GATA-3 promotes Th2 responses through three different mechanisms： induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Thl cell-specific factors

Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including StatS, Gfi- 1 and GATA-3. Stats activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stats signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation （both IL-4 dependent and IL-4 independent） and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Thl differentiation.

Network Biological Modeling:A Novel Approach to Interpret the Traditional Chinese Medicine Theory of Exterior-Interior Correlation Between the Lung and Large Intestine

Objective To study the common pathogenesis of pneumonia and colitis using modern biological network analysis tools,and to explore the theory that the lung and large intestine are exteriorly and interiorly related.Methods The relevant target genes(hereinafter,“targets”)of pneumonia and colitis were separately queried on the GeneCards database.The main targets of the two diseases were then screened out according to their correlation scores and intersected to obtain those common to the two diseases.Metascape was used to analyze the main and common targets identified,and the Database for Annotation,Visualization and Integrated Discovery(DAVID)was used to enrich and analyze the common targets.Cytoscape 3.7.2 software was used to build the network diagram.Results In total,54 targets,such as TNF,IL-10,IL-6,IL-2,IL-4,TLR4,TLR2,CXCL8,IL-17A and IFNG,etc.,are common to pneumonia and colitis,which are mainly enriched in these processes such as cytokine–cytokine receptor interaction,the Tcell receptor signaling pathway,the Toll-like receptor signaling pathway and the Jak-STAT signaling pathway.The Metascape modular analysis identified 11 modules for pneumonia,six modules for colitis,and two modules for the common targets.Conclusions Pneumonia and colitis have the same pathogenic targets and mechanisms of action and finally interact with each other through inflammatory reactions and immune responses.This provides a probable molecular mechanism that explains the theory that the lung and large intestine are exteriorly and interiorly related.

Rheum palmatum L. and Salvia miltiorrhiza Bge. Alleviates Acute Pancreatitis by Regulating Th17 Cell Differentiation: An Integrated Network Pharmacology Analysis, Molecular Dynamics Simulation and Experimental Validation

Objective: To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge.,(Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in acute pancreatitis(AP)using a network pharmacology approach and validate the findings in animal experiments. Methods: Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics simulation.Finally, the results of network pharmacology enrichment analysis were verified by immunohistochemistry,Western blot analysis and real-time quantitative PCR, respectively. Results: Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3(MAPK3), Janus kinase 2(JAK2), signal transducer and activator of transcription 3(STAT3), protein c-Fos(FOS) were identified as core targets in the protein interaction(PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. Molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. Molecular dynamics simulation revealed that FOS-isotanshinone Ⅱ and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1β, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation(P<0.01). Conclusion: DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues,which would be functioned by regulating Th17 cell differentiation-related m RNA and protein expressions.

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Immunosuppressive mediators in tuberculosis pleurisy(pleural fluid(PF))are associated with the course of disease,but they remain poorly defined.To study the local immune status of patients with tuberculosis pleurisy,we examined the effect of PF on the functions of T cells and the differentiation of Th1 cells.PF could inhibit the ability of T cells to produce cytokines.However,tumor-necrosis factor(TNF)-a derived from non-T cells was not impaired.Further analysis indicated that cell activation and cell cycle progression were also suppressed.Moreover,PF could inhibit Th1 cell differentiation.Importantly,we found that inhibitors of indoleamine 2,3-dioxygenase(IDO)and adenosine and neutralizing antibodies against IL-10 and transforming growth factor(TGF)-b could reverse cytokine production,suggesting that IDO,adenosine,IL-10 and Transforming growth factor–b1 in PF might take part in impairing T-cell functions.Taken together,our data demonstrate for the first time that several immunopathological factors participate in the downregulation of T-cell functions in local PF.

Deficiency of the G protein Gαq ameliorates experimental autoimmune encephalomyelitis with impaired DC-derived IL-6 production and Th17 differentiation

Many G protein-coupled receptors （GPCRs） are reported to be involved in the pathogenesis of multiple sclerosis （MS）, and -40% of all identified GPCRs rely on the Gaq/11 G protein family to stimulate inositol lipid signaling. However, the function of Ga subunits in MS pathogenesis is still unknown. In this study, we attempted to determine the role of Gaq in the pathogenesis of experimental autoimmune encephalomyelitis （EAE）, a well-known mouse model of MS. We discovered that compared with wild-type mice, Gaq-knockout mice exhibited less severe EAE symptoms, with lower clinical scores, reduced leukocyte infiltration and less extensive demyelination. Moreover, a significantly lower percentage of Th17 cells, one of the key players in MS pathogenesis, was observed in Gaq-knockout EAE mice. Studies in vitro demonstrated that deficiency of Gaq in CD4＋ T cells directly impaired Th17 differentiation. In addition, deficiency of Gaq significantly impaired DC-derived IL-6 production, thus inhibiting Th17 differentiation and the Gaq-PLCβ-PKC and Gaq-MAPKs signaling pathways involved in the reduced IL-6 production by DCs. In summary, our data highlighted the critical role of Gaq in regulating Th17 differentiation and MS oathogenesis.

Macrocyclic Nonapeptides Incorporating Uncharacterized Amino Acids with Inhibitory Effects on Th17 Differentiation

Four unprecedented macrocyclic nonapeptides,orberryamides A–D(1–4),were isolated from Glycosmis pentaphylla(orangeberry)and structurally characterized by obtaining solid data from numerous analytical measurements.Compound 1 incorporated a new amino acid residue,named orangeberrine(Orgb),compounds 2 and 3 integrated the rare,nonproteinogenic amino acid residues(Kyn and Dioia,respectively),and compound 4 existed as two major conformational isomers in solution at ambient temperature.The biosynthetic pathways proposed for compounds 1–4 are of considerable biological significance for the modification and metabolism of tryptophan(Trp)and/or Trp containing proteins in nature.Besides,compounds 1–4 suppressed Th17 differentiation significantly,and the effects of 1–3 was achieved through targeting the ligand-binding domain(LBD)of the retinoic acid-related orphan receptor gamma t(RORγt).

Regulation of RDN on Th1/ILC1 cell imbalance in HFMD patients caused by EV71 infection

Enterovirus 71(EV71)infection is more likely to cause hand,foot and mouth disease(HFMD)in children,which can lead to neurogenic complications and higher mortality.As a commonly used clinical medicine,Reduning injection(RDN)helps to shorten the symptoms of patients with HFMD and facilitate the early recovery of children.However,the regulatory mechanism of RDN on the HFMD immune system disorder caused by EV71 remains to be discussed.This study collected detailed treatment data of56 children with HFMD who entered the affiliated Children’s Hospital of Nanjing Medical University during 2019.Retrospective analysis of clinical data showed that the symptoms of the RDN treatment group were improved compared with the untreated group.To explore its mechanism,the relevant detection indicators were detected by flow cytometry,enzyme-linked immunosorbent assay and realtime quantitative PCR.It was found that the number and function of innate immune(ILCs)and adaptive immunity(Th1,Th2 and secreted cytokines)were reduced,suggesting that RDN plays a role by regulating cellular immunity.The in vitro differentiation inhibition test further confirmed that RDN affected Th1 differentiation by inhibiting the expression of transcription factors on the basis of Th1 cell differentiation in vitro.

Orbital dynamics satisfying the 4^(th)-order stationary extended Fisher-Kolmogorov equation

In this study,we discuss the central force problem by using the nonlocal-in-time kinetic energy approach.At low length scales,the system is dominated by the generalized 4^(th)-order extended Fisher-Kolmogorov stationary equation and by the 4^(th)-order stationary Swift-Hohenberg differential equation under explicit conditions.The energy is a conserved quantity along orbits of the extended Fisher-Kolmogorov stationary equation.The system is quantized,the system is stable,and the ground energy problem is solved.