Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties with several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used to ameliorate EAE in mice. METHODS: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and the proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for an apoptosis assay, JC-1 staining, imaging under a transmission electron microscope, and western blotting. RESULTS: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation, and decreased the expression levels of IL-2, IFN-γ, IL-1ß, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it induce apoptosis in the spinal cord. CONCLUSIONS: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

Outline of the biosynthesis and regulation of ergosterol in yeast.

Sterols are crucial functional components for eukaryotic cell membrane. Due to versatile activities, sterols show wide applications in food and pharmaceutical industries. Ergosterol not only reflects cell growth but also serves as the precursor for manufacturing steroid drugs. To date, the ergosterol biosynthetic pathway in yeast has been reported, and the industrial production of ergosterol is achieved by yeast fermentation or extraction from fungal mycelia. Here, we summarize its biosynthesis, regulation, transportation, and subcellular location of enzymes in yeast. In particular, we review the regulation of ergosterol biosynthesis at transcriptional, translational and post-translational levels. Furthermore, we advocate metabolic engineering and fermentation strategies for high-level production of ergosterol. This study may provide evaluable insights into metabolic engineering of yeast for scaled-up fermentation production of ergosterol or beyond.

Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases.

Mesenchymal stem cells (MSCs) negatively modulate immune properties. Induced pluripotent stem cells (iPSCs)-derived MSCs are alternative source of MSCs. However, the effects of iPSC-MSCs on T cells phenotypes in vivo remain unclear. We established an iPSC-MSC-transplanted host versus graft reaction mouse model using subcapsular kidney injection. Th1, Th2, regulatory T cells (Treg), and Th17 phenotypes and their cytokines were investigated in vivo and in vitro. The role of caspases and the soluble factors involved in the effects of MSCs were examined. We found that iPSC-MSC grafts led to more cell survival and less infiltration of inflammatory cells in mice. iPSC-MSC transplantation inhibited T cell proliferation, decreased Th1 and Th2 phenotypes and cytokines, upregulated Th17 and Treg subsets. Moreover, iPSC-MSCs inhibited the cleavage of caspases 3 and 8 and inhibition of caspases downregulated Th1, Th2 responses and upregulated Th17, Treg responses. Soluble factors were determined using protein array and TGF-ß1/2/3, IL-10, and MCP-1 were found to be highly expressed in iPSC-MSCs. The administration of the soluble factors decreased Th1/2 response, upregulated Treg response and inhibited the cleavage of caspases. Our results demonstrate that iPSC-MSCs regulate T cell responses as a result of a combined action of the above soluble factors secreted by iPSC-MSCs. These factors suppress T cell responses by inhibiting the cleavage of caspases. These data provide a novel immunomodulatory mechanism for the underlying iPSC-MSC-based immunomodulatory effects on T cell responses. Stem Cells 2017;35:1719-1732.

As2 O3 combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model.

Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation.

Investigation and Analysis of Risk Factors and Psychological Status of Chronic Obstructive Pulmonary Disease in Permanent Residents Aged 40 or Older in Hongyuan County, Aba Prefecture, Sichuan Province.

Background: COPD is an important public health problem worldwide, and there is a lack of epidemiological data on COPD in high-altitude areas in Sichuan province. Thus, we aimed to investigate the prevalence, risk factors and psychological status of COPD in Hongyuan County, Aba Prefecture, Sichuan Province, which is located at an average altitude of 3507 meters. Methods: The 40 years old or greater permanent residents of Hongyuan County were selected by random sampling method, and the lung function test and questionnaires were conducted to determine the disease situation of COPD. The prevalence of COPD was compared among different factors of investigation, and multivariate logistic regression analysis was used for different factors to determine the independent influencing factors of COPD disease. Results: A total of 456 permanent residents aged 40 years or older in Hongyuan County, 436 qualified for quality control, among which 53 cases confirmed COPD, the total prevalence was 12.16%, among which the prevalence was 14.55% for men and it was 8.07% for women. There were significant differences in different gender, ethnicity, age, smoking status, smoking years, educational level, heating style, history of tuberculosis, and prevalence of BMI (P <0.05). Binary logistic regression analysis showed that age ≥60 years (OR = 2.810, 95% CI: 1.0457.557), Han Nationality (OR: 3.238, 95% CI: 1.290-8.127), the heating method including biofuels (OR: 18.119, 95% CI: 4.140-79.303) and coals (OR: 6.973, 95% CI: 1.856-26.200), medical history of pulmonary tuberculosis (OR: 2.670, 95% CI: 1.278-5.578), the education level including junior high school (OR: 3.336, 95% CI: 1.2259.075), high school and above (OR: 5.910, 95% CI: 1.796-19.450), and smoking (OR: 10.774, 95% CI: 3.622-32.051) were independent risk factors for COPD disease. The prevalence of anxiety was 16.98%, and the prevalence of depression was 13.2%. Conclusion: The prevalence of COPD in Hongyuan County was higher than the national level; age, ethnic group, education, smoking, heating method, and history of tuberculosis are the independent influencing factors of COPD in Hongyuan County. The prevalence of anxiety and depression is low.

Islet transplantation reverses the effects of maternal diabetes on mouse oocytes.

Maternal diabetes adversely affects preimplantation embryo development and oocyte maturation. Thus, it is important to identify ways to eliminate the effects of maternal diabetes on preimplantation embryos and oocytes. The objectives of this study were to investigate whether islet transplantation could reverse the effects of diabetes on oocytes. Our results revealed that maternal diabetes induced decreased ovulation; increased the frequency of meiotic spindle defects, chromosome misalignment, and aneuploidy; increased the relative expression levels of Mad2 and Bub1; and enhanced the sensitivity of oocytes to parthenogenetic activation. Islet transplantation prevented these detrimental effects. Therefore, we concluded that islet transplantation could reverse the effects of diabetes on oocytes, and that this technique may be useful to treat the fundamental reproductive problems of women with diabetes mellitus.

Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice.

The role of arsenic trioxide (As2O3) in inhibiting immune rejection and prolonging islet allograft survival has been identified in islet allotransplantation. This study aims to explore the role of As2O3 in islet xenotransplantation and the action mechanism. The streptozotocin (STZ) was used in C57BL/6 mice to induce the type 1 diabetes mellitus (T1DM) for xenotransplantation models establishment. Donor islets were isolated by digesting. The flow cytometry (FCM) was used to analyze lymphocyte types. The blood sugar level was detected by using intraperitoneal glucose tolerance test (IPGTT). The serum level of cytokines was determined by the enzyme-linked immunosorbent assay (ELIZA). The cell proliferation was measured by MTT assay. The mRNA levels were quantified with qRT-PCR. As2O3 prolonged the survival of the recipient mice but had no influence on body weight. As2O3 protected the function of xenograft in insulin secretion and suppressed immune rejection of recipient. As2O3 inhibited proliferation of T lymphocyte and increased the proportion of Foxp3+ regulatory T cells in recipient mice. As2O3 inhibited activation and promoted clonal anergy of T lymphocyte. As2O3 decreased total number of B cells and reduced partial antibody levels in recipient mice. As2O3 and leflunomide showed a synergistic effect in suppressing islet xenotransplant rejection. As2O3 prolongs islet xenograft survival by inhibiting cellular immune response, and increasing Foxp3+ regulatory T cells, while decreasing partial antibody levels in serum.

Treatment of displaced radial head fractures by internal fixation with absorbable pins.

OBJECTIVE: To study the effect of internal fixation with absorbable pins on treatment of displaced radial head fractures. METHODS: From May 1999 to May 2004, 16 patients with displaced radial head fractures (Mason types II and III) were treated with internal fixation by absorbable pins. The duration of follow-up averaged 22.6 months (12-58 months). The outcome was assessed on the basis of elbow motion, radiographic findings and the functional rating score delineated by Broberg and Morrey. RESULTS: All fractures healed within 10 months without avascular necrosis of radial head. The mean elbow flexion loss was 15 degrees (0 degrees-35 degrees), and pronation and supination decreased by 10 degrees (0 degrees-30 degrees) on average compared with those of the contralateral elbow. Five patients had an excellent result, 6 a good result, and 3 a fair result according to the criteria of Borberg and Morrey. CONCLUSIONS: Internal fixation with absorbable pins is an effective method in treating displaced radial head fractures. It can maintain the biomechanical stability of forearm, improve the elbow function and avoid second operation.

Detection of Majorana fermions by Fano resonance in hybrid nanostructures.

The realization and detection of Majorana fermions in condensed matter systems are of considerable importance and interest. We propose a scheme to detect the Majorana fermions by Fano resonance in hybrid nanostructures made of semiconductor quantum dots and quantum wire in proximity to superconductor. Through detailed theoretical studies of the transport properties of our hybrid nanostructures based on the non-equilibrium Green's function technique and the equation of motion approach, it is found that the Fano resonance in the current response due to the interference among different transmission paths may give clear signature of the existence of Majorana modes. Moreover, we have found a peculiar relationship between the Fano factor q and the Majorana bound state coupling strength/the length of nanowire, which can be used for a design of an electronic nanoruler. Our method of detection of Majorana fermions based on Fano resonance is related to the global conductance profile, thus is robust to perturbations.

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation.

Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×10(6) iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (>100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4(+) and CD8(+) T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-ß was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.

Immunosuppressive effect of compound K on islet transplantation in an STZ-induced diabetic mouse model.

Islet transplantation is a therapeutic option for type 1 diabetes, but its long-term success is limited by islet allograft survival. Many factors imperil islet survival, especially the adverse effects and toxicity due to clinical immunosuppressants. Compound (Cpd) K is a synthesized analog of highly unsaturated fatty acids from Isatis tinctoria L. (Cruciferae). Here we investigated the therapeutic effect of Cpd K in diabetic mice and found that it significantly prolonged islet allograft survival with minimal adverse effects after 10 days. Furthermore, it reduced the proportion of CD4(+) and CD8(+) T cells in spleen and lymph nodes, inhibited inflammatory cell infiltration in allografts, suppressed serum interleukin-2 and interferon-γ secretion, and increased transforming growth factor-ß and Foxp3 mRNA expression. Surprisingly, Cpd K and rapamycin had a synergistic effect. Cpd K suppressed proliferation of naïve T cells by inducing T-cell anergy and promoting the generation of regulatory T cells. In addition, nuclear factor-κB signaling was also blocked. Taken together, these findings indicate that Cpd K may have a potential immunosuppressant effect on islet transplantation.

Novel function of N,N-bis(2-chloroethyl)docos-13-enamide for reversal of multidrug resistance in tongue cancer.

Multidrug resistance (MDR) is a key element in the failure of chemotherapies, and development of agents to overcome MDR is crucial to improving cancer treatments. The overexpression of glutathione-S-transferases (GSTs) is one of the major mechanisms of MDR. Because some agents used in traditional Chinese medicine have strong antitumor effects coupled with low toxicity; we investigated the ability of N,N-bis(2-chloroethyl)docos-13-enamide (compound J), the synthesized analog of a highly unsaturated fatty acid from Isatis tinctoria L., to reverse the MDR induced by adriamycin (ADM) in TCA8113/ADM cells. We found that compound J significantly increased the cytotoxicity of ADM in TCA8113/ADM cells, with a reversal fold of 2.461. Analysis of the mechanisms through which compound J reversed MDR indicated that compound J significantly decreased the activity of GSTs and enhanced the depletion of GSH in TCA8113/ADM cells, but did not affect the P-glycoprotein (P-gp) efflux. Taken together, our data suggested that compound J was an excellent candidate for reversing MDR in cancer therapy.