune cells have been observed in inflammatory bowel disease (IBD). However, how IL-35+B cells function and the manner in which they perform their roles remain unclear. In this study, human samples and animal models were used to confirm the expansion of IL-35+B cells during IBD. In addition, by using il12a-/- and ebi3-/- mice, we demonstrated that the regulatory role of B cells in IBD depends on IL-35. Mechanically, IL-35+B cells can promote its own expansion through endocrine actions and depend on the transcription factor signal transducer and activator of transcription 3. Interestingly, we found that the diversity of intestinal microbes and expression of microbial metabolites decreased during IBD. IL-35+B cells promote the high expression of indoleacetic acid (IAA), and exogenous metabolite supplementation with IAA can further promote the expansion of IL-35+B cells and rescues the disease. This study provides a new concept for the regulatory model of B cells and a new approach for the treatment of IBD.

Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer.

Regulatory B cells (Bregs) contribute to tumor immunosuppression. However, how B cells acquire their regulatory features in tumors remain unclear. Exosomes are important messengers that transmit tumor information to remodel tumor immunity. Here we revealed that tumor-derived exosomes drive Bregs to suppress anti-tumor immunity by delivering long non-coding RNAs (lncRNAs). HOTAIR was screened by lncRNA profiling in both colorectal cancer (CRC)-derived exosomes and infiltrating B cells. Tumor-derived HOTAIR polarized B cells toward a regulatory feature marked by programmed cell death-ligand 1 (PDL1) in CRC, and induced PDL1+ B cells to suppress CD8+ T cell activity. Exosomal HOTAIR bound to and protected pyruvate kinase M2 (PKM2) against ubiquitination degradation, resulting in STAT3 activation and PDL1 expression. Results from CRC patients showed a positive correlation between exosomal HOTAIR and tumor-infiltrating PDL1+ B cells. These findings reveal how B cells acquire PDL1-dominant regulatory feature in CRC, implying the clinical significance of exosomal therapy targeting HOTAIR.

Ten-eleven translocation-2 inactivation restrains IL-10-producing regulatory B cells to enable antitumor immunity in hepatocellular carcinoma.

BACKGROUND AND AIMS: IL-10-producing regulatory B cells (IL-10 + B cells), a dominant regulatory B cell (Breg) subset, foster tumor progression. However, the mechanisms underlying their generation in HCC are poorly understood. Ten-eleven translocation-2 (TET2), a predominant epigenetic regulatory enzyme in B cells, regulates gene expression by catalyzing demethylation of 5-methylcytosine into 5-hydroxymethyl cytosine (5hmC). In this study, we investigated the role of TET2 in IL-10 + B cell generation in HCC and its prospects for clinical application. APPROACH AND RESULTS: TET2 activation in B cells triggered by oxidative stress from the HCC microenvironment promoted IL-10 expression, whereas adoptive transfer of Tet2 -deficient B cells suppressed HCC progression. The aryl hydrocarbon receptor is required for TET2 to hydroxylate Il10 . In addition, high levels of IL-10, TET2, and 5hmc in B cells indicate poor prognosis in patients with HCC. Moreover, we determined TET2 activity using 5hmc in B cells to evaluate the efficacy of anti-programmed death 1 (anti-PD-1) therapy. Notably, TET2 inhibition in B cells facilitates antitumor immunity to improve anti-PD-1 therapy for HCC. CONCLUSIONS: Our findings propose a TET2-dependent epigenetic intervention targeting IL-10 + B cell generation during HCC progression and identify the inhibition of TET2 activity as a promising combination therapy with immune checkpoint inhibitors for HCC.

Memory B cells and long-lived plasma cells in AMR.

Antibody-mediated rejection (AMR) has a strongly negative impact on long-term renal allograft survival. Currently, no recognized effective treatments are available, especially for chronic antibody-mediated rejection (CAMR). Donor-specific antibodies (DSAs) secreted by long-lived plasma cells and memory B cells are acknowledged as biomarkers of AMR. Nevertheless, it may be too late for the DSA routine examination production since DSAs may have binded to graft vascular endothelial cells through complement-dependent or complement-independent pathways. Therefore, methods to effectively monitor memory B cells and long-lived plasma cells and subsequently prevent DSA production are key to reducing the adverse effects of AMR. Therefore, this review mainly summarizes the production pathways of memory B cells and long-lived plasma cells and provides suggestions for the prevention of AMR after transplantation.

Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery.

Tumor heterogeneity limits the precision treatment of targeted drugs. It is important to find new tumor targets. JWA, also known as ADP ribosylation factor-like GTPase 6 interacting protein 5 (ARL6IP5, GenBank: AF070523, 1998), is a microtubule-associated protein and an environmental response gene. Substantial evidence shows that JWA is low expressed in a variety of malignancies and is correlated with overall survival. As a tumor suppressor, JWA inhibits tumor progression by suppressing multiple oncogenes or activating tumor suppressor genes. Low levels of JWA expression in tumors have been reported to be associated with multiple aspects of cancer progression, including angiogenesis, proliferation, apoptosis, metastasis, and chemotherapy resistance. In this review, we will discuss the structure and biological functions of JWA in tumors, examine the potential therapeutic strategies for targeting JWA and explore the directions for future investigation.

Jwa participates the maintenance of intestinal epithelial homeostasis via ERK/FBXW7-mediated NOTCH1/PPARγ/STAT5 axis and acts as a novel putative aging related gene.

The intestinal epithelium is a rapid self-renewal and regenerated tissue of which the structural integrity is beneficial for maintaining health. The integrity of intestinal epithelium depends on the balance of cell proliferation, differentiation, migration, and the function of intestinal stem cells, which declines due to genetic defect or aging. Jwa participates in multiple cellular processes; it also responds to oxidative stress and repairs DNA damage. However, whether Jwa plays a role in maintaining the homeostasis of intestinal renewal and regeneration is not clear. In the present study, we firstly described that the deletion of Jwa disturbed the homeostasis of intestinal epithelial renewal and regeneration. Jwa deficiency promoted NOTCH1 degradation in the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis. These mechanisms might partially contribute to the reduction of intestinal stem cell function and alteration of intestinal epithelial cell lineage distribution, finally suppressing the renewal and regeneration of intestinal epithelium. Moreover, our results also revealed that Jwa was a novel putative aging related gene.

JAC4 Protects from X-ray Radiation-Induced Intestinal Injury by JWA-Mediated Anti-Oxidation/Inflammation Signaling.

Radiation-induced intestinal injury is one of the major side effects in patients receiving radiation therapy. There is no specific treatment for radiation-induced enteritis in the clinic. We synthesized a compound, named JAC4, which is an agonist and can increase JWA protein expression. JWA has been shown to reduce oxidative stress, DNA damage, anti-apoptosis, and anti-inflammatory; in addition, the small intestine epithelium showed dysplasia in JWA knockout mice. We hypothesized that JAC4 might exert a protective effect against radiation-induced intestinal damage. Herein, X-ray radiation models were built both in mice and in intestinal crypt epithelial cells (IEC-6). C57BL/6J mice were treated with JAC4 by gavage before abdominal irradiation (ABI); the data showed that JAC4 significantly reduced radiation-induced intestinal mucosal damage and increased the survival rate. In addition, radiation-induced oxidative stress damage and systemic inflammatory response were also mitigated by JAC4 treatment. Moreover, JAC4 treatment alleviated DNA damage, decreased cell apoptosis, and maintained intestinal epithelial cell proliferation in mice. In vitro data showed that JAC4 treatment significantly inhibited ROS formation and cell apoptosis. Importantly, all the above protective effects of JAC4 on X-ray radiation-triggered intestinal injury were no longer determined in the intestinal epithelium of JWA knockout mice. Therefore, our results provide the first evidence that JAC4 protects the intestine from radiation-induced enteritis through JWA-mediated anti-oxidation/inflammation signaling.

Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

Immunometabolism shapes B cell fate and functions.

B lymphocyte-mediated humoral immune response is essential for protection against infectious diseases. Deeper research in B cell biology, particularly metabolism is required for the better understanding of its properties in homeostasis and in diseases. Emerging immunometabolism, including anabolism and catabolism, has tremendously impacts on immune cells from development to function and markedly advances our view on immunoregulation. Growing evidence suggests that the ultimate effect of intracellular metabolism on immune cell functions is not only influenced by the external stimuli but also by the balance of the different metabolic pathways. However, B cell immunometabolism is not deeply investigated like T cells. The complex development and differentiation processes of B cell subsets have left many untouched, but fundamental aspects in B cell metabolism. Available evidence demonstrated that the intracellular metabolism has the ubiquitous impact on B cell fate and function decisions at the transcriptional regulation and signal transduction processes. In this review, we update the recent development in the immunometabolism of B cells with the latest findings including the immune-metabolic steering on B cell development, differentiation, and function skewing, and emphasis on how immunometabolism landscape may shape B cell functions in metabolic, autoimmune, and inflammatory disorders. The metabolic interaction of B cells with other immune cells in disease context will also be discussed.

A framework for the design of a closed-loop gastric pacemaker for treating conduction block.

BACKGROUND AND OBJECTIVE: Gastrointestinal (GI) motility disorders can be significantly detrimental to the quality of life. Pacing, or long pulse gastric electrical stimulation, is a potential treatment option for treating GI motility disorders by modulating the slow wave activity. Open-loop pacing of the GI tract is the current standard for modulating dysrhythmic patterns, but it is known to be suboptimal and inefficient. Recent work on sensing intracellular potentials and pacing accordingly in a closed-loop has been shown to be effective at modulating dysrhythmic patterns. However, capturing intracellular potentials in an in-vivo setting is not viable. Therefore a closed-loop gastric electrical stimulation that can sense extracellular potentials and pace accordingly to modulate dysrhythmic patterns is required. This paper presents a closed-loop Gastric Electrical Stimulator (GES) design framework, which comprises of extracellular potential generation, sensing, and closed-loop actuation. METHODS: This work leverages a pre-existing high-fidelity two-dimensional Interstitial Cells of Cajal (ICC) network modeling framework to mimic several normal and dysrhythmic patterns observed in experimental recordings of patients suffering from GI tract diseases. The activation patterns of the of the ICC network are captured by an extracellular potential generation model and is integrated with the GES in a closed-loop to validate the efficacy of the developed pacing algorithms. The proposed GES pacing algorithms extend existing offline filtering and activation detection methods to process the sensed extracellular potentials in real time. The GES detects bradygastric rhythms based on the sensed extracellular potentials and actuates the ICC network via pacing to rectify dysrhythmic patterns. RESULTS: The proposed GES model is able to sense and process the generated noisy extracellular potentials, detect the bradygastric patterns, and modulate the slow wave activities to normal propagation effectively. CONCLUSIONS: A closed-loop GES design, which can be applied in an experimental and clinical setting is developed and validated through the ICC network model. The proposed GES model has the ability to modulate a variety of bradygastric patterns, including conduction block effectively in a closed-loop.

WBC-AMNet: Automatic classification of WBC images using deep feature fusion network based on focalized attention mechanism.

The recognition and classification of White Blood Cell (WBC) play a remarkable role in blood-related diseases (i.e., leukemia, infections) diagnosis. For the highly similar morphology of different WBC subtypes, it is too confused to classify the WBC effectively and accurately for visual observation of blood cell smears. This paper proposes a Deep Convolutional Neural Network (DCNN) with feature fusion strategies, named WBC-AMNet, for automatically classifying WBC subtypes based on focalized attention mechanism. To obtain more localized attention of CNN, the fusion features of the first and the last convolutional layer are extracted by focalized attention mechanism combining Squeeze-and-Excitation (SE) and Gather-Excite (GE) modules. The new method performs successfully in classifying monocytes, neutrophils, lymphocytes, and eosinophils on the complex background with an overall accuracy of 95.66%, better than that of general CNNs. The multi-classification accuracy of WBC-AMNet with the background segmentation is over 98% in all cases. In addition, Gradient-weighted Class Activation Mapping (Grad-CAM) is employed to visualize the attention heatmaps of different feature maps.

Study on the Types of Elderly Intelligent Health Management Technology and the Influencing Factors of Its Adoption.

[Background]: In recent years, aging has become a global social problem. Intelligent health management technology (IHMT) provides solutions for the elderly to deal with various health risks. However, the elderly are facing many difficulties in using IHMT. Studying the application types of IHMT and the influencing factors of the elderly's acceptance of it will help to improve the use behavior of the elderly. [Methods]: This paper summarizes the application types of IHMT, identifies the influencing factors of the elderly's adaption of IHMT, and makes a systematic comment on the influencing factors. [Results]: We divide the different functions of IHMT for the elderly into four types: self-monitoring, medical care, remote monitoring, and health education. The influencing factors are divided into three types: individual, social, and technology. [Conclusions]: This study finds that IHMT's application covers all aspects of the health services of the elderly. Among these applications, self-monitoring is the most used. We divided the influencing factors of the elderly's acceptance of IHMT into three categories and nine subcategories, having 25 variables.

Intestinal CD11b+ B Cells Ameliorate Colitis by Secreting Immunoglobulin A.

The intestinal mucosal immune environment requires multiple immune cells to maintain homeostasis. Although intestinal B cells are among the most important immune cells, little is known about the mechanism that they employ to regulate immune homeostasis. In this study, we found that CD11b+ B cells significantly accumulated in the gut lamina propria and Peyer's patches in dextran sulfate sodium-induced colitis mouse models and patients with ulcerative colitis. Adoptive transfer of CD11b+ B cells, but not CD11b-/- B cells, effectively ameliorated colitis and exhibited therapeutic effects. Furthermore, CD11b+ B cells were found to produce higher levels of IgA than CD11b- B cells. CD11b deficiency in B cells dampened IgA production, resulting in the loss of their ability to ameliorate colitis. Mechanistically, CD11b+ B cells expressed abundant TGF-ß and TGF-ß receptor II, as well as highly activate phosphorylated Smad2/3 signaling pathway, consequently promoting the class switch to IgA. Collectively, our findings demonstrate that CD11b+ B cells are essential intestinal suppressive immune cells and the primary source of intestinal IgA, which plays an indispensable role in maintaining intestinal homeostasis.

Gut microbiota shape B cell in health and disease settings.

Recent accumulating evidence supports the hypothesis that the intricate interaction between gut microbiota and the immune system profoundly affects health and disease in humans and mice. In this context, microbiota plays an important role in educating and shaping the host immune system which, in turn, regulates gut microbiota diversity and function to maintain homeostasis. Studies have demonstrated that intestinal microbiota participates in shaping B cells in health and disease settings. Herein, we review the recent progress in understanding how microbiota regulates B-cell development, focusing on early-life B-cell repertoire generation in GALT and how microbial products, including microbial antigens and metabolites, affect B-cell activation and differentiation to ultimately regulate B-cell function. We also discuss the interaction between gut microbiota and B cells under pathogenic conditions and highlight new approaches that can be applied to treat various diseases.