Modulation of YBX1-mediated PANoptosis inhibition by PPM1B and USP10 confers chemoresistance to oxaliplatin in gastric cancer.

Gastric cancer (GC) is a common malignant tumor of the digestive tract, and chemoresistance significantly impacts GC patients' prognosis. PANoptosis has been associated with oxaliplatin-induced cell death. However, the direct regulatory role of YBX1 in cellular chemoresistance through PANoptosis remains unclear. In this study, we investigated the impact of YBX1 on regulating PANoptosis and its influence on the resistance of gastric cancer cells to oxaliplatin. Through overexpression and silencing experiments, we assessed YBX1's effect on proliferation and PANoptosis regulation in gastric cancer cells. Additionally, we identified PPM1B and USP10 as interacting proteins with YBX1 and confirmed their influence on YBX1 molecular function and protein expression levels. Our results demonstrate that YBX1 suppresses PANoptosis, leading to enhanced resistance of gastric cancer cells to oxaliplatin. Furthermore, we found that PPM1B and USP10 play critical roles in regulating YBX1-mediated PANoptosis inhibition. PPM1B directly interacts with YBX1, causing dephosphorylation of YBX1 at serine 314 residue. This dephosphorylation process affects the deubiquitination of YBX1 mediated by USP10, resulting in decreased YBX1 protein expression levels and impacting PANoptosis and oxaliplatin resistance in gastric cancer cells. Additionally, we discovered that the 314th amino acid of YBX1 has a profound impact on its own protein expression abundance, thereby affecting the functionality of YBX1. In conclusion, our study reveals the significance of PPM1B-mediated dephosphorylation of YBX1 and USP10-mediated deubiquitination in regulating PANoptosis and sensitivity to oxaliplatin in gastric cancer cells. These findings offer a potential therapeutic strategy for patients with oxaliplatin-resistant gastric cancer.

The efficacy of mindfulness-based interventions on mental health among university students: a systematic review and meta-analysis.

Introduction: We aimed to estimate the effect of mindfulness therapy on mental health. Methods: Two researchers searched 12 databases to identify relevant trials that were published from 1 January 2018 to 1 May 2023. We performed a meta-analysis to determine the effect of mindfulness therapy on depression, which was measured by the Beck Depression Inventory (BDI), Patient Health Questionnaire-9 (PHQ-9), Quick Inventory of Depressive Symptomatology (QIDS), Hamilton Depression Rating Scale (HDRS), Patient-Reported Outcomes Measurement Information System (PROMIS), Hospital Anxiety and Depression Scale (HADS), and Depression Anxiety Stress Scales (DASS); anxiety, which was measured by the Beck Anxiety Inventory (BAI), PROMIS, and DASS, Generalized Anxiety Disorder-7 (GAD-7); stress, which was measured by the Perceived Stress Scale (PSS), DASS, and GAD-7; mindfulness, which was measured by the GAD-7, Five Facet Mindfulness Questionnaire (FFMQ), Mindful Attention Awareness Scale (MAAS), Short Form-12 Mental Component Score (SF-12 MCS) and Short Form-12 Physical Component Score (SF-12 PCS); and sleep quality, which was measured by the Pittsburgh Sleep Quality Index (PSQI). After screening studies based on the inclusion and exclusion criteria, 11 randomized controlled trials (RCTs) involving 1,824 participants were ultimately included. Results: All these studies demonstrated positive effects of mindfulness therapy on depression (SMD = -0.33, 95% CI: [-0.44, -0.22], p < 0.00001, I2 = 29%), anxiety (SMD = -0.35, 95% CI: [-0.46, -0.25], p < 0.00001, I2 = 40%), stress (SMD = -0.39, 95% CI: [-0.48, -0.29], p < 0.00001, I2 = 69%) and sleep quality scores (SMD = -0.81, 95% CI: [-1.54, -0.09], p = 0.03, I2 = 0%). However, there was no significant difference in mindfulness (SMD = -0.12, 95% CI: [-0.36, -0.12], p = 0.34, I2 = 34%) between the mindfulness therapy group and the control group. Discussion: In future studies, it is necessary to consider the investigation on whether the strategies of improving the mindfulness therapy in adherence and fidelity can work on the improvement of the outcomes in mental health. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42023469301].

High-efficiency cleaning technology and lifespan prediction for the ceramic membrane treating secondary treated effluent.

Chemical cleaning is one of the key technical means to control membrane fouling, restore membrane flux and ensure the stable operation of membrane systems. In the experiment, the six most representative chemical cleaning agents for ceramic membranes, such as sulfuric acid (H2SO4), sodium hydroxide (NaOH), sodium hypochlorite (NaClO), ethylenediaminetetraacetic acid disodium salt (EDTA-Na2), sodium dodecyl sulfate (SDS) and nonylphenol polyoxyethylene ether (OP-10), were used as research objects. The cleaning effect of the two-step combined cleaning of chemical cleaning agents on the fouled membrane was systematically investigated. Results showed that the order of the chemical cleaning agent had a significant effect on the cleaning effect. The best chemical cleaning program was determined to be NaClO first and then SDS: the fouled ceramic membrane was soaked in NaClO solution at 0.15% for 2.5 h and further soaked in SDS solution at five times its own critical micelle concentration for 2.5 h. The predicted long-term lifespan of the ceramic membranes was 4.91 years. Scanning electron microscopy-energy spectrum analysis showed that the surface roughness of the cleaned ceramic membrane was slightly higher than that of the new membrane. The contact angle was slightly lower than that of the new membrane.

Deciphering transcriptome alterations in bone marrow hematopoiesis at single-cell resolution in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder, in which megakaryocyte dysfunction caused by an autoimmune reaction can lead to thrombocytopenia, although the underlying mechanisms remain unclear. Here, we performed single-cell transcriptome profiling of bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) to determine defects in megakaryopoiesis in ITP. Gene expression, cell-cell interactions, and transcriptional regulatory networks varied in HSPCs of ITP, particularly in immune cell progenitors. Differentially expressed gene (DEG) analysis indicated that there was an impaired megakaryopoiesis of ITP. Flow cytometry confirmed that the number of CD9+ and HES1+ cells from Lin-CD34+CD45RA- HSPCs decreased in ITP. Liquid culture assays demonstrated that CD9+Lin-CD34+CD45RA- HSPCs tended to differentiate into megakaryocytes; however, this tendency was not observed in ITP patients and more erythrocytes were produced. The percentage of megakaryocytes differentiated from CD9+Lin-CD34+CD45RA- HSPCs was 3-fold higher than that of the CD9- counterparts from healthy controls (HCs), whereas, in ITP patients, the percentage decreased to only 1/4th of that in the HCs and was comparable to that from the CD9- HSPCs. Additionally, when co-cultured with pre-B cells from ITP patients, the differentiation of CD9+Lin-CD34+CD45RA- HSPCs toward the megakaryopoietic lineage was impaired. Further analysis revealed that megakaryocytic progenitors (MkP) can be divided into seven subclusters with different gene expression patterns and functions. The ITP-associated DEGs were MkP subtype-specific, with most DEGs concentrated in the subcluster possessing dual functions of immunomodulation and platelet generation. This study comprehensively dissects defective hematopoiesis and provides novel insights regarding the pathogenesis of ITP.

Proteasome Inhibition with Bortezomib Induces Apoptosis of Long-Lived Plasma Cells in Steroid-Resistant or Relapsed Immune Thrombocytopaenia.

Primary immune thrombocytopaenia (ITP) is the most common haemorrhagic disease. Although most patients respond initially to mainstream therapies, such as corticosteroids, immunosuppressants or rituximab, a large proportion of patients fail to respond or relapse. These treatments only affect B lymphocytes or short-lived plasma cells, but not already existing long-lived plasma cells (LLPCs) which persistently secrete antibodies. We hypothesized that LLPCs may play a role in the corticosteroid-resistant or relapsed ITP patients, and bortezomib, a proteasome inhibitor, may act on plasma cells and offer a therapeutic effect. Although a significant difference in the proportion of CD19-CD38hiCD138+ total LLPCs was not observed by flow cytometry, a glycoprotein (GP) IIb/IIIa-specific enzyme-linked immunosorbent spot (ELISpot) assay of sorted CD19-CD138+ LLPCs confirmed the existence of anti-platelet antibody-secreting LLPCs in ITP patients in contrast to healthy controls. Moreover, the LLPCs could be eliminated in the presence of bortezomib by ELISpot assay, which was also confirmed by flow cytometry. Accordingly, a modified monoclonal antibody immobilization of platelet antigen assay of sorted CD19-CD138+ LLPCs revealed that the concentration of anti-platelet antibodies decreased remarkably when cultured with 0.25 ng/mL bortezomib for 5 days. The apoptosis assay demonstrated that bortezomib could induce apoptosis of LLPCs in a concentration-dependent manner. The proteasome activity assay showed that bortezomib significantly reduced the proteasome activity in sorted CD19-CD138+ LLPCs. Furthermore, in active ITP murine models, bortezomib eliminated LLPCs in vivo and alleviated thrombocytopaenia. We conclude that LLPCs participate in the pathogenesis of ITP and bortezomib may have potential as a novel therapeutic regimen.

Progranulin facilitates the increase of platelet count in immune thrombocytopenia.

INTRODUCTION: Progranulin (PGRN) is emerging as a critical immune mediator involved in a variety of autoimmune disorders. However, its role in immune thrombocytopenia (ITP) remains unclear. MATERIALS AND METHODS: In this study, the enzyme-linked immunosorbent assay was used for determining the plasma levels of PGRN in ITP patients vs. healthy controls. In addition, the role of PGRN in ITP was investigated in two kinds of ITP murine models. Further, we explored whether PGRN functioned by affecting the number of T regulatory cells (Tregs) using flow cytometry. RESULTS: We first observed that plasma levels of PGRN were significantly elevated in ITP patients (n = 52) compared to healthy controls (n = 40), and the levels of PGRN declined in patients after receiving treatment. Additionally, we found a negative correlation between plasma PGRN levels and platelet count of ITP patients, suggesting that PGRN is involved in the pathogenesis of ITP. PGRN deficiency further decreased platelet count in a passive-transfer ITP murine model. By contrast, administration of recombinant PGRN increased platelet count in SCID mice with chronic ITP. Meanwhile, PGRN deficiency impaired proliferation of Tregs in the passive transfer ITP murine model. These data suggest that PGRN may exert a protective role in ITP by promoting Treg proliferation. CONCLUSION: Our study revealed a new regulator involved in the pathogenesis of ITP and provided a potential strategy for management of ITP.