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Both of exosomes derived from mesenchymal stem cells (MSCs) and glial cell line-derived neurotrophic factor (GDNF) show potential for the treatment of neuropathic pain. Here, the analgesic effects of exosomes derived from bone marrow MSCs (BMSCs) were investigated. BMSCs-derived exosomes were isolated and characterized. Chronic constriction injury (CCI) was constructed to induce neuropathic pain in rats, which were then treated with exosomes. Pain behaviors were evaluated by measuring paw withdrawal thresholds and latency. The changes of key proteins, including cytokines, were explored using Western blot and ELISA. Administration of BMSCs-derived exosomes alleviated neuropathic pain, as demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia, as well as the reduced secretion of pro-inflammatory cytokines in CCI rats. These effects were comparable to the treatment of GDNF alone. Mechanically, the exosomes suppressed the CCI-induced activation of TLR2/MyD88/NF-κB signaling pathway, while GDNF knockdown impaired their analgesic effects on CCI rat. BMSCs-derived exosomes may alleviate CCI-induced neuropathic pain and inflammation in rats by transporting GDNF. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between serum selenoprotein S (SelS) and obesity in patients with type 2 diabetes mellitus (T2DM). Methods Two hundred and nine T2DM patients who were managed by the National Metabolic Management Center (MMC) of the First Affiliated Hospital of Dalian Medical University from November 2017 to November 2019 and 55 healthy people as controls in the health examination center of our hospital were enrolled in the retrospective cross-sectional study. The general condition, biochemical indexes and obesity evaluation parameters were recorded. According to the serum SelS quartile, T2DM patients were divided into Q1 group: ≤95.10 ng/dl (53 cases), Q2 group: 95.12 to 111.62 ng/dl (52 cases), Q3 group: 112.46 to 130.97 ng/dl (52 cases), Q4 group: ≥131.33 ng/dl (52 cases). Analysis of variances, rank sum test and Chi-square test were used for comparison between groups. Multiple stepwise regression was used to analyze the influencing factors of obesity evaluation index. Results There was statistically significant difference in visceral fat index (VAI) among T2DM abdominal obesity group, non-abdominal obesity group and healthy control group (H=36.679, P<0.01), but there was no statistically significant difference in serum SelS. There was statistically significant difference in serum amyloid A (SAA) level among the SelS quartile groups (H=3.560, P<0.01), but there was no statistically significant difference in visceral fat area (VFA), subcutaneous fat area (SFA), visceral fat area to subcutaneous fat area ratio (VSR) and VAI. Serum SelS was positively correlated with VFA, VSR, VAI and SAA (r=0.158 to 0.448, all P<0.05). Serum SelS was an independent risk factor for VFA (β= 0.172, P=0.003), VSR (β=0.001, P=0.01) and VAI (β=0.009, P=0.038). Conclusion Serum SelS level in T2DM patients is positively correlated with VFA, VSR and VAI, which is an independent risk factor for abdominal obesity. [ABSTRACT FROM AUTHOR]

The hyporheic zone (HZ) is a saturated sediment layer connecting groundwater (GW) and surface water (SW) along a riverbed and river channel. The HZ plays an important role in connecting SW and GW in a river ecosystem, thereby helping maintain the ecological health of rivers. Studies on the HZ have therefore increased in many disciplines. This study used the VFLUX 2 software to assess vertical fluid flux in the HZ, in which the Hatch, Kerry, McCallum, and Luce models were applied and compared. The simulations were calibrated against data measured by the US Geological Survey at a water diversion channel within the Walker River Basin in Nevada. Using COMSOL Multiphysics, we developed a two-dimensional coupled numerical model of the saturated seepage and temperature fields, calibrated against measured temperature data. We also determined the vertical seepage velocity and compared the simulations with those of the analytical models in VFLUX 2. The results showed that the temperature field distribution of the HZ is obviously nonuniform in space. With a deeper monitoring point, the thermal response of each temperature measurement pointed to periodic temperature fluctuations of the SW, which exhibited attenuation and hysteresis characteristics. When the vertical flow velocity of GW was sufficiently large, an error in the accuracy of the Kerry model amplitude ratio was observed, regardless of the heat dispersion coefficient used. Under conditions of local GW recharge by SW and a heterogeneous permeability coefficient, the use of the amplitude ratio method is recommended to quantify the vertical GW flow rate in the HZ. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is the most abundant mRNA modification. However, the role of m6A in regulating β-cell function is unknown. To address the functional role of METTL14, a key component of the m6A methyltransferase complex, in β-cells, we generated an METTL14 β-cell specific knockout mouse in adult MIP-CreERT transgenic mice. 4 weeks after tamoxifen treatment (100 mg/kg for 3 times every other day), the feeding glucose of βKO mice were 55.1% higher in βKO mice. βKO mice are also glucose intolerant. The AUC was increased by 54.7% in βKO mice (P<0.01). The fasting glucose were 307.5 ± 24.3 mg/dl in βKO mice and 219.0 ± 7.8 mg/dl in control mice (P<0.001). The response to insulin was similar between βKO and control mice. The feeding insulin levels in βKO mice were significantly decreased by 58.9% (P<0.01). The serum insulin levels from βKO mice were significantly lower at 0, 15 and 30 minutes after glucose challenge. In addition, the insulin secretion from βKO islets was less than 50% of control islets after incubated at 16.7 mM glucose. Surprisingly, β-cell mass in βKO mice was 55.9% higher than that in control mice (P<0.05). In addition, we did not detect β-cell death in βKO islets. However, β-cell proliferation in βKO islets was increased by 1.3-fold. To understand the molecular mechanism, we performed RNA-seq to detect the gene expression in βKO and control islets from male mice 8 weeks after tamoxifen treatment. Among 106 altered genes in βKO islets, 104 genes were upregulated (P<0.001) and 2 genes were downregulated. The genes response to ER stress such as Pdia4, Itpr1, Thbs1, Ire1α and Igfbp5 were among the top up-regulated genes. We applied m6A-seq in MIN6 cells and confirmed that Ire1α was modified by m6A in its last exon and 3' UTR region. We further showed that both mRNA and protein of Ire1α and spliced XBP-1 were significantly increased in βKO islets. In conclusion, METTL14 plays an important role in regulating insulin secretion, and METTL14 deficiency in β-cells induces diabetes by increasing ER stress. Disclosure: L. Men: None. J. Sun: None. D. Ren: None. Funding: National Institutes of Health (P30DK020595) [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is an initiating key step for diabetic macrovascular complications, and it is closely related to the hemodynamic microenvironment in vivo. However, diabetic patients usually coexist with other cardiovascular risk factors, and the more powerful targeting strategy for protecting endothelium is still limited. Selenoprotein S (SelS) was found in our previous study that could increase vascular endothelial cells resistance to oxidative stress associated with protein kinase C α (PKCα). Thus, in this study, we constructed a diabetic vascular endothelial bionic microenvironment mimicking hyperglycemia and/or hyperlipidemia based on microfludic chip through modulating the concentration of medium glucose and oxidized low density lipoproteins. Our results showed that under diabetic vascular endothelial bionic microenvironment, the upregulation of SelS enhanced nitric oxide synthase (eNOS) expression and reduced endothelin-1 level in human aortic endothelial cells (HAECs), accompany with increase in cell viability and SOD1 and SOD2 activity, and decrease in ROS. Furthermore, SelS overexpression attenuated the activation of PKCα, which subsequently promoted the activation of PI3K/Akt/eNOS pathway. Conversely, the knockdown of SelS resulted in an enhancement of endothelial injury. These findings suggest that SelS could protect endothelial cells from oxidative stress injury under diabetic vascular endothelial bionic microenvironment through PKCα and PI3K/Akt/eNOS pathway. Our results offer a promising and biomimetic platform for investigation on endothelial protection, and provide evidence of SelS as potential novel target to treat diabetic macrovascular complications. Disclosure: S. Yu: None. Y. Zhong: None. L. Men: None. J. Yao: None. J. Du: None. Funding: National Natural Science Foundation of China (81570727) [ABSTRACT FROM AUTHOR]

The transport of materials and energy between rivers and riparian zones are driven by lateral hyporheic exchange and plays a vital role in regulating the ecological health of rivers. Owing to the limitations of models and methods, prior research has mainly focused on vertical hyporheic exchange in river systems. Combined with the collected riparian zone temperature and water level data, a 2D hydrothermal coupling model of the riparian zone was developed using the thermal conductivity model, and the fitting effects of the Lu et al. (2007) model and Su et al. (2016) model on temperature variations in riparian zone comparatively analyzed. Then, the dynamic variation characteristics of the riparian zone temperature and the lateral hyporheic exchange recharge pattern were investigated by the constructed models. The calibrated model could reasonably illustrate the variations in the riparian zone temperature, and the sensitivity analysis revealed that the hydraulic conductivity (Ks) is the most sensitive factor to the temperature variations. [ABSTRACT FROM AUTHOR]

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in db/db mice. The db/m and db/db mice were subcutaneously injected with G31P or equivalent normal saline once a day for 6 wk. The physical and metabolic parameters, glucose tolerance, insulin sensitivity, hepatic lipid accumulation, and inflammation markers were measured. G31P improved hepatic insulin sensitivity by modulating expression of genes related to gluconeogenesis and phosphorylated Akt levels. The expressions of several genes encoding proteins involved in de novo lipogenesis were decreased in G31P-treated db/db mice. Meanwhile, immune cell infiltration and cytokine release were attenuated in db/db mice with G31P treatment. G31P also improved the ratio of proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, G31P ameliorates metabolic disturbances via inhibition of CXCR1 and CXCR2 pathways in db/db mice. These data suggest that the selective inhibition of CXC chemokines may have therapeutic effects on symptoms associated with obesity and diabetes.