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Opioid abuse alters the functions of immune cells in both in vitro and in vivo systems, including macrophages. Here, we investigated the effects of methadone, a widely used opioid receptor agonist for treatment of opiate addiction, on the expression of intracellular viral restriction factors and HIV replication in primary human macrophages. We showed that methadone enhanced the HIV infectivity in primary human macrophages. Mechanistically, methadone treatment of macrophages reduced the expression of interferons (IFN-β and IFN-λ2) and the IFN-stimulated anti-HIV genes (APOBEC3F/G and MxB). In addition, methadone-treated macrophages showed lower levels of several anti-HIV microRNAs (miRNA-28, miR-125b, miR-150, and miR-155) compared to untreated cells. Exogenous IFN-β treatment restored the methadone-induced reduction in the expression of the above genes. These effects of methadone on HIV and the antiviral factors were antagonized by pretreatment of cells with naltrexone. These findings provide additional evidence to support further studies on the role of opiates, including methadone, in the immunopathogenesis of HIV disease. [ABSTRACT FROM AUTHOR]

Hantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and have led to public health threat in China. The pathogenesis of HFRS is complex and involves capillary leakage due to the infection of vascular endothelial cells. Accumulating evidence has demonstrated that hantavirus can induce apoptosis in many cells, but the mechanism remains unclear. Our studies showed that Hantaan virus (HTNV) infection could induce TNF-related apoptosis-inducing ligand (TRAIL) expression in primary human umbilical vein endothelial cells (HUVECs) and sensitize host cells toward TRAIL-mediated apoptosis. Furthermore, TRAIL interference could inhibit apoptosis and enhance the production of HTNV as well as reduce IFN-β production, while exogenous TRAIL treatment showed reverse outcome: enhanced apoptosis and IFN-β production as well as a lower level of viral replication. We also observed that nucleocapsid protein (NP) and glycoprotein (GP) of HTNV could promote the transcriptions of TRAIL and its receptors. Thus, TRAIL was upregulated by HTNV infection and then exhibited significant antiviral activities in vitro , and it was further confirmed in the HTNV-infected suckling mice model that TRAIL treatment significantly reduced viral load, alleviated virus-induced tissue lesions, increased apoptotic cells, and decreased the mortality. In conclusion, these results demonstrate that TRAIL-dependent apoptosis and IFN-β production could suppress HTNV replication and TRAIL treatment might be a novel therapeutic target for HTNV infection. [ABSTRACT FROM AUTHOR]

Purpose: The effect of glucocorticoid(s) on connective tissue disease (CTD)-related interstitial lung disease (ILD) is controversial. This multicenter study aimed to identify glucocorticoid-sensitive patients using a radiomics approach.Methods: A total of 416 CTD-ILD patients who began glucocorticoid treatment at the discretion of the attending physician, with or without cyclophosphamide, were included in this study. High doses were defined as pulsed intravenous methylprednisolone, an initial dose of 1 mg/kg/day of prednisolone or 0.8 mg/kg/day of methylprednisolone. Low doses were defined as those less than high doses. Radiomics features were manually extracted from primary lung lesions delineated on computed tomography images, and selected by variance, univariate feature selection, and least absolute shrinkage and selection operator regression model. The prediction models were developed using data from 309 patients from two centers and externally validated in 107 patients from four other hospitals.Results: Treatment response in the training and validation groups was 38.5% and 36.4%, respectively. Eleven radiomics features were selected from 1,029 features with predictive value. Random forest models built for radiomics features to predict treatment response yielded a sensitivity of 0.897. The calibration curve of a nomogram demonstrated good agreement between prediction and observation. Decision curve analysis indicated that glucocorticoid was beneficial if the predicted response rate was 50%-60% for an individual. High doses of glucocorticoids and cyclophosphamide yielded superior efficacy.Conclusion: Radiomics-based predictive models reliably identified glucocorticoid-sensitive CTD-ILD patients. Short-term, high-dose glucocorticoid with cyclophosphamide yielded promising results as a potential therapy. [ABSTRACT FROM AUTHOR]

Background/Aims: Pterygium is a common ocular surface disease with an unknown etiology and threatens vision as it invades into the cornea. Circular RNAs (circRNAs) are a novel class of RNA transcripts that participate in several physiological and pathological processes. However, the role of circRNAs in pathogenesis of pterygium remains largely unknown. Methods: Genome-wide circRNA expression profiling was performed to identify pterygium -related circRNAs. GO analysis, pathway analysis, and miRNA response elements analysis was performed to predict the function of differentially expressed circRNAs in pterygium. MTT assays, Ki67 staining, Transwell assay, Hoechst 33342 staining, and Calcein-AM/PI staining were performed to determine the effect of circRNA silencing on pterygium fibroblast and epithelial cell function. Results: Approximately 669 circRNAs were identified to be abnormally expressed in pterygium tissues. GO analysis demonstrated that the host genes of differentially expressed circRNAs were targeted to extracellular matrix organization (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis showed that dysregulated circRNAs-mediated regulatory networks were mostly enriched in focal adhesion signaling pathway. Notably, circ_0085020 (circ-LAPTM4B) was shown as a potential biomarker for pterygium. circ_0085020 (circ-LAPTM4B) silencing affected the viability, proliferation, migration, and apoptosis of pterygium fibroblast and epithelial cells in vitro. Conclusions: This study provides evidence that circRNAs are involved in the pathogenesis of pterygium and might constitute promising targets for the therapeutic intervention of pterygium. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to describe ophthalmic findings in a family with isolated ectopia lentis (EL) caused by a specific FBN1 mutation. Methods: Detailed family histories and clinical data were recorded for six isolated EL patients of 11 family members. The ophthalmological and systematic examinations were performed on patients and unaffected members of the investigated family. The detailed ocular examinations included visual acuity, anterior chamber depth, pupil size, lens location, optometry, central corneal thickness, keratometry, slitlamp examination, fundus examination, axial length, ocular B-ultrasound, gonioscope checking, ultrasound biomicroscopy (UBM) and intraocular pressure (IOP; Goldmann applanation tonometer). Systematic examinations included the measurement of echocardiogram, height, arm span, skull, face, jaw, tooth, breast bone, spinal column, and skin. Genomic DNA was extracted using the phenol-chloroform extraction method for all subjects, and sequencing was carried out on an ABI Prism 3730 Genetic Analyzer. Results: A heterozygous mutation, c.184C>T (p.Arg62Cys) in exon 2 of FBN1 was identified in all affected members but was not found in any unaffected member of the family. Our study presented detailed clinical manifestations, including some novel ophthalmic findings, such as pupillary abnormality, different types of glaucoma, and progressive hyperopia. Conclusions: Ophthalmic findings and the p.Arg62Cys mutation of FBN1 gene were reported in a family with early-onset isolated ectopia lentis. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: This study aimed to investigate the relationship between serum tau concentrations and 3-month clinical outcomes in patients with intracerebral hemorrhage. Design and methods: Serum tau concentrations of 176 patients were quantified by enzyme-linked immunosorbent assay. The end points were mortality and poor outcome (modified Rankin Scale score>2) after 3months. Results: 110 patients (62.5%) had a poor outcome at 3months. The 3-month mortality rate was 36.4% (64/176). A forward stepwise logistic regression selected serum tau concentration as an independent predictor for 3-month mortality (P =0.002) and poor outcomes (P =0.009) of patients. A receiver operating characteristic curve analysis showed that serum tau concentration predicted 3-month mortality (P =0.001) and poor outcomes (P =0.001) statistically significantly. The area under curve of tau was similar to that of the National Institutes of Health Stroke Scale score for 3-month mortality (P =0.715) and poor outcomes (P =0.315). In a combined logistic-regression model, tau statistically significantly improved the area under curve of the National Institutes of Health Stroke Scale score for the prediction of 3-month poor outcome (P =0.039), but not for the prediction of 3-month mortality (P =0.106). Conclusions: Serum tau concentration represents a novel biomarker for predicting mortality and poor outcomes at 3months in patients with intracerebral hemorrhage. [Copyright &y& Elsevier]

Conclusion. The gentamicin-induced pathological alteration in the cochlear nucleus is not exclusively a secondary consequence of the damage in the cochlea. Instead, the toxic effect of gentamicin on the cochlear nucleus may occur simultaneously or even earlier than that on the cochlea. Objectives. To investigate the pathological alteration of cochlear nucleus neurons in guinea pigs following systemic application of gentamicin. Materials and methods. Guinea pigs were injected with gentamicin for 1 day, 3 days, 1 week, 2 weeks, and 3 weeks, respectively. In gentamicin-treated animals, the hearing function was evaluated by measuring the auditory brainstem response (ABR). The number and cross-sectional area of substance P-positive neurons in the cochlear nucleus were also measured. Results. The threshold of ABR and the number of substance P-positive neurons in the cochlear nucleus were significantly increased after 1 week and 3 days of injection of gentamicin, respectively. The cross-sectional area of substance P-positive neurons in the cochlear nucleus was significantly reduced after 1-day injection of gentamicin. [ABSTRACT FROM AUTHOR]

Abstract: β-Amyloid protein (Aβ), a major protein component of brain senile plaques in Alzheimer''s disease, is known to be directly responsible for the production of reactive oxygen species (ROS) and induction of apoptosis. In this study, the protective effect of puerarin, an isoflavone purified from the radix of the Chinese herb Pueraria lobata, on Aβ-induced rat pheochromocytoma (PC12) cultures was investigated. Although exposure of PC12 cells to 50μM Aβ25–35 caused significant viability loss and apoptotic rate increase, pretreatment of the cells with puerarin for 24h reduced the viability loss and apoptotic rate. Puerarin (1μM) significantly inhibited Aβ25–35-induced apoptosis of PC12 cells. Preincubation of the cell with puerarin also restored the ROS and mitochondrial membrane potential levels that had been altered as a result of Aβ25–35 treatment. Puerarin was also found to increase the Bcl-2/Bax ratio and reduce caspase-3 activation. These results suggest that puerarin could attenuate Aβ25–35-induced PC12 cell injure and apoptosis and could also promote the survival of PC12 cells. Therefore, puerarin may act as an intracellular ROS scavenger, and its antioxidant properties may protect against Aβ25–35-induced cell injury. [Copyright &y& Elsevier]

Calcium binding proteins are well known to be expressed by different groups of hippocampal interneurons; however, whether voltage-dependent calcium channels (Cav) are also localized in these neurons, changed during and after status epilepticus (SE), and involved in epileptic activity have not been reported. In the present study, we showed the colocalization of three subtypes of voltage-gated calcium channels (Cav1.2, Cav1.3, or Cav2.1) with different calcium binding proteins such as calbindin (CB), calretinin (CR), and parvalbumin (PV). At early stages during and after pilocarpine-induced status epilepticus (PISE), significant changes of expression of Cav1.2, Cav1.3 (L-type), and Cav2.1 (P/Q-type) were found in different groups of hippocampal neurons. Induced expression of Cav1.3 or Cav2.1 in reactive astrocytes was shown at 1 week and 2 months after PISE. At the latter time point, higher percentages of colocalization of PV and Cav1.2, CB, or PV and Cav1.3 or Cav2.1, lower percentages of CR and Cav1.3 or Cav2.1 immunoposivie neurons were observed in gliotic CA1 area. We therefore conclude that voltage-gated calcium channels are expressed by different groups of hippocampal interneurons in the mouse. At acute stages during and after PISE, up- or down-regulation of Cav1.2, Cav1.3, or Cav2.1 in functionally different groups of interneurons in CA1 area may be related to the changes of their plasticity. Up-regulation of Cav1.2, Cav1.3, or Cav2.1 in granule cells may be directly related to the occurrence of SE. The induced expression of Cav1.3 or Cav2.1 in reactive astrocytes at 1 week and 2 months after PISE suggests that Cav1.3 or Cav2.1-related calcium signaling in reactive astrocytes may be involved in initiation, maintenance or spread of seizure activity. In gliotic CA1 area at chronic stage (i.e., 2 months after PISE), the occurrence of higher percentages of colocalization of PV and Cav1.2, CB, or PV and Cav1.3 or Cav2.1, lower percentages of CR and Cav1.3 or Cav2.1 immunopositive neurons may suggest that such colocalizations may be linked to the survival or loss of particular group of hippocampal neurons. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: There is little information available on the mechanisms underlying the neuroprotective actions of the organoselenium compound ebselen. In this study, we sought to determine the relationship between alterations in the expression of Bcl-2 and Bax proteins and intracellular levels of calcium and the protective effects of ebselen with a concentration range of 0.01–20μM against glutamate toxicity in cultured mouse cortical neurons. Pretreatment with ebselen at moderate doses (4–12μM), but not at lower or higher doses, significantly improved glutamate-induced suppression of cell viability. Pretreatment with ebselen (8μM) also prevented apoptotic alterations, completely reversed the suppression of Bcl-2 expression, and significantly inhibited Bax overexpression, but did not alter elevated intracellular concentrations of calcium induced by glutamate. Pre-, co-, and post-treatment with ebselen (8μM) had similar potency in improving the decreased viability of glutamate-exposed cells. These results indicate that the neuroprotective effects of ebselen at low doses are associated with the regulation of Bcl-2 and Bax proteins but appear to be independent of glutamate-mediated elevation of intracellular calcium, suggesting that different mechanisms are involved in the actions of low and high dose regimens. Ebselen may be an effective agent used for early treatment of acute brain injuries. [Copyright &y& Elsevier]

One novel polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, laricinin A (1), two new meroterpenoids, tricycloalternarenes X and Y (2 and 3), one new coumarin, 3,4,7-trihydroxy-6-methylcoumarin (4), together with the known ethyl acetylorsellinate (5), diorcinol K (6), and tricycloalternarenes C and D (7 and 8) were obtained from culture of the fungus Botrysphaeria laricina isolated from the moss Rhodobryum umgiganteum. The structures of the new compounds were elucidated based on extensive spectroscopic techniques including HRMS and 1D and 2D NMR measurements. The absolute configuration of compound 1 was determined by ECD calculation and it was the first example of a novel group of PKS-NRPS hybrids possessing an unprecedented methyldihydropyran-isobutylpyrrolidinone skeleton. Compounds 2 , 7 , and 8 showed significant quinone reductase inducing activity in Hepa 1c1c7 cells. Chemical investigation on the endophytic fungus Botrysphaeria laricina inhabiting the moss Rhodobryum umgiganteum afforded four new compounds, including laricinin A (1), which was the first example of a polyketide synthase-nonribosomal peptide synthetase hybrid possessing an unprecedented skeleton. Some compounds showed significant quinone reductase inducing activity in Hepa 1c1c7 cells. Unlabelled Image [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS) caused by Human immunodeficiency virus type 1 (HIV-1) has a high tendency among illicit drug abusers. Recently, it is reported that abuse of fentanyl, a potent synthetic μ receptor–stimulating opioid, is an independent risk factor for HIV-1 infection. However, the mechanism of action in augmenting HIV-1 infection still remains elusive. In this study, we found that fentanyl enhanced infection of HIV-1 in MT2 cells, primary macrophages and Jurkat C11 cells. Fentanyl up-regulated CXCR4 and CCR5 receptor expression, which facilitated the entry of virion into host cells. In addition, it down-regulated interferon-β (IFN-β) and interferon-stimulated genes (APOBEC3F, APOBEC3G and MxB) expression in MT2 cells. Our findings identify an essential role of fentanyl in the positive regulation of HIV-1 infection via the upregulation of co-receptors (CXCR4/CCR5) and downregulation of IFN-β and ISGs, and it may have an important role in HIV-1 immunopathogenesis. • Fentanyl enhances infection of HIV-1 in MT2, primary macrophages, Jurkat C11 cells. • Fentanyl promotes the expression of CXCR4 and CCR5 receptors. • Fentanyl inhibits interferon-β and interferon-stimulated genes expression. [ABSTRACT FROM AUTHOR]

Three new triterpenoids, mallomacrostins A-C (1 – 3), and 11 known ones (4 – 14) were obtained from the twigs and leaves of Mallotus macrostachyus. Mallomacrostin A possessed a new trinor-D:B-friedobaccharane skeleton. The structures of the new compounds were elucidated on the basis of extensive spectroscopic techniques including HR-ESIMS and NMR and the structure of 1 was confirmed by single crystal X-ray diffraction analysis. Spectroscopic data of the known compound 4 were provided for the first time. Compounds 2 and 10 exhibited significant anti-inflammatory activity by inhibiting LPS-induced release of nitric oxide with IC 50 of 70.0 μM and 14.0 μM, respectively. Chemical investigation on the twigs and leaves of Mallotus macrostachyus led to the isolation of 14 triterpenoids, including mallomacrostin A, which possessed a new trinor-D:B-friedobaccharane skeleton. Some triterpenoids exhibited significant anti-inflammatory activity by inhibiting LPS-induced release of nitric oxide. Unlabelled Image [ABSTRACT FROM AUTHOR]

Excessive light exposure leads to retinal degeneration and accelerates the progression and severity of several ocular diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa. Long non-coding RNAs (LncRNAs) have emerged as important regulators of photoreceptor development and ocular diseases. In this study, we investigated the role of lncRNA-MEG3 in light-induced retinal degeneration. MEG3 expression was significantly up-regulated after light insult in vivo and in vitro. MEG3 silencing protected against light-induced retinal degeneration in vivo and light-induced photoreceptor cell apoptosis in vitro. Mechanistically, MEG3 regulated retinal photoreceptor cell function by acting as p53 decoy. MEG3 silencing decreased caspase 3/7 activity, up-regulated anti-apoptotic protein (Bcl-2) expression, and down-regulated pro-apoptotic protein (Bax) expression. Taken together, this study provides a promising method of MEG3 silencing for treating light-induced retinal degeneration. [ABSTRACT FROM AUTHOR]

Background Caspase-3 is a potential marker of apoptosis. We investigated whether serum caspase-3 concentrations were increased and its association with severity and prognosis after intracerebral hemorrhage (ICH). Methods This prospective clinical study recruited 112 ICH patients and 112 healthy individuals. Serum was assayed for caspase-3 using enzyme-linked immunosorbent assay. Stroke severity was quantified by National Institute of Health Stroke Scale (NIHSS) and hematoma volume. Six-month outcome was measured by modified Rankin Scale. Analyses were performed using univariate and multivariate analyses. Results Patients had significantly higher serum caspase-3 concentrations than controls. Capase-3 concentrations correlated with NIHSS score and hematoma volume. Serum caspase-3 emerged as an independent predictor for 6-month mortality and bad prognosis (modified Rankin scale score > 2). Based on receiver operating characteristic curve, caspase-3 concentrations showed similar prognostic value when compared with NIHSS score and hematoma volume. Conclusion Serum caspase-3 concentrations are increased in ICH patients as well as correlate with clinical severity and prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress caused by amyloid β-peptide (Aβ) may play an important role in the pathogenesis of Alzheimer disease (AD). Aβ is known to be directly responsible for the production of reactive oxygen species (ROS) and induction of apoptosis. Tanshinone IIA (Tan IIA) is extracted from a traditional herbal medicine Salvia miltiorrhiza BUNGE, which has been shown to protect against oxidative stress and cell death. In this study, we investigated the neuroprotective effect of Tan IIA against Aβ25–35-induced cell death in cultured cortical neurons. Exposure of cortical neurons to 30μM Aβ25–35 caused a significant viability loss, cell apoptosis and decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as increased levels of malondialdehyde (MDA) production. In parallel, Aβ25–35 significant increased the intracellular ROS elevation and decreased mitochondrial membrane potential (MMP). However, pretreatment of the cells with Tan IIA prior to Aβ25–35 exposure suppressed these Aβ25–35-induced cellular events noticeably. In addition, Tan IIA reduced the Aβ25–35-induced increase of caspase-3 activity, and reduced cytochrome c translocation into the cytosol from mitochondria. Furthermore, Tan IIA also ameliorated the Aβ25–35-induced Bcl-2/Bax ratio reduction in cortical neurons. Taken together, these data indicate that Tan IIA protected cultured cortical neurons against Aβ25–35-induced neurotoxicity through its antioxidative potential. Our results strongly suggest that Tan IIA may be effective in treating AD associated with oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: Accumulation of β-amyloid protein (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer''s disease (AD). In this study, the neuroprotective effect of emodin extracted from the traditional Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc against Aβ25 – 35-induced cell death in cultured cortical neurons was investigated. We found that pre-treatment with emodin prevented the cultured cortical neurons from β-amyloid-induced toxicity. The preventive effect of emodin was blocked by pre-treatment with a phosphatidylinositol-3-kinase (PI3K) pathway inhibitor LY294002 or an estrogen receptor (ER) specific antagonist ICI182780, but not by pre-treatment with an extracellular signal-related kinases (ERK) inhibitor U0126. Furthermore, we found that emodin exposure induced the activation of the Akt serine/threonine kinase and increased the level of Bcl-2 expression. Moreover, the application of emodin for 24h was able to induce the activation of Aβ25 – 35-suppressed Akt and decrease the activation of the Jun-N-terminal kinases (JNK), but not of ERK. Interestingly, the up-regulation of Akt and Bcl-2 did not occur in the presence of LY294002 or ICI182780, suggesting that emodin-up-regulated Bcl-2 is mediated via the ER and PI3K/Akt pathway. Taken together, our results suggest that emodin is an effective neuroprotective drug and is a viable candidate for treating AD. [Copyright &y& Elsevier]