Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity.

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

Luteolin inhibits the proliferation, adhesion, migration and invasion of choroidal melanoma cells in vitro.

Choroidal melanoma is a devastating disease that causes visual loss and a high mortality rate due to metastasis. Luteolin, a potential anticancer compound, is widely found in natural plants. The aim of this study was to evaluate the antiproliferative, antiadhesive, antimigratory and anti-invasive effects of luteolin on choroidal melanoma cells in vitro and to explore its potential mechanism. Cell counting kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) assays, Cell adhesion, migration, and invasion assays were performed to examine the inhibitory effects of luteolin on cell cell viability, proliferation, adhesion, migration and invasion capacities, respectively. Considering the correlation between Matrix metalloenzymes and tumor metastasis, Enzyme-linked immunosorbent assays (ELISAs) were used to assess matrix metalloproteases MMP-2 and MMP-9 secretion. Western blotting was performed to detect p-PI3K P85, Akt, and p-Akt protein expression. The cytoskeletal proteins vimentin were observed with cell immunofluorescence staining. Luteolin can inhibit OCM-1 cell proliferation, migration, invasion and adhesion and C918 cell proliferation, migration, and invasion through the PI3K/Akt signaling pathway. Therefore, Luteolin may have potential as a therapeutic medication for Choroidal melanoma.

Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.

Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

LncRNA MIAT Promotes Inflammation and Oxidative Stress in Sepsis-Induced Cardiac Injury by Targeting miR-330-5p/TRAF6/NF-κB Axis.

Sepsis is a whole-body inflammation and main cause of death in intensive care units worldwide. We aimed to investigate the roles of lncRNA MIAT and miR-330-5p in modulating inflammatory responses and oxidative stress in lipopolysachariden (LPS)-induced septic cardiomyopathy. Serum and heart tissue were collected from in vivo septic mice model, ELISA and qRT-PCR were used to measure the expression of pro-inflammation cytokines, MIAT and miR-330-5p, respectively. The knockdown of MIAT and overexpression of miR-330-5p were conducted to assess their effects on regulating inflammation response and intracellular oxidative stress in LPS-stimulated HL-1 cells. The reactive oxygen (ROS) level, mitochondrial membrane potential (MMP), GSH/GSSH ratio, and lipid peroxidation assessment (MDA) were used to evaluate the intracellular oxidative stress. Dual-luciferase reporter assay was performed to identify the association between MIAT and miR-330-5p, TRAF6 and miR-330-5p, respectively. In septic mice, the expression of MIAT and pro-inflammation cytokines was elevated while the expression of miR-330-5p decreased. Knockdown of MIAT or overexpression of miR-330-5p restrained inflammation and oxidative stress induced by LPS in vitro; MIAT directly targeted miR-330-5p to regulate NF-κB signaling, and miR-330-5p targeted against TRAF6 to suppress the activation of NF-κB signaling. We determined that lncRNA MIAT directly binds to miR-330-5p to activate TRAF6/NF-κB signaling axis and further promotes inflammation response as well as oxidative stress in LPS-induced septic cardiomyopathy. This finding suggests the potential therapeutic role of lncRNA MIAT and miR-330-5p in LPS-induced myocardial injury.

The effects of CXCL10 polymorphisms on COPD susceptibility.

The polymorphisms of cytokine genes has been reported to modulate the individual's susceptibility to environmental stimuli in COPD development. C-X-C motif chemokine 10 (CXCL10) mediates recruitment inflammatory cells such as monocytes. Therefore, it may play a key role in COPD. Here, a case-control study was conducted to evaluate the association between CXCL10 tag-SNPs and COPD risk. Four tag-SNPs including rs4256246, rs4508917, rs56061981, and rs56316945 were identified based on the linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between these four tag-SNPs and COPD risk were further evaluated in 480 COPD cases and 488 controls. We found that the "T" allele of rs56061981 was significantly associated with reducing risk of COPD, while "G" allele of rs56316945 was significantly associated with increasing risk of COPD. SNP rs56316945 was significantly associated with increasing risk of COPD under different models except recessive model after adjusting the sex, age, pack year, and biomass. SNP rs56061981 was significantly associated with decreasing COPD risk under different models except recessive model after adjusting the sex, age, pack year, and biomass. Stratified analysis of smoking status and biomass with SNPs supported rs56061981 may interact with biomass and smoking thus modulate COPD susceptibility and rs56216945 was apparently associated with the severity of pulmonary function of COPD patients. This study suggests that rs56061981 and rs56216945 in CXCL10 gene promoter contribute COPD susceptibility.

[miR-362 regulates the proliferation and apoptosis of porcine immature Sertoli cells through targeting the ZNF644 gene].

In testicular tissue, immature Sertoli cell proliferation ability determines the size of mature Sertoli cell populations, which further regulates the spermatogenesis in the adult male animals. Studies have demonstrated that microRNAs (miRNAs) participate in the regulation of the immature Sertoli cell proliferation and apoptosis, but the functions of most identified miRNAs remain unclear. In this study, based on previous RNA-seq results, we analyzed the regulatory role (s) of miR-362 in proliferation and apoptosis of porcine immature Sertoli cells. The ZFN644 gene was predicted to be a target gene of miR-362 using bioinformatics methods. The expression levels of miR-362 and ZNF644 gene were measured using qRT-PCR assay in developing porcine testicular tissues and in immature Sertoli cells transfected with either miR-362 mimic or miR-362 inhibitor. The dual luciferase reporter assay was used to determine the regulatory relationship between miR-362 and ZNF644. The results showed that a putative target site of miR-362 was located in the 3'UTR of ZNF644. The expression of miR-362 was significantly and negatively correlated with ZNF644 expression in the developing porcine testicular tissues. Co-transfection of miR-362 and psiCHECK2-ZNF644-WT 3'UTR luciferase vector significantly suppressed luciferase activity. The ZNF644 gene expression level was significantly regulated by miR-362, demonstrating that miR-362 targets ZNF644 gene and inhibits its expression in porcine immature Sertoli cells. Flow cytometry, CCK8, and EdU assays were used to measure the effects of over-expression of miR-362 or knockdown of ZNF644 on porcine immature Sertoli cell proliferation; Annexin V-FITC/PI staining assays and qRT-PCR technology were used to test the apoptosis and the expression levels of cell survival-related genes, respectively. Over-expression of miR-362 and knockdown of ZNF644 arrested the porcine immature Sertoli cells in G1 and G2 phases of the cell cycle, respectively, and inhibited proliferation, enhanced apoptosis in the porcine immature Sertoli cells, and significantly regulated the expression levels of cell survival-related genes. Taken together, these data indicate that miR-362 inhibits proliferation and promotes apoptosis in porcine immature Sertoli cells by targeting the ZNF644 gene, thereby providing the scientific basis for further study on the function(s) of miR-362 in the porcine spermatogenesis.

Role of interleukin-6 to differentiate sepsis from non-infectious systemic inflammatory response syndrome.

Differentiating between sepsis and non-infectious systemic inflammatory response syndrome (SIRS) poses a great challenge. Several potential bloodstream biomarkers including Interleukin 6 (IL-6) have been investigated for their ability to diagnose sepsis. We conducted the present meta-analysis to evaluate the diagnostic quality of IL-6 in differentiating sepsis from non-infectious SIRS in adults. We also compared its accuracy with procalcitonin (PCT) and C-reactive protein (CRP). PubMed and EMBASE were systematically searched for studies published up to January 18, 2016. Twenty articles containing 22 studies and 2680 critically ill patients were included, of which, 21 studies also involved PCT and 14 involved CRP. Quantitative synthesis of studies showed that the pooled sensitivity/specificity of IL-6 and PCT were 0.68/0.73 and 0.78/0.67. The area under the curve (AUC) of IL-6, PCT and CPR for diagnosis of sepsis was 0.80, 0.83, and 0.71, respectively. This meta-analysis provides evidence that the IL-6 test has moderate diagnostic performance in differentiating sepsis from non-infectious SIRS in adults. IL-6 and PCT test has similar diagnostic value but higher than CRP. Considering its relatively high specificity, we recommend the use of IL-6 as a diagnostic aid to confirm infection rather than exclude infection in patients with SIRS.

The role of ubiquitin-proteasome pathway in spermatogenesis.

Ubiquitin-proteasome pathway (UPP) is the main pathway of protein degradation in eukaryotic cells. The UPP plays very important roles in cell cycle progression, apoptosis, stress response and growth and development through regulating protein interaction, protein activity, protein localization and signal transduction. Previous studies have shown that the UPP is essential for regulating acrosome and tail biogenesis during spermatogenesis in human and animals. The dysregulation of UPP during spermatogenesis results in sperm deformity and reduced sperm motility and leads to reproductive system diseases such as oligospermatism, infertility and testicular tumors. In this review, we summarized the signal transduction and regulation mechanism of UPP in spermatogenesis, which may provide references for future studies.

[Research and Application of Narrowband Polarizing Beam Splitter in the Optical Fiber Communication].

In fiber-optic communications, in order to achieve more data channels in the wavelength division multiplexing (WDM) system without changing the modulation wavelength range, a new type of small-sized narrowband polarizing beam splitter was designed. It can be used for data communication network expansion and improve the Signal to Noise Ratio (SNR) of the optical signal. Two kinds new film system designed were deposited on the polarizing beam splitter. One layer is narrowband filter film, while the other layer is polarizing beam splitter film. TFCalc software was used for simulation analysis, and the results shown that the bandwidth of the narrowband filter film was about 0.4 nm, and the permeability of p light from the polarizing beam splitter film was better than 99.8% in the range of 1 530～1 560 nm. Based on the above film system design, two groups film system was made on BK7 optical glass. In the experiment, light through film was spectral analysis with Agilent 8164-A type optical measuring instrument. Experimental results show that the actual bandwidth of the narrowband filter film is better than 0.4 nm, gain flatness is not less than -0.05 dB. It has a narrower bandwidth compared to the existing common 0.8 nm filter film, and it can be realized to increase the amount of data channels in the wavelength division multiplexing system with the same modulation wavelength range. Actual transmittance of p light was 99.6% through polarizing filter film, and it's slightly lower than the simulated values, but it remains better than the design requirements. Compared to conventional polarizing beam splitter, its optical signal was stronger, and it has a higher SNR. In summary, the polarizing beam splitter has better application value and practical significance.

Hyperthermic intraperitoneal chemotherapy plus high-frequency diathermic therapy followed by intravenous chemotherapy versus intravenous chemotherapy alone for postoperative adjuvant treatment of gastrointestinal cancer: a comparative research study.

PURPOSE: To evaluate the therapeutic efficacy and toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) plus high-frequency diathermic therapy (HFDT) followed by intravenous chemotherapy vs intravenous chemotherapy alone for adjuvant treatment of postoperative gastrointestinal neoplasms. METHODS: Fifty-two gastrointestinal carcinoma patients who were radically operated were enrolled and divided into the treatment group and the control group. In the treatment group, 25 patients were treated with combination of HIPEC+HFDT and subsequent intravenous chemotherapy, while in the control group 27 patients received intravenous chemotherapy alone. Post-therapeutic complications and adverse reactions, time to progression (TTP) and overall survival (OS) were compared between these two groups. RESULTS: Difference in toxic reactions between the two groups was not statistically significant (p>0.05). Postoperative progression- free survival (PFS) rate at 12 and 40 months after radical surgery was 72.0 and 54.0% respectively in the treatment group, and 65.8 and 11.5% respectively in the control group (p=0.108). TTP was statistically significantly longer in the treatment group than in the control group (median TTP 40.1 vs 18.5 months, p=0.027). Postoperative OS at 12 and 20 months after radical surgery was 88.0 and 78.0% respectively in the treatment group and 92.6 and 72.7% in the control group, without significant difference. CONCLUSION: After radical surgery, combination of HIPEC+HFDT and subsequent intravenous chemotherapy brings about superior PFS compared with intravenous adjuvant chemotherapy alone, while having no more complications and adverse reactions.

Nonhuman transferrin receptor 1 is an efficient cell entry receptor for Ocozocoautla de Espinosa virus.

Ocozocoautla de Espinosa virus (OCEV) is a novel, uncultured arenavirus. We found that the OCEV glycoprotein mediates entry into grivet and bat cells through transferrin receptor 1 (TfR1) binding but that OCEV glycoprotein precursor (GPC)-pseudotyped retroviruses poorly entered 53 human cancer cell lines. Interestingly, OCEV and Tacaribe virus could use bat, but not human, TfR1. Replacing three human TfR1 amino acids with their bat ortholog counterparts transformed human TfR1 into an efficient OCEV and Tacaribe virus receptor.

Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus.

Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2)) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-ß specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.

Effect of arctiin on glomerular filtration barrier damage in STZ-induced diabetic nephropathy rats.

Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permeability of glomerular basement membrane plays an important role in DN pathogenesis. This study was performed to assess the effect of arctiin, the lignan constituent from Arctium lappa L., on metabolic profile and aggravation of renal lesions in a rat model of streptozotocin (STZ)-induced DN. STZ-induced diabetic rats were treated with arctiin at the dosage of 60 or 40 mg/kg/day via intraperitoneal injection for 8 weeks. Blood glucose and 24-h urinary albumin content were measured, and kidney histopathological changes were monitored. RT-PCR and immunohistochemistry were used to detect the mRNA and protein levels of nephrin, podocin and heparanase (HPSE) in the kidney cortex of rats, respectively. Treatment with arctiin significantly decreased the levels of 24-h urinary albumin, prevented the sclerosis of glomeruli and effectively restored the glomerular filtration barrier damage by up-regulating the expression of nephrin and podocin and down-regulating HPSE level. Our studies suggest that arctiin might be beneficial for DN. The effects of arctiin on attenuating albuminuria and glomerulosclerosis are possibly mediated by regulating the expression of nephrin and podocin and HPSE in STZ-induced diabetic rats.

[Effects of Microplastic High-density Polyethylene on Cotton Growth, Occurrence of Fusarium wilt, and Rhizosphere Soil Bacterial Community].

Plastic mulch, especially polyethylene mulch, is widely used in agricultural production in China, but the microplastics formed by its degradation gradually have accumulated in soil, causing a series of environmental problems. At present, there have been many reports on the environmental biological effects of microplastics in farmland soil, but studies on the effects of microplastics on crop growth, disease occurrence, and rhizosphere soil bacterial communities are still lacking. In the previous study, it was found that 1% high-density polyethylene (HDPE, 500 mesh) could increase the incidence rate of cotton Fusarium wilt (33.3%) and inhibit growth, but this phenomenon was not found after soil sterilization. It was speculated that HDPE could affect the growth and occurrence of Fusarium wilt by regulating the soil microbial community. Therefore, high-throughput sequencing technology, combined with network and FAPROTAX function analysis, were used to investigate the effects of HDPE on the bacterial community structure, interaction network, and soil function in cotton rhizosphere in order to analyze the mechanism of HDPE. NovaSeq sequencing showed that the bacterial community of HDPE-treated cotton rhizosphere soil was composed of 54 phyla and 472 genera; the number of phyla and genera was higher than that in untreated soil. The α and ß diversity and ANOSIM/Adonis analyses showed that HDPE significantly reduced the richness of the bacterial community and changed the composition of the community structure. Based on a T-test species difference analysis, HDPE significantly reduced the relative abundance of bacteria with biological control, pollutant degradation, and antifungal drug synthesis (such as Kribbella, Massiliam, Hailiangium, and Ramlibacter).The change in the bacterial community will lead to the change in soil bacterial function. Further analysis of FAPROTAX function revealed that HDPE weakened some biochemical functions of bacteria in the cotton rhizosphere soil, such as aerobic chemoheterotrophy, fermentation, and nitrate reduction. The correlation network at the genus level showed that HDPE treatment weakened the interaction between rhizosphere bacteria, reduced the number of positive correlation connections, increased the number of negative correlation connections, simplified network structure, and changed the key flora. The above results showed that HDPE could reduce the cotton growth and the occurrence of Fusarium wilt by changing the bacterial community, interaction, and functional metabolism in rhizosphere soil, which can provide guidance for evaluating the ecological risk of polyethylene microplastics and the remediation of contaminated soil.

Inhibition of Ebola virus entry by a C-peptide targeted to endosomes.

Ebola virus (EboV) and Marburg virus (MarV) (filoviruses) are the causative agents of severe hemorrhagic fever. Infection begins with uptake of particles into cellular endosomes, where the viral envelope glycoprotein (GP) catalyzes fusion between the viral and host cell membranes. This fusion event is thought to involve conformational rearrangements of the transmembrane subunit (GP2) of the envelope spike that ultimately result in formation of a six-helix bundle by the N- and C-terminal heptad repeat (NHR and CHR, respectively) regions of GP2. Infection by other viruses employing similar viral entry mechanisms (such as HIV-1 and severe acute respiratory syndrome coronavirus) can be inhibited with synthetic peptides corresponding to the native CHR sequence ("C-peptides"). However, previously reported EboV C-peptides have shown weak or insignificant antiviral activity. To determine whether the activity of a C-peptide could be improved by increasing its intracellular concentration, we prepared an EboV C-peptide conjugated to the arginine-rich sequence from HIV-1 Tat, which is known to accumulate in endosomes. We found that this peptide specifically inhibited viral entry mediated by filovirus GP proteins and infection by authentic filoviruses. We determined that antiviral activity was dependent on both the Tat sequence and the native EboV CHR sequence. Mechanistic studies suggested that the peptide acts by blocking a membrane fusion intermediate.

miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia.

A growing body of evidence suggests that microRNA (miRNA) dysregulation contributes to many types of human disease, including central nervous system disorders. In this study, we identified an inverse correlation between the expression of miR-21 and Fas ligand (FasL) during hypoxia-induced microglial activation. Specifically, hypoxia caused the upregulation of FasL expression but the downregulation of miR-21 expression in microglia. Furthermore, we demonstrated that miR-21 suppresses FasL production by directly binding to its 3'-untranslated region. The overproduction of FasL following hypoxic microglial activation induced neuronal apoptosis, whereas the ectopic expression of miR-21 partially protected neurons from cell death caused by hypoxia-activated microglia. Finally, we confirmed that the function of miR-21 in microglia-mediated neuronal injury is dependent on FasL. Our study demonstrates an important role for miRNAs in microglia-mediated neuronal apoptosis, and suggests potential novel therapeutic interventions for cerebral hypoxic diseases associated with microglial activation.

The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor.

BACKGROUND: Post-ischemic microglial activation may contribute to neuronal damage through the release of large amounts of pro-inflammatory cytokines and neurotoxic factors. The involvement of microRNAs (miRNAs) in the pathogenesis of disorders related to the brain and central nervous system has been previously studied, but it remains unknown whether the production of pro-inflammatory cytokines is regulated by miRNAs. METHODS: BV-2 and primary rat microglial cells were activated by exposure to oxygen-glucose deprivation (OGD). Global cerebral ischemia was induced using the four-vessel occlusion (4-VO) model in rats. Induction of pro-inflammatory and neurotoxic factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and nitric oxide (NO), were assessed by ELISA, immunofluorescence, and the Griess assay, respectively. The miRNA expression profiles of OGD-activated BV-2 cells were subsequently compared with the profiles of resting cells in a miRNA microarray. BV-2 and primary rat microglial cells were transfected with miR-181c to evaluate its effects on TNF-α production after OGD. In addition, a luciferase reporter assay was conducted to confirm whether TNF-α is a direct target of miR-181c. RESULTS: OGD induced BV-2 microglial activation in vitro, as indicated by the overproduction of TNF-α, IL-1ß, and NO. Global cerebral ischemia/reperfusion injury induced microglial activation and the release of pro-inflammatory cytokines in the hippocampus. OGD also downregulated miR-181c expression and upregulated TNF-α expression. Overproduction of TNF-α after OGD-induced microglial activation provoked neuronal apoptosis, whereas the ectopic expression of miR-181c partially protected neurons from cell death caused by OGD-activated microglia. RNAinterference-mediated knockdown of TNF-α phenocopied the effect of miR-181c-mediated neuronal protection, whereas overexpression of TNF-α blocked the miR-181c-dependent suppression of apoptosis. Further studies showed that miR-181c could directly target the 3'-untranslated region of TNF-α mRNA, suppressing its mRNA and protein expression. CONCLUSIONS: Our data suggest a potential role for miR-181c in the regulation of TNF-α expression after ischemia/hypoxia and microglia-mediated neuronal injury.

Ebolavirus delta-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry.

With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Δ-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Taï Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.

[Influence of clinical characteristics on health-related quality of life after mid-low rectal cancer surgery].

OBJECTIVE: The present study aims to investigate health-related quality of life (HRQOL) in disease-free survivors after radical surgery for mid-low rectal cancer. METHODS: A retrospective cross-sectional study was performed in patients with rectal cancer who underwent primary surgery between August 2002 and February 2011 by use of the European Organization for Research and Treatment of Cancer QLQ-C30 and CR-38 questionnaires (n = 330). The impact of clinical characteristics on HRQoL were assessed and compared by univariate and multivariate regression analyses. RESULTS: Two hundred and four effective responses were received. Patients with stoma were more impaired in HRQoL than those without stoma, especially in the field of social psychology, such as emotional function (M(50) = 91.67, U = 2668.5, P = 0.026), social function (M(50) = 83.33, U = 2095.5, P < 0.001), financial difficulties (M(50) = 0, U = 2240.5, P < 0.001) and body image (M(50) = 88.89, U = 2507.0, P = 0.013). Only in the constipation scale (M(50) = 14.29, U = 2376.0, P = 0.001), nonstoma patients had a better score. The analysis in different types of surgical procedure paralleled those of stoma. Patients with complication had a poorer function in some symptom scales such as dyspnoea (M(50) = 0, U = 1505.0, P < 0.001), gastro-intestinal symptom (M(50) = 6.67, U = 1766.0, P = 0.034) and financial difficulties (M(50) = 33.33, U = 1795.5, P = 0.044), and in some functioning scales such as emotional function (M(50) = 83.33, U = 1608.5, P = 0.009), cognitive function (M(50) = 66.67, U = 1612.5, P = 0.010) and body image (M(50) = 66.67, U = 1617.0, P = 0.012). In our study, HRQoL after rectal cancer surgery improved with time. Our multivariate analysis displayed that stoma and postoperative time were the most significant characteristics. Variables associated with worse financial status were less postoperative months, occurrence of complications and presence of stoma. CONCLUSIONS: Different scales of HRQoL in patients of China after curative surgery for mid-low rectal cancer are significantly influenced by different clinical characteristics.

Identification of genetic variants of the IL-22 gene in association with an altered risk of COPD susceptibility.

The incidence of chronic obstructive pulmonary disease (COPD) is related to the interaction between environmental exposure and genetic factors. Far more than 15% of smokers eventually develop COPD. In addition to smoking, genetic susceptibility may be another factor in the development of COPD. IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Here, we conducted a case-control study to evaluate the association between IL-22 tag-single nucleotide polymorphisms (SNPs) and COPD risk. Four tag-SNPs (rs2227478, rs2227481, rs2227484 and rs2227485) were identified according to linkage disequilibrium (LD) analysis in 30 healthy controls. A total of 513 COPD cases and 504 controls were recruited to perform an association study between these four tag-SNPs and COPD risk. We found that the "C" allele of rs2227478T>C and the "T" allele of rs2227481C>T were obviously related to decreased COPD susceptibility. Genetic model analysis showed that rs2227478T>C and rs2227481C>T were significantly associated with a decreased risk of COPD under dominant models after adjusting for the above factors. In the recessive model, rs2227485T>C was obviously associated with decreased COPD risk. Our data showed that only rs2227485T>C was associated with a decreased COPD risk after Bonferroni correction. The eQTL analysis showed that rs2227485T>C was significantly associated with IL-22 expression. The pGL4-rs2227485-C gene reporter had a higher promoter activity than pGL4-rs2227485-T. In our study, rs2227485T>C, located in the promoter region of IL-22, was associated with a decreased risk of COPD and increased IL-22 promoter activity, suggesting that this variant might modulate COPD susceptibility.