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Background Radiation-induced lung fibrosis (RILF) is a severe and life-threatening complication of thoracic radiotherapy. Cell death is the key issue in RILF. Ferroptosis is a form programmed cell death implicated in the pathologies of inflammation. This study aimed to investigate the role of ferroptosis in RILF, and the effectiveness and the potential underlying mechanism of ferroptosis inhibitor on RILF. Methods Immunofluorescence, western blot and RT-PCR assays were performed to examine the ferroptosis maker glutathione peroxidase 4 (GPX4) in a mice RILF model. The lung tissue sections were stained with hematoxylin and eosin (H&E), Masson trichrome staining and Sirius-Red staining to evaluate the histopathological changes in RILF mice. Reactive oxygen species (ROS) and hydroxyproline (HYP) in lungs were measured by the relevant kits. The serum levels of inflammatory cytokines (TNF-α, IL-6, IL-10, and TGF-β1) were measured with Elisa. The protein and mRNA levels of GPX4, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO1) and quinone oxidoreductase 1 (NQO1) in lungs were examined by western blot and RT-PCR. Results GPX4 levels of the irradiated lungs were significantly down-regulated than the groups with no irradiation, and the ferroptosis inhibitor, liproxstatin-1, increased GPX4 levels significantly in RILF mice. Treatment with liproxstatin-1 lowered the Szapiel and Ashcroft scores significantly, down-regulated the levels of ROS and HYP in lungs and reduced the serum inflammatory cytokines levels in RILF mice. The protein and the mRNA levels of Nrf2, HO1 and NQO1 were up-regulated by liproxsratin-1 in RILF. Conclusions Our data suggested that ferroptosis played a critical role in RILF, ferroptosis inhibitor liproxstatin-1 alleviated RILF via down-regulation of TGF-β1 by the activation of Nrf2 pathway. The effectiveness of ferroptosis inhibition on RILF provides a novel therapeutic target for RILF.

Antibacterial materials have found widespread interest in different fields nowadays. In this study, curcumin (Cur) was incorporated into the polyvinyl butyral (PVB) matrix by dissolving in ethanol for improving the functional properties of a pure PVB film. We found that Cur was uniformly dispersed in the PVB matrix, which showed good compatibility. Moreover, the incorporation of Cur could also improve thermal stability, hydrophilicity, and mechanical property. The UV-vis spectra of the PVB–Cur film demonstrated that the film could block ultraviolet radiation. Subsequently, the antibacterial activity of the PVB–Cur film was measured by the colony-counting method against and . The results showed that the PVB–Cur film exhibited good antibacterial activity. Therefore, the PVB–Cur film was considered as a promising material for food and medical packaging applications.

Oxygen vacancies (O v ) on metal oxide surfaces exhibit high catalytic activity for activating peroxymonosulfate (PMS) in wastewater decontamination, yet their in-situ regeneration remains a significant challenge. This study successfully achieves in-situ real-time regeneration of O v on CuO surfaces through simple alkali etching without interrupting the contaminant removal process. The surface hydroxyl groups introduced by alkali treatment significantly reduce the formation energy of O v on CuO surfaces from 1.60 eV to 0.38 eV. Both experimental results and density functional theory calculations reveal that the high activity of CuO relies on the synergy of surface hydroxyl groups and O v . This synergy increases the antibonding states below the Fermi level and the electron spin density of Cu near O v , thereby promoting electron transfer from CuO to PMS. As a result, by just adding an equimolar amount of alkali relative to PMS in CuO/PMS system, the degradation rate constant of sulfamethoxazole (SMX) greatly increases by 42 times. The primary reactive oxygen species in this system are sulfate radicals and hydroxyl radicals. Furthermore, OH - /CuO/PMS system exhibits a long-term stability (> 300 h) for SMX removal in a real water matrix. This work provides a highly executable method to in-situ real-time regenerate O v on CuO surfaces, representing significant progress in the critical yet underappreciated field of catalyst regeneration. This study demonstrates that simple alkali etching enables in-situ regeneration of oxygen vacancies on CuO, enhancing peroxymonosulfate activation for efficient pollutant degradation with a 42-fold increase and long-term stability.

Due to rapid urbanization, industrialization, agricultural development, and mining activities, soil heavy metal pollution has become a severe issue in China. To explore the regional heavy metal ecological risk of lake sediment and surrounding topsoil, we analyzed 237 lakes, with 1797 lake sediment sampling points and 1164 surrounding topsoil sampling points. Lower mean concentrations were detected for most heavy metals in soils than sediment (except for Hg). Cd and Hg in sediments and soils showed a more significant variation, with the coefficient of variation exceeding 110%. Linear regressions and Pearson’s correlation analyses demonstrated that sediments and soils exhibited significant positive correlations. The principal heavy metals exceeding the Agricultural Soil Control Standard (ASCS) in sediments and soils were As and Cd, respectively. The Yunnan-Guizhou Plateau Lake Region (YGPLR) was the most seriously affected, exceeding the ASCS for Cd. The lakes with the most severe pollution were located in YGPLR impacted by the high background concentration of heavy metals in soil and mineral development activities. The Eastern Plain Lake Region, the Southeast Lake Region, and the Northeast Plain and Mountain Lake Region showed a clear anthropogenic impact. Lakes in the Inner Mongolia-Xinjiang Lake Region and the Tibetan Plateau Lake Region were estimated to have relatively low ecological risks due to their sparse population and slight environmental disturbance. The impact of geochemical factors on the ecological risk of heavy metals in lake sediments is more substantial than that of human activities at the regional scale.

HIV/AIDS prevention Clinical trials of microbicides as a means of preventing the transmission of HIV-1 to women have proved disappointing. Now a study in the simian immunodeficiency virus (SIV)–rhesus macaque vaginal transmission model for HIV infection suggests that a prophylactic approach might yet be worth pursuing. The commonly used antimicrobial compound glycerol monolaurate (GML) was found to suppress SIV infection even after repeated virus exposure. But its mechanism of action was surprising. The host's inflammatory response to the virus, rather than helping, was shown to fuel the infection by recruiting the very CD4 + T cells that the virus targets. GML's prophylactic action appeared to result from its ability to block this host response, rather than from a direct effect on the virus. This points to cell signalling and innate host responses in the mucosal cells as potential targets for drugs and vaccines aimed at preventing infection by HIV — and by other pathogens too if they use similar infection strategies. Glycerol monolaurate in a microbicide is shown to protect monkeys from infection after intra-vaginal exposure to high doses of SIV. The suppressive activity may be due to the inhibition of target cell recruitment due to glycerol-monolaurate-mediated inhibition of epithelial cell signalling and inflammatory cytokine expression. Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection 1 , preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission 2 , 3 , 4 . Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque ( Macacca mulatta ) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry 5 , 6 . Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5 + cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4 + T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound 7 with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines 8 —can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro , and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.

HIV: stop it in its tracks Two papers in this issue shed light on the early stages of HIV infection. HIV gradually infects and destroys disease-fighting CD4 + T cells in the blood, but also causes loss of CD4 + T cells from mucosal surfaces such as the gut in the initial infection phase. Studies in monkeys infected with simian immunodeficiency virus (SIV) now show that the virus infects and kills memory CD4 + T cells, a T-cell subset responsible for remembering previous infections. Mattapallil et al . found that SIV infects about 50% of memory CD4 + T cells within days of infection. Li et al . show that as well as killing by direct infection, the virus triggers uninfected cells to self-destruct via apoptosis. These findings have clinical implications, stressing the need to reduce viral load at the early stage of infection. In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system 1 , is a principal site of both virus production and depletion of primarily lamina propria memory CD4 + T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4 + T cells. Surprisingly, most of the initially infected memory cells were not, as expected 10 , 11 , activated but were instead immunophenotypically ‘resting’ cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes 12 , 13 , are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4 + T-cell targets to sustain infection, virus production also triggered 14 an immunopathologically limiting Fas–Fas-ligand-mediated apoptotic pathway 15 , 16 in lamina propria CD4 + T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4 + T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4 + T cells in the effector arm of GALT. The scale of this CD4 + T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.

Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.

Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV.

Accumulating evidences supported that knock-down of DHCR24 is linked to the pathological risk factors of AD, suggesting a potential role of DHCR24 in AD pathogenesis. However, the molecular mechanism link between DHCR24 and tauopathy remains unknown. Here, in order to elucidate the relationship between DHCR24 and tauopathy, we will focus on the effect of DHCR24 on the tau hyperphosphorylation at some toxic sites. In present study, we found that DHCR24 knock-down significantly lead to the hyperphosphorylation of tau sites at Thr181, Ser199, Thr231, Ser262, Ser396. Moreover, DHCR24 knock-down also increase the accumulation of p62 protein, simultaneously decreased the ratio of LC3-II/LC3-I and the number of autophagosome compared to the control groups, suggesting the inhibition of autophagy activity. In contrast, DHCR24 knock-in obviously abolished the effect of DHCR24 knock-down on tau hyperphosphrylation and autophagy. In addition, to elucidate the association between DHCR24 and tauopathy, we further showed that the level of plasma membrane cholesterol, lipid raft-anchored protein caveolin-1, and concomitantly total I class PI3-K (p110α), phospho-Akt (Thr308 and Ser473) were significantly decreased, resulting in the disruption of lipid raft/caveola and inhibition of PI3-K/Akt signaling in silencing DHCR24 SH-SY5Y cells compared to control groups. At the same time, DHCR24 knock-down simultaneously decreased the level of phosphorylated GSK3β at Ser9 (inactive form) and increased the level of phosphorylated mTOR at Ser2448 (active form), leading to overactivation of GSK3β and mTOR signaling. On the contrary, DHCR24 knock-in largely increased the level of membrane cholesterol and caveolin-1, suggesting the enhancement of lipid raft/caveola. And synchronously DHCR24 knock-in also abolished the effect of DHCR24 knock-down on the inhibition of PI3-K/Akt signaling as well as the overactivation of GSK3β and mTOR signaling. Collectively, our data strongly supported DHCR24 knock-down lead to tau hyperphosphorylation and the inhibition of autophagy by a lipid raft-dependent PI3-K/Akt-mediated GSK3β and mTOR signaling. Taking together, our results firstly demonstrated that the decrease of plasma membrane cholesterol mediated by DHCR24 deficiency might contribute to the tauopathy in AD and other tauopathies.

Indian rhesus macaques are vaccinated with simian immunodeficiency virus (SIV)-restricted CD8 + T-cell epitopes, and these vaccinated animals are shown to mediate elite control of virus replication. Making more of natural resistance to HIV Indian rhesus macaques expressing the Mamu-B * 08 molecule, which has important structural similarities to the human leukocyte antigen class I molecule HLA-B * 27, show a degree of control over the highly pathogenic SIVmac239 virus. This system provides a model for the rare cases in which people with HIV achieve 'elite control' over the virus. Here, David Watkins and colleagues show that vaccine-induced CD8 + T cells narrowly directed against three immunodominant T-cell epitopes bound by Mamu-B * 08 (Vif RL8, Vif RL9 and Nef RL10) can control the replication of SIVmac239 in Mamu-B * 08 + macaques. This work could provide pointers to the development of vaccines capable of achieving long-term control over HIV. Developing a vaccine for human immunodeficiency virus (HIV) may be aided by a complete understanding of those rare cases in which some HIV-infected individuals control replication of the virus 1 , 2 , 3 . Most of these elite controllers express the histocompatibility alleles HLA-B*57 or HLA-B*27 (ref. 3 ). These alleles remain by far the most robust associations with low concentrations of plasma virus 4 , 5 , yet the mechanism of control in these individuals is not entirely clear. Here we vaccinate Indian rhesus macaques that express Mamu-B*08 , an animal model for HLA-B*27-mediated elite control 6 , with three Mamu-B*08-restricted CD8 + T-cell epitopes, and demonstrate that these vaccinated animals control replication of the highly pathogenic clonal simian immunodeficiency virus (SIV) mac239 virus. High frequencies of CD8 + T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon were associated with viral control. Moreover, the frequency of the CD8 + T-cell response against the Nef RL10 epitope (Nef amino acids 137–146) correlated significantly with reduced acute phase viraemia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8 + T-cell responses in the control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8 + T-cell responses can control replication of the AIDS virus.