Chemokine receptor CCR5 functionally couples to inhibitory G proteins and undergoes desensitization

Chemokine receptor CCR5 is not only essential for chemotaxis of leukocytes but also has been shown to be a key coreceptor for HIV-1 infection. In the present study, hemagglutinin epitope-tagged human CCR5 receptor was stably expressed in Chinese hamster ovary cells or transiently expressed in NG108–15 cells to investigate CCR5-mediated signaling events. The surface expression of CCR5 was confirmed by flow cytometry analysis. The CCR5 agonist RANTES stimulated [³⁵S]GTPγS binding to the cell membranes and induced inhibition on adenylyl cyclase activity in cells expressing CCR5. The effects of RANTES were CCR5 dependent and could be blocked by pertussis toxin. Furthermore, overexpression of Giα2 strongly increased both RANTES-dependent G-protein activation and inhibition on adenylyl cyclase in cells cotransfected with CCR5. These data demonstrated directly that activation of CCR5 stimulated membrane-associated inhibitory G proteins and indicated that CCR5 could functionally couple to G-protein subtype Giα2. The abilities of CCR5 to activate G protein and to inhibit cellular cAMP accumulation were significantly diminished after a brief prechallenge with RANTES, showing rapid desensitization of the receptor-mediated responsiveness. Prolonged exposure of the cells to RANTES caused significant reduction of surface CCR5 as measured by flow cytometry, indicative of agonist-dependent receptor internalization. Our data thus demonstrated that CCR5 functionally couples to membrane-associated inhibitory G proteins and undergoes agonist-dependent desensitization and internalization. J. Cell. Biochem. 71:36–45, 1998. © 1998 Wiley-Liss, Inc.     

Serum Concentrations of 15 Elements Among <Emphasis Type="Italic">Helicobacter Pylori</Emphasis>-Infected Residents from Lujiang County with High Gastric Cancer Risk in Eastern China

Data on the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress among women with polycystic ovary syndrome (PCOS) are scarce. The objective of this study was to assess the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress in women with PCOS. Sixty PCOS women were randomized into two groups and treated with 100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D supplements (n = 30), or placebo (n = 30) twice a day for 12 weeks. Hormonal profiles, biomarkers of inflammation, and oxidative stress were assessed at baseline and at end-of-treatment. After the 12-week intervention, compared with the placebo, magnesium-zinc-calcium-vitamin D co-supplementation resulted in significant reductions in hirsutism (?2.4 ± 1.2 vs. ?0.1 ± 0.4, P < 0.001), serum high sensitivity C-reactive protein (?0.7 ± 0.8 vs. +0.2 ± 1.8 mg/L, P < 0.001), and plasma malondialdehyde (?0.4 ± 0.3 vs. +0.2 ± 1.0 μmol/L, P = 0.01), and a significant increase in plasma total antioxidant capacity concentrations (+46.6 ± 66.5 vs. ?7.7 ± 130.1 mmol/L, P = 0.04). We failed to find any significant effect of magnesium-zinc-calcium-vitamin D co-supplementation on free androgen index, and other biomarkers of inflammation and oxidative stress. Overall, magnesium-zinc-calcium-vitamin D co-supplementation for 12 weeks among PCOS women had beneficial effects on hormonal profiles, biomarkers of inflammation, and oxidative stress.     

Biobased poly(propylene sebacate) as shape memory polymer with tunable switching temperature for potential biomedical applications

From the point of better biocompatibility and sustainability, biobased shape memory polymers (SMPs) are highly desired. We used 1,3-propanediol, sebacic acid, and itaconic acid, which have been industrially produced via fermentation or extraction with large quantities as the main raw materials for the synthesis of biobased poly(propylene sebacate). Diethylene glycol was used to tailor the flexibility of the polyester. The resulted polyesters were found to be promising SMPs with excellent shape recovery and fixity (near 100% and independent of thermomechanical cycles). The switching temperature and recovery speed of the SMPs are tunable by controlling the composition of the polyesters and their curing extent. The continuously changed switching temperature ranging from 12 to 54 °C was realized. Such temperature range is typical for biomedical applications in the human body. The molecular and crystalline structures were explored to correlate to the shape memory behavior. The combination of potential biocompatibility and biodegradability of the biobased SMPs makes them suitable for fabricating biomedical devices.     

Autophagy regulates apoptosis by targeting NOXA for degradation

Apoptosis and autophagy mutually regulate various cellular physiological and pathological processes. The crosstalk between autophagy and apoptosis is multifaceted and complicated. Elucidating the molecular mechanism of their crosstalk will advance the therapeutic applications of autophagy for treating cancer and other diseases. NOXA, a BH3-only member of the BCL-2 family, was reported to induce apoptosis and promote autophagy. Here, we report that autophagy regulates apoptosis by targeting NOXA for degradation. Inhibiting autophagy increases NOXA protein levels by extending the protein half-life. NOXA accumulation effectively suppresses tumor cell growth by inducing apoptosis, which is further enhanced when p53 is present. Mechanistically, NOXA is hijacked by p62 as autophagic cargo, and its three lysine residues at the C-terminus are necessary for NOXA degradation in lysosomes. Taken together, our study demonstrates that NOXA serves as a bridge in the crosstalk between autophagy and apoptosis and implies that autophagy inhibitors could be an effective therapy for cancer, especially wild-type p53-containing cancer.     

Indoor Thin‐Film Photovoltaics: Progress and Challenges

Energy generation and consumption have always been an important component of social development. Interests in this field are beginning to shift to indoor photovoltaics (IPV) which can serve as power sources under low light conditions to meet the energy needs of rapidly growing fields, such as intelligence gathering and information processing which usually operate via the Internet‐of‐things (IoT). Since the power requirements for this purpose continue to decrease, IPV systems under low light may facilitate the realization of self‐powered high‐tech electronic devices connected through the IoT. This review discusses and compares the characteristics of different types of IPV devices such as those based on silicon, dye, III‐V semiconductors, organic compounds, and halide perovskites. Among them, specific attention is paid to perovskite photovoltaics which may potentially become a high performing IPV system due to the fascinating photophysics of the halide perovskite active layer. The limitations of such indoor application as they relate to the toxicity, stability, and electronic structure of halide perovskites are also discussed. Finally, strategies which could produce highly functional, nontoxic, and stable perovskite photovoltaics devices for indoor applications are proposed.     

Inhibition of fatty acid synthase suppresses U-2 OS cell invasion and migration via downregulating the activity of HER2/PI3K/AKT signaling pathway in vitro

FASN plays an important role in the malignant phenotype of various tumors. Our previous studies show that inhibition FASN could induce apoptosis and inhibit proliferation in human osteosarcoma (OS) cell in vivo and vitro. The aim in this study was to investigate the effect of inhibition FASN on the activity of HER2/PI3K/AKT axis and invasion and migration of OS cell. The expression of FASN, HER2 and p-HER2(Y1248) proteins was detected by immunohistochemistry in OS tissues from 24 patients with pulmonary metastatic disease, and the relationship between FASN and p-HER2 as well as HER2 was investigated. The results showed that there was a positive correlation between FASN and HER2 as well as p-HER2 protein expression. The U-2 OS cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid. FASN mRNA was measured by RT-PCR. Western blot assays was performed to examine the protein expression of FASN, HER2, p-HER2(Y1248), PI3K, Akt and p-Akt (Ser473). Migration and invasion of cells were investigated by wound healing and transwell invasion assays. The results showed that the activity of HER2/PI3K/AKT signaling pathway was suppressed by inhibiting FASN. Meanwhile, the U-2OS cells migration and invasion were also impaired by inhibiting the activity of FASN/HER2/PI3K/AKT. Our results indicated that inhibition of FASN suppresses OS cell invasion and migration via down-regulation of the “HER2/PI3K/AKT” axis in vitro. FASN blocker may be a new therapeutic strategy in OS management.     

Triptolide inhibits colon cancer cell proliferation and induces cleavage and translocation of 14‐3‐3 epsilon

Triptolide is a diterpenoid triepoxide derived from the traditional Chinese medical herb Tripterygium wilfordii. In the present study, we demonstrated that this phytochemical attenuated colon cancer growth in vitro and in vivo. Using a proteomic approach, we found that 14‐3‐3 epsilon, a cell cycle‐ and apoptosis‐related protein, was altered in colon cancer cells treated with triptolide. In this regard, triptolide induced cleavage and perinuclear translocation of 14‐3‐3 epsilon. Taken together, our findings suggest that triptolide may merit investigation as a potential therapeutic agent for colon cancer, and its anticancer action may be associated with alteration of 14‐3‐3 epsilon. Copyright © 2012 John Wiley & Sons, Ltd.     

Analysis of multivariate recurrent event data with time‐dependent covariates and informative censoring

Multivariate recurrent event data are usually encountered in many clinical and longitudinal studies in which each study subject may experience multiple recurrent events. For the analysis of such data, most existing approaches have been proposed under the assumption that the censoring times are noninformative, which may not be true especially when the observation of recurrent events is terminated by a failure event. In this article, we consider regression analysis of multivariate recurrent event data with both time‐dependent and time‐independent covariates where the censoring times and the recurrent event process are allowed to be correlated via a frailty. The proposed joint model is flexible where both the distributions of censoring and frailty variables are left unspecified. We propose a pairwise pseudolikelihood approach and an estimating equation‐based approach for estimating coefficients of time‐dependent and time‐independent covariates, respectively. The large sample properties of the proposed estimates are established, while the finite‐sample properties are demonstrated by simulation studies. The proposed methods are applied to the analysis of a set of bivariate recurrent event data from a study of platelet transfusion reactions.