IL-10-producing B cells (B10 cells) have been shown to play a suppressive role in the peripheral blood of humans, with their numbers and function altered in several autoimmune diseases. However, the role of B10 cells in Graves’ disease (GD) remains unknown. In this study, we demonstrated that B10 cells in human peripheral blood belonged to a CD24hiCD27+ B cell subpopulation. The proportion of B10 cells along with the CD19+CD24hiCD27+ B cell subset was significantly lower in new-onset patients compared with healthy individuals. In recovered patients, these proportions were restored to levels similar to those seen in healthy individuals. Additionally, we found that CD19+CD24hiCD27+ B cells from healthy individuals inhibited proliferation and TNF-α production of CD4+ T cells via an IL-10–independent pathway. They also inhibited IFN-γ production by CD4+ T cells, through an IL-10–dependent pathway. In contrast, their suppressive function on CD4+ T cell proliferation and cytokine production was impaired in new-onset and recovered patients compared with healthy individuals. Our study provides evidence that CD19+CD24hiCD27+ B cells may possess the capacity to downregulate immune responses, partially by production of IL-10 in human peripheral blood. Impairment of their immunosuppressive function may contribute to GD pathogenesis and relapse.
Biodegradable polymer nanoparticle drug delivery systems provide targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and fewer side effects. These drug delivery systems are widely used for delivering cytotoxic agents. In the present study, we synthesized GC/5-FU nanoparticles by combining galactosylated chitosan (GC) material with 5-FU, and tested its effect on liver cancer in vitro and in vivo. The in vitro anti-cancer effects of this sustained release system were both dose- and time-dependent, and demonstrated higher cytotoxicity against hepatic cancer cells than against other cell types. The distribution of GC/5-FU in vivo revealed the greatest accumulation in hepatic cancer tissues. GC/5-FU significantly inhibited tumor growth in an orthotropic liver cancer mouse model, resulting in a significant reduction in tumor weight and increased survival time in comparison to 5-FU alone. Flow cytometry and TUNEL assays in hepatic cancer cells showed that GC/5-FU was associated with higher rates of G0–G1 arrest and apoptosis than 5-FU. Analysis of apoptosis pathways indicated that GC/5-FU upregulates p53 expression at both protein and mRNA levels. This in turn lowers Bcl-2/Bax expression resulting in mitochondrial release of cytochrome C into the cytosol with subsequent caspase-3 activation. Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 (PARP-1) at mRNA and protein levels, further promoting apoptosis. These findings indicate that sustained release of GC/5-FU nanoparticles are more effective at targeting hepatic cancer cells than 5-FU monotherapy in the mouse orthotropic liver cancer mouse model.
Although elevated glucose levels are reported to be associated with adverse outcomes of coronavirus disease 2019 (COVID-19), the optimal range of glucose in patients with COVID-19 and diabetes remains unknown. This study aimed to investigate the threshold of glycemia and its association with the outcomes of COVID-19. RESEARCH DESIGN AND METHODS Glucose levels were assessed through intermittently scanned continuous glucose monitoring in 35 patients for an average period of 10.2 days. The percentages of time above range (TAR), time below range (TBR), time in range (TIR), and coefficient of variation (CV) were calculated. Composite adverse outcomes were defined as either the need for admission to the intensive care unit, need for mechanical ventilation, or morbidity with critical illness. RESULTS TAR using the threshold of 160-200 mg/dL was significantly associated with composite adverse outcomes after adjustment of covariates. Both TBR (<70 mg/dL) and TIR (70-160 mg/dL), but not mean sensor glucose level, were significantly associated with composite adverse outcomes and prolonged hospitalization. The multivariate-adjusted odds ratios of the CV of sensor glucose across tertiles for composite adverse outcomes of COVID-19 were 1.00, 1.18, and 25.2, respectively. CONCLUSIONS Patients with diabetes and COVID-19 have an increased risk of adverse outcomes with glucose levels >160 mg/dL and <70 mg/dL and a high CV. Therapies that improve these metrics of glycemic control may result in better prognoses for these patients. Epidemiological studies have reported that approximately one-half of patients with coronavirus disease 2019 (COVID-19) have comorbidities, of which diabetes is the second most common (1,2). There was more than a fourfold chance of patients with diabetes and COVID-19 meeting the primary composite end point of need for intensive
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