Immune disorders are linked to the development of type 2 diabetes (T2D) and its complications. The relationship of CD4(+)CD25(hi) T regulatory cells (Treg) and pro-inflammatory Th17 and Th1 subsets in T2D patients with metabolic disorders and complications need to be determined. The ratios of CD4(+)CD25(hi) Treg/Th17 cells and CD4(+)CD25(hi) Treg/Th1 cells, but not Th17/Th1 cells, were significantly decreased in T2D patients. The thymic output CD4(+)Foxp3(+)Helios(+) Tregs were normal but peripheral induced CD4(+)Foxp3(+)Helios(-) Tregs were decreased in T2D patients. The Bcl-2/Bax ratio decreased in CD4(+)CD25(hi) Tregs in T2D patients, supporting the increased sensitivity to cell death of these cells in T2D. CD4(+)CD25(hi)CD127(-) Tregs in T2D patients with microvascular complications were significantly less than T2D patients with macrovascular complications. Importantly, CD4(+)CD25(hi)CD127(-) Tregs were positively correlated with plasma IL-6, whereas IL-17(+)CD4(+)cells were negatively related to high-density lipoprotein (HDL). Our data offered evidence for the skewed balance of anti- and pro-inflammatory T cell subsets in T2D patients and identified that HDL closely modulate T cell polarization. These results opened an alternative explanation for the substantial activation of immune cells as well as the development of T2D and complications, which may have significant impacts on the prevention and treatment of T2D patients.
SummaryGut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.
CD4(+)CD25(+) regulatory T cells (Treg cells) are an important subset of T cells for keeping proper immune responses and tolerance. However, the effects of gamma radiation on CD4(+)CD25(high) Foxp3(+) Treg cells have not been examined previously. In the present study, we compared the sensitivity of mouse CD4(+)CD25(high) Foxp3(+) Treg cells and CD4(+)CD25(-) T cells to gamma radiation in vitro and in vivo. After C57BL/6 mice received a whole-body dose of 5 Gy gamma rays, the numbers of lymphocyte subsets in blood, lymph nodes, spleens and thymuses clearly decreased. However, gamma radiation significantly enhanced the ratios of CD4(+)CD25(high) Treg cells and CD4(+)CD25(high) Foxp3(+) Treg cells to CD4(+) T cells in the blood, lymph nodes, spleens and thymuses of mice. More dead cells were observed in CD4(+)CD25(-) T cells than in CD4(+)CD25(high) Treg cells or CD4(+)CD25(high) Foxp3(+) Treg cells when the cells were irradiated in vitro, indicating that CD4(+)CD25(high) Foxp3(+) Treg cells are more resistant to gamma radiation than other T cells. Moreover, a higher expression of Bcl-2 in CD4(+)CD25(high) Treg cells was detected compared with that in CD4(+)CD25(-) T cells. CD4(+)CD25(+) Treg cells from irradiated mice were functional, though their immunosuppressive ability was somewhat impaired compared to those from nonirradiated mice as determined by an in vitro assay. These results indicate that mouse CD4(+)CD25(+) Treg cells and CD4(+)CD25(-) T effector cells have different sensitivities to gamma radiation in mice.
Aiming for an adoptive natural killer (NK) cell therapy, we have developed a novel protocol to expand NK cells from peripheral blood. With this protocol using anti-human CD16 antibody and interleukin (IL)-2, NK (CD3−CD56+) cells could be expanded about 4000-fold with over 70% purity during a 21-day culture. The expanded NK (exNK) cells were shown to be highly cytotoxic to multiple myeloma (MM) cells (RPMI8226) at low NK-target cell ratios. Furthermore, NK cells expanded in the presence of a blocking antibody (exNK+PD1-blockage) against programmed cell death protein-1 (PD1), a key counteracting molecule for NK and T cell activity, demonstrated more potent cytolytic activity against the RPMI8226 than the exNK cells without PD1 blocking. In parallel, the exNK cells showed significantly higher expression of NK activation receptors NKG2D, NKp44 and NKp30. In a murine model of MM, transfusion of exNK cells, exNK+PD1-blockage, and exNK plus intratumor injection of anti-PD-L2 antibody (exNK+PD-L2 blockage) all significantly suppressed tumor growth and prolonged survival of the myeloma mice. Importantly, exNK+PD1-blockage presented more efficient therapeutic effects. Our results suggest that the NK cell expansion protocol with PD1 blockade presented in this study has considerable potential for the clinical application of allo- and auto-NK cell-based therapies against malignancies.
Shenqi is a traditional Chinese polyherbal medicine has been widely used for the treatment of allergic rhinitis (AR). The aim of this study was to investigate the anti-allergic rhinitis activity of Shenqi and explore its underlying molecular mechanism. Ovalbumin (OVA)-induced allergic rhinitis rat model was used to evaluate the anti-allergic rhinitis effect of Shenqi. The effect of Shenqi on IgE-mediated degranulation was measured using rat basophilic leukemia (RBL-2H3) cells. Primary spleen lymphocytes were isolated to investigate the anti-allergic mechanism of Shenqi by detecting the expression of transcription factors via Western blot and the level of cytokines (IL-4 and IFN-γ) via ELISA. In OVA-induced AR rat models, Shenqi relieved the allergic rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and reduced the levels of IL-4 and IgE. The results from the in vitro study certified that Shenqi inhibited mast cell degranulation. Furthermore, the results of GATA3, T-bet, p-STAT6, and SOCS1 expression and production of IFN-γ and IL-4 demonstrated that Shenqi balanced the ratio of Th1/Th2 (IFN-γ/IL-4) in OVA-stimulated spleen lymphocytes. In conclusion, these results suggest that Shenqi exhibits an obvious anti-allergic effect by suppressing the mast cell-mediated allergic response and by improving the imbalance of Th1/Th2 ratio in allergic rhinitis.
Type 2 diabetes [T2D] and thyroid dysfunction [TD] often co-occur, have overlapping pathologies, and their risk increases with age. Since 1995, universal salt iodization has been implemented in China to prevent disorders caused by iodine deficiency. However, after two decades of implementation of universal salt iodization, the prevalence of TD in elderly Chinese patients with T2D is not well described and may have been underestimated. We conducted a questionnaire-based survey across 24 endocrinology centers in China between December 2015 and July 2016. Demographic and clinical data from 1677 patients with T2D were obtained and analyzed to examine the prevalence of TD along with T2D in these patients. We assessed TD prevalence according to the four TD subtypes [subclinical hypothyroidism, clinical hypothyroidism, subclinical hyperthyroidism, and clinical hyperthyroidism], TD history, gender, and age. The diagnosis rates were calculated for TD and also for the TD subtype. The number of patients reaching treatment goals for T2D [hemoglobin A1c <7%] and TD [normal free thyroxine and thyroid-stimulating hormone [TSH]] and the incidences of complications and comorbidities were recorded. Among the enrolled patients with T2D [N = 1677], TD was diagnosed in 23.79% [399/1677] out of which 61% (245/399) were previously diagnosed and 38.59% (154/399) were newly diagnosed cases. Subclinical hypothyroidism, clinical hypothyroidism, subclinical hyperthyroidism, and clinical hyperthyroidism were reported in 4.89%, 9.3%, 1.13%, and 3.16% of the total population, respectively. Among patients previously diagnosed with TD, the incidence in women [166/795; 20.88%] was higher than in men [79/882; 8.96%]. The treatment goals for TD and T2D were attained in 39.6% [97/245] and 34.41% [577/1677] of the cases, respectively. Diabetic complications and comorbidities were reported in 99.7% of patients, with peripheral neuropathy being the most common [43.46%] followed by cataract [24.73%]. We had found that the incidences of dyslipidemia, elevated LDL levels, and osteoporosis were significantly higher in patients with TD than those without TD. TD is underdiagnosed in elderly Chinese patients with T2D.
The Yarlung Tsangpo River, which flows from west to east across the southern part of the Tibetan Plateau, is the longest river on the plateau and an important center for human habitation in Tibet. Suspended sediment in the river can be used as an important proxy for evaluating regional soil erosion and ecological and environmental conditions. However, sediment transport in the river is rarely reported due to data scarcity. Results from this study based on a daily dataset of 3 years from four main stream gauging stations confirmed the existence of great spatiotemporal variability in suspended sediment transport in the Yarlung Tsangpo River, under interactions of monsoon climate and topographical variability. Temporally, sediment transport or deposition mainly occurred during the summer months from July to September, accounting for 79% to 93% of annual gross sediment load. This coincided with the rainy season from June to August that accounted for 51% to 80% of annual gross precipitation and the flood period from July to September that accounted for approximately 60% of annual gross discharge. The highest specific sediment yield of 177.6 t/km2/yr occurred in the upper midstream with the highest erosion intensity. The lower midstream was dominated by deposition, trapping approximately 40% of total sediment input from its upstream area. Sediment load transported to the midstream terminus was 10.43 Mt/yr with a basin average specific sediment yield of 54 t/km2/yr. Comparison with other plateau‐originated rivers like the upper Yellow River, the upper Yangtze River, the upper Indus River, and the Mekong River indicated that sediment contribution from the studied area was very low. The results provided fundamental information for future studies on soil and water conservation and for the river basin management. Copyright © 2017 John Wiley & Sons, Ltd.
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