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.

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 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.

Circulating Growth Differentiation Factor 15 and Preeclampsia: A Meta-Analysis.

Growth differentiation factor 15 (GDF-15) has been suggested as a potential biomarker of preeclampsia. However, previous studies evaluating circulating GDF-15 in women with preeclampsia showed inconsistent results. A meta-analysis was performed accordingly in this study. Observational studies comparing circulating GDF-15 between women with preeclampsia normal pregnancy were identified by search of electronic databases including PubMed, Embase, Web of Science, Wanfang, and CNKI. The Newcastle-Ottawa Scale (NOS) was used for assessing the quality of the studies. A randomized-effect model incorporating the possible between-study heterogeneity was used to pool the results. Eleven observational studies including 498 women with preeclampsia and 2349 women with normal pregnancy contributed to the meta-analysis. Results showed that compared to controls of women with normal pregnancy at least matched for gestational ages, women with preeclampsia had significantly higher circulating GDF-15 at the diagnosis [standard mean difference (SMD): 0.66, 95% confidence interval (CI): 0.16 to 1.17, p=0.01, I2=93%]. Subgroup analysis showed consistent results in women with preterm and term preeclampsia in Asian and non-Asian women and in studies with different quality scores, which were not statistically significant between subgroups (p for subgroup difference>0.05). Moreover, a higher level of GDF-15 was also found before the diagnosis in women who subsequently developed preeclampsia than those who did not (SMD: 1.32, 95% CI: 0.45 to 2.18, p=0.003, I2=89%). In conclusion, a higher circulating GDF-15 is observed in women with preeclampsia even before the diagnosis of the disease.

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.

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.

The crosstalk between gut bacteria and host immunity in intestinal inflammation.

The gut of mammals is considered as a harmonious ecosystem mediated by intestinal microbiota and the host. Both bacteria and mammalian immune cells show region-related distribution characteristics, and the interaction between the two could be demonstrated by synergetic roles in maintaining intestinal homeostasis and dysregulation in intestinal inflammation. The harmonious interplay between bacteria and host requires fine-tuned regulations by environmental and genetic factors. Thus, the disturbed immune response to microbial components or metabolites and dysbiosis related to immunodeficiency are absolute risk factors to intestinal inflammation and cancer. In this review, we discuss the crosstalk between bacteria and host immunity in the gut and highlight the critical roles of bidirectional regulation between bacteria and the mammalian immune system involved in intestinal inflammation.

The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer.

Follicular T helper (Tfh) cells play important roles in facilitating B-cell differentiation and inducing the antibody response in humoral immunity and immune-associated inflammatory diseases, including infections, autoimmune diseases, and cancers. However, Tfh cell differentiation is mainly achieved through self-directed differentiation regulation and the indirect regulation mechanism of antigen-presenting cells (APCs). During the direct intrinsic differentiation of naïve CD4+ T cells into Tfh cells, Bcl-6, as the characteristic transcription factor, plays the core role of transcriptional regulation. APCs indirectly drive Tfh cell differentiation mainly by changing cytokine secretion mechanisms. Altered metabolic signaling is also critically involved in Tfh cell differentiation. This review summarizes the recent progress in understanding the direct and indirect regulatory signals and metabolic mechanisms of Tfh cell differentiation and function in immune-associated diseases.

Functional differentiation and regulation of follicular T helper cells in inflammation and autoimmunity.

Follicular T helper (TFH ) cells are specialized T cells that support B cells, which are essential for humoral immunity. TFH cells express the transcription factor B-cell lymphoma 6 (Bcl-6), chemokine (C-X-C motif) receptor (CXCR) 5, the surface receptors programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), the cytokine IL-21 and other molecules. The activation, proliferation and differentiation of TFH cells are closely related to dynamic changes in cellular metabolism. In this review, we summarize the progress made in understanding the development and functional differentiation of TFH cells. Specifically, we focus on the regulatory mechanisms of TFH cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of TFH cells. In addition, TFH cells are closely related to immune-associated diseases, including infections, autoimmune diseases and cancers.

Hippo Kinases MST1/2 Regulate Immune Cell Functions in Cancer, Infection, and Autoimmune Diseases.

Mammalian STE20-like protein kinases (MST), including MST1, MST2, MST3, and MST4, belong to the germinal center kinase (GCK) family. Kinase MST1/2 is an important component of the Hippo pathway in regulating cell proliferation, tissue homeostasis, and organ development. Recent studies have shown that Hippo kinase MST1/2 plays a crucial role in immune-associated diseases, which has attracted extensive attention of researchers. This review summarizes recent research on Hippo kinases MST1/2 in regulating the function of immune cells in innate and adaptive immune systems, and also includes its regulatory role and significance in cancer, infection, and autoimmune diseases.

Metabolic regulation of inflammasomes in inflammation.

Inflammasome activation and subsequent inflammatory cytokine secretion are essential for innate immune defence against multiple stimuli and are regarded as a link to adaptive immune responses. Dysfunction of inflammasome activation has been discovered at the onset or progression of infectious diseases, autoimmune diseases and cancer, all of which are also associated with metabolic factors. Furthermore, many studies concerning the metabolic regulation of inflammasome activation have emerged in recent years, especially regarding the activity of the NLRP3 inflammasome under metabolic reprogramming. In this review, we discuss the molecular mechanisms of the interactions between metabolic pathways and inflammasome activation, which exerts further important effects on various diseases.

The effect of microwave on the interaction of flavour compounds with G-actin from grass carp (Catenopharyngodon idella).

BACKGROUND: In order to investigate the influence of non-thermal effects of microwaves on the flavour of fish and meat products, the G-actin of grass carp in ice baths was exposed to different microwave powers (0, 100, 300 or 500 W); the surface hydrophobicity, sulfhydryl contents, secondary structures and adsorption capacity of G-actin to ketones were determined. RESULTS: As microwave power increased from 0 to 300 W, the surface hydrophobicity, total and reactive sulfhydryls increased; α-helix, ß-sheet and random coil fractions turned into ß-turn fractions. As microwave power increased from 300 to 500 W, however, hydrophobicity and sulfhydryl contents decreased; ß-turn and random coil fractions turned into α-helix and ß-sheet fractions. The tendencies of adsorbed capacity of ketones were similar to hydrophobicity and sulfhydryl contents. CONCLUSION: The increased adsorbing of ketones could be attributed to the unfolding of secondary structures by revealing new binding sites, including thiol groups and hydrophobic binding sites. The decreased binding capacity was related to the refolding and aggregation of protein. The results suggested that microwave powers had obvious effects on the flavour retention and proteins structures in muscle foods. © 2017 Society of Chemical Industry.

Sirtuin 2 regulates neutrophil functions through NAD+ synthesis pathway in virus infection.

Neutrophils play an important role in antiviral immunity, but the underlying mechanisms remain unclear. Here, we found that SIRT2 deficiency inhibited the infiltration of neutrophils, as well as the secretion of inflammatory cytokines and the formation of neutrophil extracellular traps (NETs), ameliorating disease symptoms during acute respiratory virus infection. Mechanistically, SIRT2 deficiency upregulates quinolinic acid (QA)-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) and leads to expression of quinolinate phosphoribosyltransferase (QPRT), which promotes the synthesis of QA for NAD+ and limits viral infection when de novo NAD+ synthesis is blocked. Tryptophan-2,3-oxygenase expressed in epithelial cells metabolizes tryptophan to produce kynurenine and 3-hydroxyaminobenzoic acid, which is a source of intracellular QA in neutrophils. Thus, our findings reveal a previously unrecognized QPRT-mediated switch in NAD+ metabolism by exploiting neutrophil-derived QA as an alternative source of replenishing intracellular NAD+ pools induced by SIRT2 to regulate neutrophil functions during virus infection, with implications for future immunotherapy approaches.

Two-dimensional charge-separated metal-organic framework for hysteretic and modulated sorption.

A charge-separated metal-organic framework (MOF) has been successfully synthesized from an imidazolium tricarboxylate ligand, N-(3,5-dicarboxylphenyl)-N'-(4-carboxylbenzyl)imidazolium chloride (DCPCBImH3Cl), and a zinc(II) dimeric secondary building unit, namely, DCPCBim-MOF-Zn, which shows an unprecedented 3,6-connected two-dimensional net topology with the point (Schläfli) symbol (4(2).6)2(4(4).6(9).8(2)). The framework contains one-dimensional highly polar channels, and density functional theory calculations show that positive charges are located on the imidazolium/phenyl rings and negative charges on the carboxylate moieties. The charge-separated nature of the pore surface has a profound effect in their adsorption behavior, resulting in remarkable hysteretic sorption of various gases and vapors. For CO2, the hysteretic sorption was observed to occur even up to 298 K. Additionally, trace chloride anions present in the pore channels are able to modulate the gas-sorption behavior.

Preparation, structural characterization, bioactivities, and applications of Crataegus spp. polysaccharides: A review.

Crataegus, is a genus within the Rosaceae family. It is recognized as a valuable plant with both medicinal and edible qualities, earning it the epithet of the "nutritious fruit" owing to its abundant bioactive compounds. Polysaccharides are carbohydrate polymers linked by glycosidic bonds, one of the crucial bioactive ingredients of Crataegus spp. Recently, Crataegus spp. polysaccharides (CPs) have garnered considerable attention due to their diverse range of bioactivities, including prebiotic, hypolipidemic, anticancer, antibacterial, antioxidant, and immunobiological properties. Herein, we provide a comprehensive overview of recent research on CPs. The analysis revealed that CPs exhibited a broad molecular weight distribution, ranging from 5.70 Da to 4.76 × 108 Da, and are composed of various monosaccharide constituents such as mannose, rhamnose, and arabinose. Structure-activity relationships demonstrated that the biological function of CPs is closely associated with their molecular weight, galacturonic acid content, and chemical modifications. Additionally, CPs have excellent bioavailability, biocompatibility, and biodegradability, which make them promising candidates for applications in the food, medicine, and cosmetic industries. The article also scrutinized the potential development and future research directions of CPs. Overall, this article provides comprehensive knowledge and underpinnings of CPs for future research and development as therapeutic agents and multifunctional food additives.

Aryl hydrocarbon receptor nuclear translocator limits the recruitment and function of regulatory neutrophils against colorectal cancer by regulating the gut microbiota.

BACKGROUND: Although the role and mechanism of neutrophils in tumors have been widely studied, the precise effects of aryl hydrocarbon receptor nuclear translocator (ARNT) on neutrophils remain unclear. In this study, we investigated the roles of ARNT in the function of CD11b+Gr1+ neutrophils in colitis-associated colorectal cancer. METHODS: Wild-type (WT), ARNT myeloid-specific deficient mice and a colitis-associated colorectal cancer mouse model were used in this study. The level and functions of CD11b+Gr1+ cells were evaluated by flow cytometry and confocal microscopy. RESULTS: We found that ARNT deficiency drives neutrophils recruitment, neutrophil extracellular trap (NET) development, inflammatory cytokine secretion and suppressive activities when cells enter the periphery from bone marrow upon colorectal tumorigenesis. ARNT deficiency displays similar effects to aryl hydrocarbon receptor (AHR) deficiency in neutrophils. CXCR2 is required for NET development, cytokine production and recruitment of neutrophils but not the suppressive activities induced by Arnt-/- in colorectal cancer. The gut microbiota is essential for functional alterations in Arnt-/- neutrophils to promote colorectal cancer growth. The colorectal cancer effects of Arnt-/- neutrophils were significantly restored by mouse cohousing or antibiotic treatment. Intragastric administration of the feces of Arnt-/- mice phenocopied their colorectal cancer effects. CONCLUSION: Our results defined a new role for the transcription factor ARNT in regulating neutrophils recruitment and function and the gut microbiota with implications for the future combination of gut microbiota and immunotherapy approaches in colorectal cancer.

Canopy structure: An intermediate factor regulating grassland diversity-function relationships under human disturbances.

Grasslands are one of the largest coupled human-nature terrestrial ecosystems on Earth, and severe anthropogenic-induced grassland ecosystem function declines have been reported recently. Understanding factors influencing grassland ecosystem functions is critical for making sustainable management policies. Canopy structure is an important factor influencing plant growth through mediating within-canopy microclimate (e.g., light, water, and wind), and it is found coordinating tightly with plant species diversity to influence forest ecosystem functions. However, the role of canopy structure in regulating grassland ecosystem functions along with plant species diversity has been rarely investigated. Here, we investigated this problem by collecting field data from 170 field plots distributed along an over 2000 km transect across the northern agro-pastoral ecotone of China. Aboveground net primary productivity (ANPP) and resilience, two indicators of grassland ecosystem functions, were measured from field data and satellite remote sensing data. Terrestrial laser scanning data were collected to measure canopy structure (represented by mean height and canopy cover). Our results showed that plant species diversity was positively correlated to canopy structural traits, and negatively correlated to human activity intensity. Canopy structure was a significant indicator for ANPP and resilience, but their correlations were inconsistent under different human activity intensity levels. Compared to plant species diversity, canopy structural traits were better indicators for grassland ecosystem functions, especially for ANPP. Through structure equation modeling analyses, we found that plant species diversity did not have a direct influence on ANPP under human disturbances. Instead, it had a strong indirect effect on ANPP by altering canopy structural traits. As to resilience, plant species diversity had both a direct positive contribution and an indirect contribution through mediating canopy cover. This study highlights that canopy structure is an important intermediate factor regulating grassland diversity-function relationships under human disturbances, which should be included in future grassland monitoring and management.

Dendritic cell Piezo1 directs the differentiation of TH1 and Treg cells in cancer.

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFß1 and IL-12, leading to increased TGFßR2-p-Smad3 activity and decreased IL-12Rß2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFß1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.

[Exploring and practicing over 80 years in traditional Chinese medicine: the academic career of professor XUE Chong-cheng].

This paper reviewes the clinical and scientific research history of professor XUE Chong-cheng and summarizes his academic thoughts and main achievements. Professor XUE Chong -cheng created the first personality and constitution inventory in China to lay the foundation for the discipline of TCM psychology; discovered meridian sensory conduction in phantom limbs and proposed the extension of the central model; invented a method for treating mental illness with a low-dose electroacupuncture convulsion therapy instrument; and interpreted the TCM medical model as a Time-Space-Social- Psychological-Biological medical model.