Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.

BACKGROUND AND AIMS: Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion. METHODS: The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription. RESULTS: Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion. CONCLUSIONS: This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.

Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys.

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by in vivo and in vitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15 weeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.

Analysis of the Elderly's Preferences for Choosing Medical Service Facilities from the Perspective of Accessibility: A Case Study of Tertiary General Hospitals in Hefei, China.

The accessibility of medical service facilities is a vital influence on elderly people choosing medical treatment. Encouraging residents to seek nearby medical treatment can facilitate the rational layout and diversion of urban medical facilities and reduce health resource waste. However, due to accessibility factors, elderly people may not choose the nearest hospital. In order to investigate such factors, we conducted a questionnaire survey among the elderly from 10 tertiary general hospitals in Hefei, China. On the basis of the origin-destination (OD) cost matrix analysis and statistical analysis of 830 valid questionnaires, this paper analyzed the elders' selection rules when choosing medical facilities and the factors considered when making a choice. The study found that although 85% of elderly participants valued a short distance to tertiary hospitals, only 31% of them attended the closest hospitals in reality, which correlated with regularity according to their education level, travel activity status, and place of residence. The elderly highlighted road congestion, convenience of public transport stations, and number of transfers as critical in determining whether they sought nearby medical treatment. According to the results, effective ways to encourage the elderly to attend their nearest hospital, from the perspective of accessibility, include easing road congestion, improving the layout of public transport stations, and optimizing urban public transport routes. In particular, when planning future medical facilities, attention should be paid to the elderly with primary school education or below, who cannot travel independently, and those who live far from the city center.

Influence of Hospital Outdoor Rest Space on the Eye Movement Measures and Self-Rating Restoration of Staff.

Objective: To investigate the effect of hospital outdoor rest space on the eye movement measures and self-rating restoration of staff. Background: Relieving the pressure of hospital staff through exposure to hospital outdoor rest space is essential, but there is a scarcity of research on the impact of hospital outdoor rest space on the eye movement measures and self-rating restoration of staff, especially for large Chinese hospitals. Methods: Cross-analysis was conducted based on the eye movement measures of 76 staff members obtained by eye movement tracking equipment in combination with the self-rating restoration scale and hospital outdoor rest space picture attributes (element proportion and position, brightness and saturation). Results: The differences in eye movement measures of different staff attributes (occupation, age, and gender) were identified, and the effects of hospital outdoor rest space picture attributes on the eye movement measures and self-rating restoration scale of staff were summarized. A number of proposals were also formulated: hospital outdoor rest space should be set up close to the working area of the group of medical staff; attention should be paid to the actual needs of senior staff members and the work pressure of junior nurses; the exposure to natural environment should be increased and the proportion of hard artificial elements should be reduced; the natural environment should be placed in the visual center; the saturation and brightness of hospital outdoor rest space should be increased; and staff members should have access to the sky environment in a variety of ways. Conclusion: The present study is an empirical study of evidence-based design on hospital outdoor rest space in China, and the results reveal the effects of hospital outdoor rest space on the eye movement measures and self-rating restoration of staff.

Influence of Hospital Outdoor Space on Physiological Electroencephalography (EEG) Feedback of Staff.

OBJECTIVES: To investigate the differences and relationships between different outdoor spaces of hospitals on the physiological electroencephalography (EEG) feedback (PEEGF) of staff. BACKGROUND: Relieving the pressure of hospital staff is essential, and several studies have revealed that even short-term exposure to outdoor space has a decompression effect. Yet, the focus is scarcely centered on the differences and influential relationships between the PEEGF from different outdoor spaces where the staff spend time, particularly in large-scale hospitals in China. METHODS: EEG measurement equipment was utilized to obtain the value of ß wave (vßw) that represents the stress and anxiety of staff in three different outdoor spaces: open, traffic, and rest. On the basis of EEG data, correlation analysis was conducted in accordance with the proportion of space elements. RESULTS: The proportion of natural elements, such as landscape (r = -.800** p=.005) and waterscape (r = -.782* p=.013), were negatively correlated with the vßw produced by staff, while the proportion of hard paving was positive (r = .817** p=.004) with more vßw produced by staff. In other words, the percentage of landscape and waterscape can reduce stress, while hard paving has the opposite effect. Further, there was a difference in the amount of vßw generated between nurses and administrators in the open space at the entrance of the main building (p = .043). CONCLUSIONS: The present study revealed the influence of different outdoor space elements of the hospital on the physiological feedback of staff, demonstrated the practical necessity of evidence-based design, and proposed relevant optimization suggestions.

Dynamic changes in insulin and glucagon during disease progression in rhesus monkeys with obesity-related type 2 diabetes mellitus.

AIMS: To investigate the progression of obesity-related type 2 diabetes mellitus (T2DM) in rhesus monkeys, especially dynamic changes in insulin and glucagon. MATERIALS AND METHODS: We followed a cohort of 52 rhesus monkeys for 7 years throughout the progression of obesity-related T2DM. Intravenous glucose tolerance tests were performed every 6 months to evaluate dynamic changes in glucose, insulin and glucagon levels. RESULTS: Obesity in rhesus monkeys increased the overall mortality and T2DM morbidity. During the progression of T2DM, glucagon remained consistently elevated, while insulin initially increased in compensation but then dropped to below normal levels when the monkeys developed overt T2DM. After a glucose challenge, both the first and second phases of insulin secretion increased during the early stage of T2DM; in later stages the first phase was delayed and the second phase was diminished. CONCLUSION: Our findings showed that, beside the decreased insulin level, hyperglucagonaemia also plays an important role in the development of T2DM.

Central role of RIPK1-VDAC1 pathway on cardiac impairment in a non-human primate model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by destructive polyarthritis and systemic complications. It increases cardiovascular morbidity and mortality. However, the mechanism underlying RA-related cardiac damage remains largely unknown. Here, we found and characterized a non-human primate (NHP) model with spontaneous RA similar to the human conditions. Compared with the control group, the cardiac function in RA monkeys showed progressively deterioration; histologically, we found significantly increased inflammatory cell infiltration, cell death, and fibrosis in RA monkey heart tissue. Mechanistically, the upregulated receptor-interacting protein kinase 1 (RIPK1) in RA monkey heart tissue bound to voltage-dependent anion-selective channel 1 (VDAC1), increased VDAC1 oligomerization, and subsequently induced cardiac cell death and functional impairment. These findings identified that RIPK1-VDAC1 pathway is a promising target to treat cardiac impairment in RA. This unique model of RA will provide a valuable tool for mechanistic and translational studies.

RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2+ Uptake and Promotes Colorectal Oncogenesis.

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat colorectal cancer.Significance: RIPK1-mediated cell proliferation through MCU is a central mechanism underlying colorectal cancer progression and may prove to be an important therapeutic target for colorectal cancer treatment. Cancer Res; 78(11); 2876-85. ©2018 AACR.

Tetra-aqua-bis-[N,N'-bis-(pyridin-3-yl-methyl-idene)benzene-1,4-diamine]-zinc dinitrate 1.49-hydrate.

In the title compound, [Zn(C(18)H(14)N(4))(2)(H(2)O)(4)](NO(3))(2)·1.49H(2)O, the Zn(II) atom, lying on an inversion center, is coordinated by two N atoms from two N,N'-bis-(pyridin-3-yl-methyl-idene)benzene-1,4-diamine ligands and four water mol-ecules in a distorted octa-hedral geometry. The nitrate anion is disordered over two sets of sites, with an occupancy ratio of 0.744 (4):0.256 (4). The uncoordinated water mol-ecule is also disordered with an occupancy factor of 0.744 (4). O-H⋯O and O-H⋯N hydrogen bonds link the complex cations, nitrate anions and uncoordinated water mol-ecules into a supra-molecular layer parallel to (102).