Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4(+) T Cells.

Distinct metabolic programs support the differentiation of CD4(+) T cells into separate functional subsets. In this study, we investigated metabolic mechanisms underlying the differentiation of IL-9-producing CD4(+) T cells (Th9) in allergic airway inflammation and cancerous tumors. We found that histone deacetylase SIRT1 negatively regulated Th9 cell differentiation. A deficiency of SIRT1 induced by either conditional deletion in mouse CD4(+) T cells or the use of small interfering RNA (siRNA) in mouse or human T cells increased IL-9 production, whereas ectopic SIRT1 expression inhibited it. Notably, SIRT1 inhibited Th9 cell differentiation that regulated anti-tumor immunity and allergic pulmonary inflammation. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF1α) was required for the differentiation of Th9 cells that conferred protection against tumors and is involved in allergic airway inflammation. Our results define the essential features of SIRT1-mTOR-HIF1α signaling-coupled glycolytic pathway in inducing Th9 cell differentiation, with implications for metabolic reprogramming as an immunotherapeutic approach.

Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.

The mechanism of the development of granulocyte progenitor cells into neutrophils under steady-state and pathological conditions remains unclear. In this study, our results showed that with the development of neutrophils from hematopoietic stem cells to mature neutrophils, the expression level of the Hippo kinase MST1 gradually increased. Mst1-specific deficiency in myeloid cells caused neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte-macrophage progenitors under steady-state conditions and during Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling are required for regulating the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation, which is crucial for Mst1-/--induced proliferation of granulocyte-monocyte progenitors, lineage-decision factor C/EBPα expression, and granulopoiesis. HIF1α directly regulated C/EBPα promoter activities. Blocking mTOR and HIF1α or adjusting the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation reversed the granulopoiesis induced by Mst1-/- under steady-state conditions or infection in mice. Thus, our findings identify a previously unrecognized interplay between Hippo kinase MST1 signaling and mTOR-HIF1α metabolic reprogramming in granulocyte progenitor cells that underlies granulopoiesis.

Regulation of neutrophil extracellular traps in cancer.

Neutrophil extracellular trap (NET) is one of the defense functions of neutrophils, which has a rapid ability to kill infections and is also crucial in a variety of immune-associated diseases including infections, tumors and autoimmune diseases. Recent studies have shown that NETs are closely related to the development of tumors. The regulatory role of NETs in tumors has been of interest to researchers. In addition to awakening latent tumor cells, NETs can also promote the proliferation and development of tumor cells and their metastasis to other sites. At the same time, NETs also have the effect of inhibiting tumors. At present, there are some new advances in the impact of NETs on tumor development, which will provide a more theoretical basis for developing NET-targeted drugs. Therefore, this review just summarized the formation process of NETs, the regulation of tumor development and the treatment methods based on NETs.

Protein Tyrosine Phosphatase PTPRO Signaling Couples Metabolic States to Control the Development of Granulocyte Progenitor Cells.

Protein tyrosine phosphatase (PTPase) is critically involved in the regulation of hematopoietic stem cell development and differentiation. Roles of novel isolated receptor PTPase PTPRO from bone marrow hematopoietic stem cells in granulopoiesis have not been investigated. PTPRO expression is correlated with granulocytic differentiation, and Ptpro -/- mice developed neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors under steady-state and potentiated innate immune responses against Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling engaged glucose metabolism and initiated a transcriptional program involving the lineage decision factor C/EBPα, which is critically required for the PTPRO deficiency-directed granulopoiesis. Genetic ablation of mTOR or HIF1α or perturbation of glucose metabolism suppresses progenitor expansion, neutrophilia, and higher glycolytic activities by Ptpro -/- In addition, Ptpro -/- upregulated HIF1α regulates the lineage decision factor C/EBPα promoter activities. Thus, our findings identify a previously unrecognized interplay between receptor PTPase PTPRO signaling and mTOR-HIF1α metabolic reprogramming in progenitor cells of granulocytes that underlies granulopoiesis.

The immediate effect of cervical rotation-traction manipulation on cervical paravertebral soft tissue: a study using soft tissue tension cloud chart technology.

BACKGROUND: To evaluate the reliability of the Soft Tissue Tension Cloud Chart (STTCC) technology, an original method combining multi-point Cervical Paravertebral Soft Tissue Test (CPSTT) with MATLAB software, we conducted a preliminary analysis on the immediate effects of Orthopaedic Manual Therapy (OMT) on cervical paravertebral soft tissue. METHODS: 30 patients with Cervical Spondylotic Radiculopathy (CSR) were included in this study. We analyzed the differences in CPSTT before and after treatment with Cervical Rotation-Traction Manipulation (CRTM), a representative OMT technique in Traditional Chinese Medicine, using the STTCC technology. RESULTS: The STTCC results demonstrated that post-treatment CPSTT levels in CSR patients were significantly lower than pre-treatment levels after application of CRTM, with a statistically significant difference (P < 0.001). Additionally, pre-treatment CPSTT levels on the symptomatic side (with radicular pain or numbness) were higher across the C5 to C7 vertebrae compared to the asymptomatic side (without symptoms) (P < 0.001). However, this difference disappeared after CRTM treatment (P = 0.231). CONCLUSIONS: The STTCC technology represents a reliable method for analyzing the immediate effects of OMT. CSR patients display uneven distribution of CPSTT characterized by higher tension on the symptomatic side. CRTM not only reduces overall cervical soft tissue tension in CSR patients, but can also balance the asymmetrical tension between the symptomatic and asymptomatic sides. TRIAL REGISTRATION: This study was approved by the Chinese Clinical Trials Registry (Website: . https://www.chictr.org.cn .) on 20/04/2021 and the Registration Number is ChiCTR2100045648.

New insights into follicular regulatory T cells in the intestinal and tumor microenvironments.

Follicular regulatory T (Tfr) cells are a novel and unique subset of effector regulatory T (Treg) cells that are located in germinal centers (GCs). Tfr cells express transcription profiles that are characteristic of both follicular helper T (Tfh) cells and Treg cells and negatively regulate GC reactions, including Tfh cell activation and cytokine production, class switch recombination and B cell activation. Evidence also shows that Tfr cells have specific characteristics in different local immune microenvironments. This review focuses on the regulation of Tfr cell differentiation and function in unique local immune microenvironments, including the intestine and tumor.

CD8+ T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy.

CD8+ T cells play a crucial role in anti-tumour immunity, but they often undergo exhaustion, which affects the anti-tumour activity of CD8+ T cells. The effect and mechanism of exhausted CD8+ T cells have become the focus of anti-tumour immunity research. Recently, a large number of studies have confirmed that long-term antigen exposure can induce exhaustion. Cytokines previously have identified their effects (such as IL-2 and IL-10) may play a dual role in the exhaustion process of CD8+ T cells, suggesting a new mechanism of inducing exhaustion. This review just focuses our current understanding of the biology of exhausted CD8+ T cells, including differentiation pathways, cellular characteristics and signalling pathways involved in inducing exhaustion, and summarizes how these can be applied to tumour immunotherapy.

The hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells.

Follicular helper T (TFH ) cells are essential for inducing germinal centre (GC) reactions to mediate humoral adaptive immunity and antiviral effects, but the mechanisms of TFH cell differentiation remain unclear. Here, we found that the hippo kinase MST1 is critical for TFH cell differentiation, GC formation, and antibody production under steady-state conditions and viral infection. MST1 deficiency intrinsically enhanced TFH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signalling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed TFH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for TFH cell differentiation induced by Mst1-/- . Thus, our findings identify a previously unrecognized relationship between hippo kinase MST1 signalling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signalling in reprogramming TFH cell differentiation.

Regulation of follicular T helper cell differentiation in antitumor immunity.

Follicular T helper (Tfh) cells are a subset of CD4+ T cells that play an important role in the formation of germinal centers and the maturation and differentiation of affinity-matured B cells. Recent studies have demonstrated important functions of Tfh cells in tertiary lymphoid structures of tumors, revealing great potential of Tfh cells in tumor immunity. However, Tfh development is incompletely understood. The differentiation of Tfh cells is a complex, multistage process regulated at the DNA, RNA and protein levels. This review just summarizes current research on the molecular mechanisms of Tfh cell differentiation to better understand the role of Tfh cells in antitumor immunity.

Deacetylase sirtuin 2 negatively regulates myeloid-derived suppressor cell functions in allograft rejection.

Although myeloid-derived suppressor cells (MDSCs) are critical for allograft survival, their regulatory mechanism remains unclear. Herein, our results showed that metabolism sensor sirtuin 2 (SIRT2) negatively regulates the functions of MDSCs in inducing allogeneic skin graft rejection. Genetic deletion of SIRT2 in myeloid cells (Sirt2Δmye) increased the number of CD11b+Gr1+ MDSCs in bone marrow, spleens, draining lymph nodes, and allografts, inhibited the production of proinflammatory cytokine tumor necrosis factor ɑ, enhanced the production of anti-inflammatory cytokine interleukin 10, and potentiated the suppressive activation of MDSCs in prolonging allograft skin survival. C-X-C motif chemokine receptor 2 is critical for mediating the recruitment and cytokine production of MDSCs induced by SIRT2. Mechanistically, Sirt2Δmye enhanced NAD+ levels, succinate dehydrogenase subunit A (SDHA) activities, and oxidative phosphorylation (OXPHOS) levels in MDSCs after transplantation. Pharmacologically blocking nicotinamide phosphoribosyltransferase effectively reverses the production of cytokines and suppressive activities of MDSC induced by Sirt2Δmye. Blocking OXPHOS with knockdown of SDHA or pharmacological blocking of SDHA significantly restores Sirt2Δmye-mediated stronger MDSC suppressive activity and inflammatory factor productions. Thus, our findings identify a previously unrecognized interplay between NAD+ and SDH-mediated OXPHOS metabolic pathways in regulating MDSC functions induced by the metabolic sensor SIRT2 in allogeneic transplantation.

Biosorption of lead ion by lactic acid bacteria and the application in wastewater.

Through the study of biosorption of Pb2+ by lactic acid bacteria, two strains called CN-011 and CN-005 with high tolerance and great adsorption to lead were screened. The minimum bactericidal concentration of lead ions for both CN-011 and CN-005 was 1.45 mmol/L. The optimal culture conditions for the removal of 30 mg/L lead ions were achieved by culturing lactic acid bacteria at an initial pH of 7.0, 37 °C and 120 rpm for 48 h. The adsorption rate of CN-011 and CN-005 for Pb2+ were 85.95% and 86.78%, respectively. In simulated wastewater samples, the average adsorption rate of Pb2+ was 73.38% for CN-011 and 74.15% for CN-005. The mechanism of biosorption was characterized by Fourier Transform infrared spectroscopy, Scanning Electron Microscope-Energy Dispersive Spectrometer, X-ray Photoelectron Spectroscopy, which revealed that Pb2+ mainly reacted with hydroxyl ions in peptidoglycan or polysaccharide, and carboxylate radical in teichoic acid or protein on the surface of lactic acid bacteria cell wall. The deposits produced on the bacterial surface were identified as lead oxide and lead nitrate.

Mechanisms of Neutrophil Extracellular Trap Formation and Regulation in Cancers.

As one of the most important components of the innate immune system, neutrophils are always at the forefront of the response to diseases. The immune functions of neutrophils include phagocytosis, degranulation, production of reactive oxygen species, and the production of neutrophil extracellular traps (NETs). NETs are composed of deconcentrated chromatin DNA, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), playing an important role in the resistance to some pathogenic microbial invasions. Until recent years, when NETs were found to play a critical role in cancer. NETs play bidirectional regulation both positive and negative roles in the development and progression of cancer. Targeted NETs may provide new therapeutic strategies for the treatment of cancer. However, the molecular and cellular regulatory mechanisms underlying the formation and role of NET in cancer remain unclear. This review just summarizes the recent progress in regulatory mechanisms about the formation of NETs and their role in cancers.

Study on the mechanical parameters of neuromuscular joint facilitation rehabilitation techniques for lumbar intervention.

[Purpose] To measure the reliability of and quantify the force on the spinous process during lumbar neuromuscular joint facilitation using mechanical measuring gloves. [Participants and Methods] We recruited 12 healthy participants. The operator wore a mechanical measuring glove and performed evaluations in the four modes of neuromuscular joint facilitation of the lumbar spine. The mechanical glove was used to measure the force applied by the fingers on the spinous process during the intervention. [Results] The reliability of measuring the supraspinous force during lumbar neuromuscular joint facilitation with mechanical gloves was found to be good; the force was 30.9 ± 6.6 N for front lifting, 37.1 ± 9.1 N for rear descent, 36.8 ± 9.0 N for forward descent, and 24.6 ± 4.7 N for rear lifting. Overall, the average force was 32.3 ± 9.0 N. No statistical difference was observed between passive and resistance motion. [Conclusion] This study confirmed that the measurement of the force on the spinous process in lumbar neuromuscular joint facilitation using mechanical measurement gloves has good reliability. Furthermore, we determined the average force exerted on the spinous process during lumbar neuromuscular joint facilitation and quantified the operation specifications of this manipulation were.

N6 -methyladenosine RNA methylation: A novel regulator of the development and function of immune cells.

N6 -methyladenosine (m6 A) RNA methylation is a reversible posttranscriptional modification in eukaryotes involving three types of functional proteins: "writers", "erasers", and "readers". m6 A regulates the metabolism of messenger RNAs and noncoding RNAs through RNA structure, splicing, stability, export, and translation, thereby participating in various physiological and pathological processes. Here, we summarize the current state of m6 A methylation researches, focusing on how these modifications modulate the fate decisions of innate and adaptive immune cells and regulate immune responses in immune-associated diseases, including viral infections and cancer. These studies showed that m6 A modifications and m6 A modifying proteins play a critical role in pathogen recognition, immune cell activation, immune cell fate decisions, and immune reactions. m6 A is a novel regulator of immune system homeostasis and activation.

Selenium metabolism and regulation of immune cells in immune-associated diseases.

Selenium, as one of the essential microelements, plays an irreplaceable role in metabolism regulation and cell survival. Selenium metabolism and regulation have great effects on physiological systems especially the immune system. Therefore, selenium is tightly related to various diseases like cancer. Although recent research works have revealed much about selenium metabolism, the ways in which selenium regulates immune cells' functions and immune-associated diseases still remain much unclear. In this review, we will briefly introduce the regulatory role of selenium metabolism in immune cells and immune-associated diseases.

Modulation of tumor-associated macrophages in colitis-associated colorectal cancer.

Intestinal macrophages are the most abundant immune cells in the small and large intestine, which maintain intestinal homeostasis by clearing invading bacteria and dead cells, secreting anti-inflammatory cytokines, and inducing tolerance to symbiotic bacteria and food particles. In addition, as antigen-presenting cells, they also participate in eliciting adaptive immune responses through bridging innate immune responses. After the intestinal homeostasis is disrupted, the damaged or apoptotic intestinal epithelial cells cannot be effectively cleared, and the infection of exogenous pathogens and leakage of endogenous antigens lead to persistent intestinal inflammation. Long-term chronic inflammation is one of the important causes of colitis-associated carcinogenesis (CAC). Tumor microenvironment (TME) is gradually formed around tumor cells, in which tumor associated macrophage (TAMs) is not only the builder, but also regulated by TME. This review just briefly summarized the role of intestinal macrophages under physiological and pathological inflammatory and cancerous conditions, and current therapeutic strategies for intestinal diseases targeting macrophages.

The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.

Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-ß mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.

Isolation and characterization of antioxidative monoterpenes from Cynanchum atratum roots.

One novel monoterpene rhamnoside (1) and 7 known monoterpenes (2-8) were isolated from the ethanol extract of Cynanchum atratum for the first time. Their structures were identified by comprehensive spectroscopic data analysis such as nuclear magnetic resonance, high-resolution electrospray ionization mass spectra, optical rotatory dispersion, and acid hydrolysis. In the subsequent antioxidant assay, compound 8 exhibited obvious 2,2-diphenyl-2-picrylhydrazyl hydrate radical scavenging activity.

A Novel Nomogram for Predicting Poor 6-Month Function in Patients With Acute Ischemic Stroke Receiving Thrombolysis.

BACKGROUND: Patients with acute ischemic stroke (AIS) receiving thrombolysis with good function at discharge are usually ignored. Their functional deterioration after discharge not only compromises the effectiveness of thrombolytic therapy but also reduces their long-term quality of life, which is not conducive to the advancement of medical healthcare and continuing care. OBJECTIVE: The aims of this study were to explore the risk factors for poor 6-month function in patients with AIS receiving thrombolysis with good function at discharge and construct a novel nomogram model. METHODS: This case-control study retrospectively analyzed the medical data of 149 patients with AIS receiving thrombolysis with good function at discharge from January 2017 to June 2019. Patients were divided into a poor function group (<3 points) and a good function group (≥3 points) according to their modified Rankin Scale scores at 6 months. Logistic regression was used to identify risk factors for poor 6-month function. A novel nomogram prediction model for poor 6-month function was constructed, and its prediction performance and concordance were evaluated. RESULTS: Of 149 patients, 21 (14%) had poor 6-month function and 128 (86%) had good 6-month function. Multivariate regression analysis showed that physical inactivity, neutrophil count, cerebral small vessel disease score, and hospitalization days were independent risk factors for poor 6-month function. A regression model was established according to the multivariate analysis, and the area under the curve was 0.9363. The accuracy was 71.99%, the sensitivity was 78.83%, and the specificity was 70.26%. A nomogram model was constructed, and its concordance index was 0.836 after internal validation. CONCLUSION: The novel nomogram model facilitates risk prediction of poor 6-month function in patients with AIS receiving thrombolysis with good function at discharge and is helpful for making discharge plans.

Immunoregulatory Role of the Mechanosensitive Ion Channel Piezo1 in Inflammation and Cancer.

Piezo1 was originally identified as a mechanically activated, nonselective cation ion channel, with significant permeability to calcium ions, is evolutionally conserved, and is involved in the proliferation and development of various types of cells, in the context of various types of mechanical or innate stimuli. Recently, our study and work by others have reported that Piezo1 from all kinds of immune cells is involved in regulating many diseases, including infectious inflammation and cancer. This review summarizes the recent progress made in understanding the immunoregulatory role and mechanisms of the mechanical receptor Piezo1 in inflammation and cancer and provides new insight into the biological significance of Piezo1 in regulating immunity and tumors.