Summary
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.
The progress about the development and functional differentiation of TFH cells. The regulatory mechanisms of TFH cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of TFH cells. TFH cells are closely related to immune‐associated diseases, including infections, autoimmune diseases, and cancers.
The calcineurin/nuclear factor of activated T cell (CN/NFAT) signaling pathway plays a critical role in the immune response. Therefore, inhibition of the CN/NFAT pathway is an important target for ...inflammatory disease. The conserved PXIXIT and LXVP motifs of CN substrates and targeting proteins have been recognized. Based on the affinity ability and inhibitory effect of these docking sequences on CN, we designed a bioactive peptide (named pep3) against the CN/NFAT interaction, which has two binding sites derived from the RCAN1-PXIXIT motif and the NFATc1-LXVP motif. The shortest linker between the two binding sites in pep3 is derived from A238L, a physiological binding partner of CN. Microscale thermophoresis revealed that pep3 has two docking sites on CN. Pep3 also has the most potent inhibitory effect on CN. It is suggested that pep3 contains an NFATc1-LXVP–substrate recognition motif and RCAN1-PXIXIT–mediated anchoring to CN. Expression of this peptide significantly suppresses CN/NFAT signaling. Cell-permeable 11-arginine–modified pep3 (11R-pep3) blocks the NFAT downstream signaling pathway. Intranasal administration of the 11R-pep3 peptide inhibits airway inflammation in an ovalbumin-induced asthma model. Our results suggest that pep3 is promising as an immunosuppressive agent and can be used in topical remedies.
Atrial fibrillation (AF) is common in older people and increases the risk of stroke. The feasibility and effectiveness of the implementation of a patient-led AF screening program for older people are ...unknown.
This study aims to examine the feasibility and effectiveness of an AF screening program comprising patient-led monitoring of single-lead electrocardiograms (ECGs) with clinician-coordinated central monitoring to diagnose AF among community-dwelling people aged ≥75 years in Australia.
This is a nationwide randomized controlled implementation trial conducted via the internet and remotely among 200 community-dwelling adults aged ≥75 years with no known AF. Randomization will be performed in a 1:1 allocation ratio for the intervention versus control. Intervention group participants will be enrolled in the monitoring program at randomization. They will receive a handheld single-lead ECG device and training on the self-recording of ECGs on weekdays and submit their ECGs via their smartphones. The control group participants will receive usual care from their general practitioners for the initial 6 months and then commence the 6-month monitoring program. The ECGs will be reviewed centrally by trained personnel. Participants and their general practitioners will be notified of AF and other clinically significant ECG abnormalities.
This study will establish the feasibility and effectiveness of implementing the intervention in this patient population. The primary clinical outcome is the AF detection rate, and the primary feasibility outcome is the patient satisfaction score. Other outcomes include appropriate use of anticoagulant therapy, participant recruitment rate, program engagement (eg, frequency of ECG transmission), agreement in ECG interpretation between the device automatic algorithm and clinicians, the proportion of participants who complete the trial and number of dropouts, and the impact of frailty on feasibility and outcomes. We will conduct a qualitative evaluation to examine the barriers to and acceptability and enablers of implementation. Ethics approval was obtained from the human research ethics committee at the University of Sydney (project number 2020/680). The results will be disseminated via conventional scientific forums, including peer-reviewed publications and presentations at national and international conferences.
By incorporating an integrated health care approach involving patient empowerment, centralized clinician-coordinated ECG monitoring, and facilitation of primary care and specialist services, it is possible to diagnose and treat AF early to reduce stroke risk. This study will provide new information on how to implement AF screening using digital health technology practicably and feasibly for older and frail populations residing in the community.
Australian New Zealand Clinical Trials Registry ACTRN12621000184875; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380877.
DERR1-10.2196/34778.
Immunomodulatory signaling imposes tight regulations on metabolic programs within immune cells and consequentially determines immune response outcomes. Although the glucocorticoid receptor (GR) has ...been recently implicated in regulating the function of myeloid-derived suppressor cells (MDSCs), whether the dysregulation of GR in MDSCs is involved in immune-mediated hepatic diseases and how GR regulates the function of MDSCs in such a context remains unknown. Here, we revealed the dysregulation of GR expression in MDSCs during innate immunological hepatic injury (IMH) and found that GR regulates the function of MDSCs through modulating HIF1α-dependent glycolysis. Pharmacological modulation of GR by its agonist (dexamethasone, Dex) protects IMH mice against inflammatory injury. Mechanistically, GR signaling suppresses HIF1α and HIF1α-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs. Our studies reveal a role of GR-HIF1α in regulating the metabolism and function of MDSCs and further implicate MDSC GR signaling as a potential therapeutic target in hepatic diseases that are driven by innate immune cell-mediated systemic inflammation.
To investigate the function and underlying mechanism of cysteine and glycine-rich protein 2 (CSRP2) in neuroblastoma (NB).OBJECTIVETo investigate the function and underlying mechanism of cysteine and ...glycine-rich protein 2 (CSRP2) in neuroblastoma (NB).The correlation between the expression level of CSRP2 mRNA and the prognosis of NB children in NB clinical samples was analyzed in R2 Genomics Analysis and Visualization Platform. The small interfering RNA (siRNA) targeting CSRP2 or CSRP2 plasmid were transfected to NB cell lines SK-N-BE(2) and SH-SY5Y. Cell proliferation was observed by crystal violet staining and real-time cellular analysis. The ability of colony formation of NB cells was observed by colony-forming unit assay. Immunofluorescence assay was used to detect the expression of the proliferation marker Ki-67. Flow cytometry analysis for cell cycle proportion was used with cells stained by propidium iodide (PI). Annexin V/7AAD was used to stain cells and analyze the percentage of cell apoptosis. The
Objective To explore the effect of open reading frame 66 (C12ORF66) located at chromosome 12 on the viability of MYCN amplified NB cell lines. Methods DDatasets GSE16476 and GSE49710 in R2 database ...were analyzed for expression level of C12ORF66 in MYCN amplified and MYCN non-amplified NB cells and its potential correlation with the prognosis of pediatric patients. C12ORF66 mRNA expression level in normal tissue immortalized cell lines, MYCN amplified and MYCN non-amplified cell lines were detected by RT-qRCR. Transient or stable knockdown of C12ORF66 cell lines were constructed to compare the difference in real time cellular analysis (RTCA), colony formation, Ki67 positive cells between the control group and the C12ORF66 knockdown group. Results By analyzing R2 datasets, C12ORF66 level in MYCN amplified samples was significantly higher than that in MYCN non-amplified samples, and the expression of C12ORF66 was negatively correlated with the prognosis of pediatric patients(P＜0.05). C12ORF66 highly expressed in
To assess the safety and feasibility of early oral hydration (EOH) in the postanesthesia care unit (PACU) after laparoscopic cholecystectomy.
Prospective, randomized, controlled trial.
Patients were ...randomly assigned to the EOH group or the conventional oral hydration (COH) group. Outcomes were the incidence of nausea and vomiting, thirst scale, incidence of oropharyngeal discomfort, and patient satisfaction.
Compared with the COH group, the EOH group had lower incidence of nausea before and after the first drink in the ward (P < .05); lower incidence of vomiting before and after the first drink in the ward (P < .05); lower thirst scale when patients were transferred out of the PACU (P < .05) and at 6 hours postoperatively (P < .05); and greater patient satisfaction on postoperative day 1 (P < .05).
Early oral hydration in the PACU following laparoscopic cholecystectomy was safe and well-tolerated.
mTOR negatively controls suppressive functions of MDSCs in immune‐mediated hepatic injury mouse models.
The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, ...including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid‐derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune‐related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune‐mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR‐deficient CD11b+Gr1+ MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR‐deficient CD11b+Gr1+ MDSCs are suppressive immune modulators that result in less IFN‐γ‐producing TH1 cells and more Foxp3+ Tregs. Mechanistically, mTOR activity down‐regulation in MDSCs induced iNOS expressions and NO productions. Pharmacologic inhibitions of iNOS completely eliminate MDSC‐suppressive function and lose their inducible effects on T cell differentiation. Importantly, HIF1α‐dependent glycolytic activity is responsible for mTOR‐deficient, increased MDSC functional changes in IMH inflammation. Thus, these data demonstrate that mTOR acts as a fundamental “rheostat” in MDSCs to link immunologic signals to glycolytic pathways and functional fitness and highlights a central role of metabolic programming of MDSC‐suppressive activity in protecting against immune hepatic injuries.
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