Mucosal Macrophage Polarization Role in the Immune Modulation

Immunotherapy has advantages including few side effects and low probability of abuse by patients. Recently, functional materials with immunomodulatory functions, which act through reduction of free radicals, have been developed for cancer and anti-inflammatory therapy. However, the therapeutic application of natural functional materials involves a complex mechanism along with various organic factors. These substances, including polysaccharides and triterpenoids, have immunomodulatory effects. However, to our knowledge, the mechanism underlying the action of such substances in the physiological immunity of animals remains unclear. Immune cells, particularly macrophages, are crucial in the modulation of immune response. Macrophages polarise into two types, namely, M1 and M2, from the M0 form, based on the physiological microenvironment factors. M1 macrophages have functions in pathogen elimination through phagocytosis, oxidative damage, and complement system activation. M2 macrophages are involved in tissue recovery and tumour tissues containing ample M2 macrophages that release growth factors, which promote angiogenesis. In this study, we focus on the immunomodulation of the macrophage to further understand the effects of the physiological microenvironment factors on macrophage polarisation

Toward a Community-oriented Development of Internet Platforms: a Qualitative Case Study

In this study, we seek to identify the development process of the virtual community. This study investigates the development process of two virtual communities: HSC (Home-stay Community) and UTC (University Teaching Community). This case study has produced two major findings. First, the sets of values established in a virtual community are related to the particular system functions employed in that community. While HSC members use blogs to collect related information and utilize forums to make bi-directional communication, UTC members seldom access blogs or edit Wiki pages. Second, motivation leads participants to join their community and to shape its boundaries. The information sharing process is shown to be an effective way of improving community development in the virtual context. Thus, managers are advised to pay attention to active and strongly-motivated players in the virtual context. Future studies may enrich the current investigation by focusing upon the relevant business models

Nutritional roles of selenium in cellular and mouse aging

Oxidative stress and persistent DNA damage response can lead to cellular senescence and aging. The ATM kinase and p53 protein play critical roles in the DNA damage response to reactive oxygen species and other DNA-damaging agents. Although the majority of selenoproteins carry antioxidant activities, little is known about the nutritional role of selenium (Se) in aging. Previous studies indicated that selenoprotein H (SelH) is very sensitive to dietary Se deficiency. Moreover, SelH is a nuclear selenoprotein that is proposed to carry redox domains and to transactivate redox genes including one for glutathione biosynthesis. To determine the role of SelH in genome maintenance, SelH and scrambled shRNA knockdown were stably established in MRC-5 human diploid fibroblast or immortalized cancer cells. SelH shRNA MRC-5 cells showed more pronounced induction of β-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation (γH2AX and phospho-ATM Ser-1981) as compared to scrambled shRNA cells. Interestingly, the slow proliferation in SelH shRNA MRC-5 cells was alleviated in the presence of ATM kinase inhibitors KU 55933 and KU 60019, by p53 shRNA knockdown, or by maintaining the cells in 3% O2 incubator (vs. ambient O2). Phospho-ATM Ser-1981 and γH2AX induction by H2O2 treatment (20 M) was temporally exacerbated in SelH shRNA but reversed in the scrambled shRNA MRC-5 cells 1-5 days after recovery. GFP-SelH did not relocalize to sites of oxidative DNA damage. Results from cologenic assays indicated that SelH shRNA HeLa cells were hypersensitive to paraquat and H2O2 but not to other clastogens including hydroxyurea, neocarzinostatin or camptothecin. The H2O2-induced cell death was attenuated in the presence of N-acetyl cysteine (NAC), a glutathione analogue, in SelH but not in scrambled shRNA HeLa cells. In conclusion, SelH protects against cellular senescence specifically to oxidative stress through a genome maintenance pathway involving ATM and p53. While recent research has demonstrated that mice unable to express selenoproteins in epidermal cells or in osteo-chondroprogenitor cells showed an apparently aging phenotype characterized by alopecia or bone abnormality, respectively. Thus, a role of selenium, particularly at nutritional levels of intake, in aging is largely unknown. What is lacking is an appropriate aging model of dietary Se deprivation displaying many features of normal aging. Telomere attrition provokes DNA damage response and, subsequently, replicative senescence. Because the chromosomes of mice carry longer telomeres than those of humans, the proposed hypothesis is that lengthy telomeres preclude mice deprived of Se to display aging phenotypes and age-related disorders. To test this hypothesis, weanling late generation Terc-/- mice were fed a Se-deficient diet or the diet supplemented with selenate (0.15 ppm) throughout their life. The objectives are to elucidate the role of Se in reducing age-related loss of function and begin to identify the key molecular mediators and selenoproteins during the aging process. As evidenced by changes in metabolic markers (body weight, glucose intolerance, insulin resistance and bone structure) and aging phenotypes (gray hair, alopecia, wound healing and telomere attrition), these data strongly indicate health span deterioration by dietary Se deficiency in the short telomere mice. MicroRNAs (miRNAs) are regulators of messenger RNA stability and translation and have been proposed as biomarkers for a variety of diseases and physiological conditions, including aging. A high-throughput platform, TaqMan low density array, was used to profile more than 800 miRNAs in plasma whose expression were validated by using individual quantitative PCR. The expression of a couple of miRNAs were induced both by dietary Se deprivation and aging. Altogether, a very interesting model of aging is established in this project by deprivation of Se that displays many hallmarks of human aging and can reveal the roles of Se at nutritional levels, in contrast with previous approaches, in which these essential roles in delaying health span deterioration may have been masked by lengthy telomeres

USING STEADY STATE AND TIME RESOLVED RAMAN SPECTROSCOPY TO STUDY THE VOLUME PHASE TRANSITION MOLECULAR MECHANISM OF POLY(N-ISOPROPYLACRYLAMIDE)

Thermo-responsive hydrogels undergo volume phase transition (VPT). The temperature responsive VPT can be utilized for preparation of ‘smart’ materials. An ideal smart responsive material (SRM) would be triggered by a slight chemical or environmental change and respond in a desirable and reproducible way. Cross-linked Poly(N-isopropyl)acrylamide (PNIPAM) has one of the largest and fastest VPT, exhibiting a volume difference up to 30 fold within 1µs when temperature increases past the lower critical solution temperature (LCST). As a result, PNIPAM is a great candidate for developing SRM. However, even though PNIPAM is the most widely studied thermal responsive polymer, a deep understanding of the molecular mechanisms involved in the VPT is still lacking. Our previous study found the time constant for dehydration of the amide group during VPT to be ~360 ns. In this study, a visible temperature jump (T-jump) Raman spectroscopy was constructed to monitor vibrational frequency of the isopropyl group and methylene backbone within PNIPAM during VPT. We found the VPT molecular mechanism occurs as the following: As the temperature elevates, the dehydration of the isopropyl groups occurs very quickly with a time constant ~68 ns, shortly after it is the dehydration of the polymer chains with a time constant ~104 ns. Finally, the dehydration of the amide group with a time constant ~ 360 ns

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation