Muscone inhibits the progression of atherosclerotic plaques in mice aorta by inhibiting the NF-κB/p65 pathway.

Atherosclerosis (AS) is considered to be one of the main pathogenic factors of coronary heart disease, cerebral infarction and peripheral vascular disease. Oxidative stress and inflammation run through the occurrence and development of atherosclerosis and related cardiovascular events. Muscone is a natural extract of deer musk and also the main physiological active substance of musk. This study investigated the impact of muscone on atherosclerosis. ApoE-/- mice were used to establised AS model and injected with low-dose (4 mg/kg/day) or high-dose (8 mg/kg/day) of muscone intraperitoneally for 4 weeks. Then aortic tissues were collected, and pathological sections of the aorta were prepared for oil red staining, HE and masson staining. The changes of MDA, SOD, VCAM-1, NF-κB, and TNF-α were observed by Western blotting or immunofluorescence staining. The results showed that high-dose muscone could effectively reduce the plaque area/aortic root area and relative atherosclerotic area, reduce the collagen composition in plaque tissue. In addition, we also found that high-dose muscone can effectively increase MDA level, reduce the level of SOD, and inhibit the expression of VCAM-1, NF-κB/p65, TNF-α in arterial plaques. Our results indicate that the administration of muscone has the benefit of inhibiting atherosclerosis. The potential mechanisms may be associated with antioxidant effect and inhibition of inflammatory reaction in arterial plaques. With the increasing understanding of the relationship between muscone and atherosclerosis, muscone has high potential value as a new drug to treat atherosclerosis.

Mechanism of new coronavirus pneumonia agreement prescription on 2019 novel coronavirus-infected pneumonia based on network pharmacology analysis and the validation.

PURPOSE: To investigate the mechanism of action underlying the effective treatment of New Coronavirus Pneumonia Agreement Prescription (NCPAP) on 2019 Novel Coronavirus-Infected Pneumonia (2019-NCIP) using network pharmacology. METHODS: In this retrospective study, 50 patients with 2019-NCIP were recruited, including 16 who received symptomatic treatment and 34 that received NCPAP formula treatment on the basis of symptomatic treatment. Hospitalization and lymphocyte percentages were served as efficacy evaluation indicators. Moreover, pharmacological analysis was performed to identify the target disease of NCPAP. Active ingredients in herbs were screened using the Traditional Chinese Medications Systems Pharmacology (TCMSP) database, and related target genes were identified. We then queried therapeutic target data for coronavirus-associated genes. The protein-protein interaction network was constructed to examine the relationships between these targets. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) network enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. RESULTS: NCPAP significantly reduced hospitalization time and increased both the absolute value and percentage of lymphocytes. Bioinformatics and cytokine analysis suggested that preventing cytokine storm syndrome and regulating immune response are the key mechanisms of NCPAP in treating 2019-NCIP. CONCLUSIONS: The possible mechanisms of NCPAP in the treatment of 2019-NCIP are reduction of cytokine storms and regulation of the immune response.

METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis.

Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.

Perfluorooctane sulfonate promotes hepatic lipid accumulation and steatosis in high-fat diet mice through AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathway.

Perfluorooctane sulfonate (PFOS) is a hepatotoxic environmental organic pollutant that can cause aberrant lipid accumulation in the liver. However, the molecular mechanism underlying PFOS-induced hepatic steatosis remains unclear. Our research showed that subchronic PFOS exposure inhibited AMP-activated protein kinase (AMPK) phosphorylation, leading to increased acetyl-CoA carboxylase (ACC) activity, attenuated fatty acid ß-oxidation, and consequent liver lipid accumulation. We found that 1 mg/kg/day PFOS exposure significantly aggravated steatosis in high-fat diet (HFD)-fed mice, along with reduced AMPK activity. Oil Red O results showed that PFOS exposure caused fat accumulation in HepG2 cells. As predicted, PFOS treatment reduced the level of phosphorylated AMPK in a concentration-dependent manner, leading to subsequent increase in ACC activity and lipid droplet accumulation in HepG2 cells. Treatment with 200-µM AMPK agonist AICAR alleviated PFOS-induced ACC activation and lipid accumulation. In summary, our data highlight a crucial role of AMPK/ACC pathway in PFOS-mediated liver lipid metabolic disorders.

Double-Enhanced Core-Shell-Shell Sb2S3/Sb@TiO2@C Nanorod Composites for Lithium- and Sodium-Ion Batteries.

For most alloying- and conversion-type anode materials, a huge volume expansion and structure degradation of the electrodes always hinder their applications. In this work, a novel core-shell-shell Sb2S3/Sb@TiO2@C nanorod composite has been designed layer by layer, which includes an inner Sb2S3/Sb heterostructure core protected by an oxygen-deficient TiO2 shell and a conductive carbon shell. It is interesting to observe that, during the carbothermic reduction process, the previous Sb2S3 nanorod cores are partially reduced into a metallic Sb phase and the reduced TiO2 also creates many oxygen vacancies, which can greatly enhance the conductivity of the semiconductor Sb2S3. Thanks to the double effects of the TiO2 middle shell and carbon outer shell, the unique double-shelled structure design creates an enhanced dual protection, which can better accommodate the volume-expansive deformation and preserve the structural integrity of the active Sb2S3/Sb core. Especially, the TiO2 middle layer is self-assembled by numerous nanoparticles acting as a nanopillar backbone, which supports between the nanorod core and outer carbon shell to better buffer the volume changes. As a result, the core-shell-shell Sb2S3/Sb@TiO2@C anode shows lithium and sodium storage performances superior to those of the pristine Sb2S3 and core-shell Sb2S3@TiO2 electrodes. For lithium-ion batteries, the Sb2S3/Sb@TiO2@C nanorod composite achieves an initial discharge/recharge capacity of 1244.9/1005.1 mAh g-1 with an initial Coulombic efficiency of about 80.7%, an enhanced rate capability with a capacity of 593.2 mA h g-1 at 5.0 A g-1, and prolonged cycling life for 500 cycles with a reversible capacity of 495.8 mAh g-1 at 0.5 A g-1. For sodium-ion batteries, the nanorodalso exhibits an improved performance with an initial discharge/recharge capacity of 781.4/574.0 mAh g-1 (initial Coulombic efficiency of about 73.46%) and cycling for 400 cycles with a reversible capacity of 422.6 mAh g-1 at 0.8 A g-1. This research sheds light upon double-shell structure designs with an effective middle shell to enhance the energy storage performance of electrode materials.

Perfluorooctane sulfonate aggravates CCl4-induced hepatic fibrosis via HMGB1/TLR4/Smad signaling.

Perfluorooctane sulfonate (PFOS) is a widespread environmental pollutant and may cause a variety of adverse health effects. The hepatotoxicity of PFOS has attracted particular attention, given the fact that the liver has one of the highest PFOS accumulations among human tissues. In this study, we revealed that subchronic PFOS exposure may exacerbate carbon tetrachloride (CCl4 )-induced liver fibrosis in animal models. Administration with 1 mg/kg PFOS every other day for 56 days dramatically enhanced CCl4 -mediated liver injury and hepatic stellate cell (HSC) activation. Furthermore, PFOS exposure may promote the activation of high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) signaling pathway through inducing the secretion of HMGB1 from hepatocytes. PFOS exposure induced the translocation of HMGB1 from the nucleus into the cytoplasm of hepatocytes and cultured BRL-3A cells at a starting concentration of 50 µM. This process is accompanied with concurrent flux of calcium, suggesting a link between calcium signaling and HMGB1 release following PFOS exposure. Finally, we showed that PFOS-exposed conditional medium (PFOS-CM) of hepatocytes may induce the translocation of Smad2/3 in HSCs in a TLR4-dependent manner. Taken together, subchronic PFOS exposure might play a pro-fibrotic role via a HMGB1/TLR4-dependent Smad signaling in HSCs. Our findings for the first time uncovered an involvement of PFOS exposure in liver fibrosis via HMGB1/TLR4/Smad signaling.

PFOS facilitates liver inflammation and steatosis: An involvement of NLRP3 inflammasome-mediated hepatocyte pyroptosis.

Perfluorooctane sulfonate (PFOS) is a fluorinated organic pollutant with substantial accumulation in mammalian liver tissues. However, the impact of chronic PFOS exposure on liver disease progression and the underlying molecular mechanisms remain elusive. Herein, we for the first time revealed that micromolar range of PFOS exposure initiates the activation of NLR pyrin domain containing 3 (NLRP3) inflammasome to drive hepatocyte pyroptosis. We showed that 5 mg/kg/day PFOS exposure may exacerbated liver inflammation and steatosis in high-fat diet (HFD)-fed mice with concurrently elevated expression of NLRP3 and caspase-1. PFOS exposure resulted in viability impairment and LDH release in BRL-3A rat liver cells. 25-100 µM concentrations of PFOS exposure activated the NLRP3 inflammasome, leading to consequent GSDMD cleavage, IL-1ß release and the initiation of pyroptosis in a dose-dependent manner, whereas treatment with 10 µM NLRP3 inhibitor MCC950 abrogated this effect. Moreover, pretreatment of 5 mM ROS scavenger N-acetyl-L-cysteine (NAC) ameliorated PFOS-induced NLRP3 inflammasome activation and pyroptosis. Collectively, our data highlight a pivotal role of pyroptotic death in PFOS-mediated liver inflammation and metabolic disorder.

SYVN1/GPX5 axis affects ischemia/reperfusion induced apoptosis of AC16 cells by regulating ROS generation.

Ischemia/reperfusion (I/R) induced injury is a major cause of coronary heart disease (CHD). Increased production of reactive oxygen species (ROS) can lead to an I/R injury in CHD, and the ROS level can be regulated by Glutathione peroxidase (GPX) enzyme family. In this study, we investigated the role and underlying molecular mechanism of GPX5 in I/R-induced AC16 cells. We found that the serum level of GPX5 was down-regulated in patients with CHD and I/R-induced AC16 cells. Overexpression of GPX5 inhibited I/R-induced apoptosis by suppressing the production of ROS. On the other hand, knock-down of GPX5 promoted apoptosis in AC16 cells by up-regulating the level of ROS. Furthermore, we found that GPX5 was regulated by synovial apoptosis inhibitor 1 (SYVN1)-mediated ubiquitination in AC16 cells. In I/R-induced AC16 cells, the expression of SYVN1 was up-regulated, and SYVN1 knock-down decreased the ROS levels and apoptotic rate but increased GPX5 levels. Moreover, GPX5 knockdown promoted ROS production and apoptosis, while its effects were attenuated by SYVN1 knockdown. Furthermore, SYVN1 was up-regulated while GPX5 was down-regulated in the myocardial tissue of I/R-injured rats. Taken together, our data demonstrate that GPX5 inhibits I/R-induced apoptosis of AC16 cells by down-regulating ROS level, and its stabilization is regulated by SYVN1-mediated ubiquitination.

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA.

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

Preparation of Nanocomposite Peptide and Its Inhibitory Effect on Myocardial Injury in Type-II Diabetic Rats.

Complications of diabetes are the main cause of death and disability in diabetic patients. Cardiovascular diseases, especially diabetic cardiomyopathy, are one of the major complications and causes of death in type 2 diabetes. Peptide drugs have a better effect on improving cellular oxidative damage, reducing tissue inflammation and inhibiting intracellular calcium overload. The application of nanotechnology to the preparation of peptide drugs and myocardial injury can effectively improve myocardial stun, arrhythmia and myocardial systolic dysfunction in patients with type 2 diabetes. The use of nanotechnology to develop more stable Glucagon-like peptide 1 analogues or sustained-release preparations, improve patient compliance and improve the efficacy of diabetes, is of great significance for the prevention and treatment of diabetic cardiomyopathy. Therefore, this study used nanotechnology to prepare PLGA-GLP-1 nanoparticles using polyglycolic acid glycolic acid as a drug carrier, which achieved long-acting drug and its morphology by transmission electron microscopy. At the same time, this study explored the anti-cardiomyocyte injury and anti-myocardial damage of PLGA-GLP-1 nanocomposite peptide and its molecular mechanism by using animal models and cell models. Experimental studies have shown that PLGA-GLP-1 nanocomposite peptide has a protective effect on myocardial injury in diabetic rats. Its mechanism is related to the PLGA-GLP-1 nanocomposite peptide enhancing the body's antioxidant capacity, anti-cardiomyocyte apoptosis, and promoting mitochondrial DNA repair in cardiomyocytes.

ROS-mediated JNK pathway critically contributes to PFOS-triggered apoptosis in SH-SY5Y cells.

Recent studies have indicated that perfluorooctane sulfonate (PFOS) and its derivatives can lead to neurotoxicity. In the present study, we showed that PFOS may trigger neuronal apoptosis through a c-Jun N-terminal kinase (JNK)-related mechanism. We revealed that c-Jun N-terminal kinase (JNK) was robustly activated in PFOS-exposed neuronal cells. The doses of PFOS that initiates JNK activation coincides with that inducing neuronal apoptosis, as confirmed by western blot and Annexin V-PE/7-AAD analyses. In addition, we found that reactive oxidative species (ROS) accumulation plays a casual role in PFOS-initiated JNK activation, as treatment with ROS scavenger N-acetyl-l-cysteine (NAC) abrogated PFOS-induced mitochondrial and nuclear translocation of phosphorylated JNK (p-JNK). In keeping with this notion, the expression of JNK downstream pro-apoptotic target Bim was increased following PFOS exposure in JNK- and ROS-dependent manners. Finally, Annexin V-PE/7-AAD analysis uncovered that treatment with NAC or SP600125 could significantly impair PFOS-induced neuronal apoptosis. These findings implicate that JNK signaling is critically involved in PFOS-induced neuronal death by virtue of mitochondrial translocation and the transcription of pro-apoptotic genes.

FGF5 promotes osteosarcoma cells proliferation via activating MAPK signaling pathway.

Objective: This study aimed to investigate the role of fibroblast growth factor-5 (FGF5) in osteosarcoma (OS) and explore the potential mechanisms. Methods: OS gene expression data was downloaded from the Gene Expression Omnibus (GEO; GSE12865) and analyzed by R software. OS tissues and cell lines were collected. The expression level of FGF5 in tumor tissues and cell lines was detected using qRT-PCR. Knockout of FGF5 was performed using CRISPR/Cas9 system. The effects of FGF5 knockout on OS cell proliferation and tumor growth were determined through cell counting kit-8 assay and xenograft nude mice, respectively. Additionally, recombinant FGF5 (rFGF5) was added into OS cell and the effects of rFGF5 on the proliferation and apoptosis of OS cell lines were assayed. Furthermore, the protein expression levels of mitogen-activated protein kinase (MAPK) signaling pathway were detected through Western blot. Results: FGF5 was significantly upregulated in OS tissues and cells, and closely associated with poor differentiation, larger tumor size, lymph node metastasis, and advanced TNM stage. FGF5 knockout could inhibit proliferation of OS cells and tumor growth in nude mouse model. Addition of exogenous rFGF5 promoted OS cell proliferation while inhibited OS cell apoptosis. The expression levels of MAPK signaling pathway proteins in FGF5 knockout group were significantly lower than that in control when there was no rFGF5. Additionally, their expression level in rFGF5 addition group was higher than that in without rFGF5 group. Conclusion: We demonstrated for the first time that FGF5 was overexpressed in OS cell lines and clinical tissue samples and promotes OS cell proliferation by activating MAPK signaling pathway, which indicated that FGF5 was a potential therapeutic target for OS.

The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common irregular heart rhythm which influence approximately 1-2% of the general population. As a potential factor for ischemic stroke, AF could also cause heart failure. The mechanisms behind AF pathogenesis is complex and remains elusive. As a new category of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been known as the key of developmental processes, regulation of cell function, pathogenesis of heart diseases and pathological responses which could provide novel sight into the pathogenesis of AF. circRNAs function as modulators of microRNAs in cardiac disease. To investigate the regulatory mechanism of circRNA in AF, especially the complex interactions among circRNA, microRNA and mRNA, we collected the heart tissues from three AF patients and three healthy controls and profiled their circRNA expressions with circRNA Microarray. The differentially expressed circRNAs were identified and the biological functions of their interaction microRNAs and mRNAs were analyzed. Our results provided novel insights of the circRNA roles in AF and proposed highly possible interaction mechanisms among circRNAs, microRNAs, and mRNAs.

Nrf2 Signaling Elicits a Neuroprotective Role Against PFOS-mediated Oxidative Damage and Apoptosis.

Perfluorooctanesulfonate (PFOS) may cause neurotoxicity through the initiation of oxidative stress. In the current study, we investigated the role of anti-oxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in PFOS-induced neurotoxicity. We found that human neuroblastoma SH-SY5Y cells exhibited significant apoptotic cell death following PFOS exposure, and this process was accompanied with apparent accumulation of reactive oxidative species (ROS). In addition, we revealed that PFOS exposure caused marked activation of Nrf2 pathway and the expression of Nrf2 transcription target heme oxygenase-1. We further found that pre-treatment with ROS scavenger N-acetyl-L-cysteine (NAC) dramatically ameliorated PFOS-induced ROS production and Nrf2 signaling. In keeping with these findings, western blot and Cell Counter Kit-8 analyses revealed that pre-incubation with NAC suppressed PFOS-induced expression of pro-apoptotic proteins and impairment of neuronal viability. Moreover, antagonizing Nrf2 pathway with Nrf2 inhibitor brusatol resulted in increased ROS production and enhanced PFOS-induced expression of apoptosis related proteins. Finally, we showed that PFOS exposure altered mitochondrial transmembrane potential and disrupted normal mitochondrial morphology in SH-SY5Y cells. Whereas treatment with NAC ameliorated PFOS-induced mitochondrial disorders, co-incubation with brusatol augmented PFOS-induced mitochondrial deficits, consequently contributing to neuronal apoptosis. These results manifest that Nrf2 pathway plays a protective role in PFOS-induced neurotoxicity, providing new insights into the prevention and treatment of PFOS-related toxicities.

Correlation between Depression, Posttraumatic Stress Disorder, and Inflammatory Factors in Patients with Severe Burn Injury.

We aim to investigate the relation between depression, posttraumatic stress disorder (PTSD), and inflammatory factors in patients with severe burn injury. Psychological assessment was carried out using PTSD checklist (PCL) involving a 17-item self-report questionnaire (PCL-17) and the Hamilton Rating Scale for depression (HAMD-24). The serum IL-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were determined using enzyme-linked immunosorbent assay. Correlation analysis was performed to analyze the correlation between the factors and scores of PTSD and depression. Compared with the PCL-17 score, HAMD-24 score, and inflammatory factors at month 3, a significant decrease was noticed in the PCL-17 score, HAMD-24 score, and inflammatory factors at months 6 and 9 (P < 0.01). For the HAMD-24 score, significant improvements were noticed in the anxiety/somatization, cognitive disorder, blocking, sleep disorders, and depression at months 3, 6, and 9. The levels of IL-1ß, IL-8, and TNF-α were positively correlated with the PCL-17 score (P < 0.05). The levels of IL-1ß, IL-6, IL-8, and TNF-α were positively correlated with the HAMD-24 score (P < 0.05). Patients with severe burn injury showed obvious stress alternation displaying specific depression-related characteristics, and inflammation may involve in the pathogenesis of PTSD and depression in burn patients.

Perfluorooctanesulfonate induces neuroinflammation through the secretion of TNF-α mediated by the JAK2/STAT3 pathway.

Perfluorooctanesulfonate (PFOS)-containing compounds are widely used in all aspects of industrial and consumer products. Recent studies indicated that PFOS is ubiquitous in environments and is considered to be a new type of persistent organic pollutant (POP). This has raised concerns regarding its adverse effects on human health. The nervous system is regarded as a sensitive target of environmental contaminants, including PFOS. Previous findings showed that PFOS can induce neurobehavioral deficits. However, the molecular mechanism underlying PFOS neurotoxicity remains obscure. Astrocyte activation and the resulting pro-inflammatory cytokine release play an integral role in protecting neurons from neurotoxin-mediated damage. If uncontrolled, sustained astrocyte activation may cause the secretion of excessive levels of pro-inflammatory cytokines that exacerbate the initial damage. In this study, we showed that PFOS could promote excessive secretion of tumor necrosis factor-α (TNF-α) in dose- and time-dependent manners in astrocytes. Furthermore, PFOS exposure could induce the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). This suggests that the JAK2/STAT3 signal transduction pathway is involved in PFOS-mediated astrocyte activation and secretion of TNF-α. Indeed, targeted blockage of the JAK2/STAT3 pathway prevented the phosphorylation of JAK and STAT3, and it also caused abnormal expression of TNF-α. Finally, we demonstrated that SH-SY5Y neuronal cells underwent rapid apoptosis via a TNF-α-dependent mechanism after exposure to PFOS-treated astrocyte-conditioned medium. In summary, our findings reveal that PFOS mediates a rapid activation of JAK2/STAT3 signal transduction in C6 astrocytes, which plays a pivotal role in the initiation of PFOS-mediated neurotoxicity.

Perfluorooctane sulfonate mediates secretion of IL-1ß through PI3K/AKT NF-кB pathway in astrocytes.

Perfluorooctane sulfonate (PFOS) is a persistent and bioaccumulative compound that has been widely used in various fields of life and industrial productions, because of its special chemical and physical properties. Numerous studies have indicated significant neurotoxic effect of PFOS, especially on neurons and microglia. However, the influence of PFOS on astrocyte physiology remains unclear. In this study, we showed that PFOS triggered reactive astrocytosis in time- and dose-dependent manners. The low-doses of PFOS increased the cell number and the expression of glial fibrillary acidic protein (GFAP), a well-known hallmark of reactive astrocytes, in C6 astrocyte cells. ELISA and RT-PCR analysis showed that PFOS promoted the expression and secretion of Interleukin-1 beta (IL-1ß) in dose- and time-dependent manners. Furthermore, PFOS exposure could induce the phosphorylation and degradation of IκBα, and the translocation of NF-κB p65 from the cytoplasm to the nucleus in C6 glioma cell line. Thus, the NF-кB signaling pathway can be activated after PFOS exposure. In addition, pretreatment with AKT inhibitor LY294002 could obviously attenuate PFOS-induced NF-κB activation and IL-1ß secretion. Taken together, these results indicated that PFOS could facilitate reactive astrocytosis and the secretion of pro-inflammatory cytokines through AKT-dependent NF-κB signaling pathway.

Scaling Up Human Immunodeficiency Virus Screening and Antiretroviral Therapy Among Men Who Have Sex With Men to Achieve the 90-90-90 Targets in China.

INTRODUCTION: The Joint United Nations Programme on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome has proposed the 90-90-90 targets by 2020. Human immunodeficiency virus epidemic is spreading rapidly among men who have sex with men (MSM) in China. This study investigates how the scale-up of HIV testing and treatment in achieving the targets and its cost-effectiveness. METHODS: We constructed a compartmental model to forecast the HIV epidemic in Chinese MSM based on various "test-and-treat" scale-up scenarios. We assessed their cost effectiveness based on the cost for each HIV infection, death, and disability-adjusted life years (DALYs) prevented by the scale-up. RESULTS: If the current epidemic continued, HIV prevalence among Chinese MSM would increase from 9.2% in 2016 to 12.6% (9.2-15.6%) in 2020 and 16.2% (11.3-20.0%) in 2025. By 2020, 49.2% of infected MSM would be diagnosed and 40.1% of whom on treatment, falling short of the 90-90-90 targets, so would be even by 2025. To achieve these targets by 2020, additional 850,000 HIV screening tests and 112,500 person-years of antiretroviral treatment (ART) annually are necessary. This spending is US $478 million during 2016 to 2020, which almost tripled the status quo. However, by delaying to 2025, an investment of US $1210 million over 2016 to 2025 corresponding to 52% increase to the status quo, will enable extra 340,000 HIV screening tests and 60,000 person-year on ART annually. In both scenarios, the incremental cost-effectiveness ratio was US $733 to 960 for each DALY prevented, indicating highly cost-effective scenarios. CONCLUSIONS: Achieving the 90-90-90 targets by 2020 requires steep increase in investment, but delaying the targets to 2025 is practical and cost-effective.

A Global Estimate of the Acceptability of Pre-exposure Prophylaxis for HIV Among Men Who have Sex with Men: A Systematic Review and Meta-analysis.

Pre-exposure prophylaxis (PrEP) is a new biomedical intervention for HIV prevention. This study systematically reviews the acceptability of PrEP among men who have sex with men (MSM) worldwide. We searched major English databases to identify English-language articles published between July 2007 and July 2016, which reported the acceptability of PrEP and associated population characteristics. Meta-analysis was conducted to estimate a pooled acceptability, and meta-regression and subgroup analysis were used to analyse heterogeneities. The estimated acceptance from included sixty-eight articles was 57.8% (95% confidence internal 52.4-63.1%). MSM who were younger (4/5 studies, range of adjusted odds ratio (aOR) = 1.39-3.47), better educated (aOR = 1.49-7.70), wealthier (aOR = 1.31-13.03) and previously aware of PrEP (aOR = 1.33-3.30) showed significantly higher acceptance. Male sex workers (84.0% [26.3-98.7%] were more likely to accept PrEP than general MSM. Self-perceived low efficacy, concern about side effects, adherence, affordability, and stigma were main barriers. This review identifies a moderate acceptability of PrEP in MSM. Efficacy, perception of HIV risk and experienced stigma determine its acceptance.

Downregulation of Mfn2 participates in manganese-induced neuronal apoptosis in rat striatum and PC12 cells.

Manganese (Mn) is a widely distributed trace element that is essential for normal brain function and development. However, chronic exposure to excessive Mn has been known to lead to neuronal loss and manganism, a disease with debilitating motor and cognitive deficits, whose clinical syndrome resembling idiopathic Parkinson's disease (IPD). However, the precise molecular mechanism underlying Mn neurotoxicity remains largely unclear. Accumulating evidence indicates that abnormal mitochondrial functionality is an early and causal event in Mn-induced neurodegeneration and apoptosis. Here, we investigated whether Mitofusin 2 (Mfn2), a highly conserved dynamin-related protein (DRP), played a role in the regulation of Mn-induced neuronal apoptosis. We revealed that Mfn2 was significantly dysregulated in rat striatum and PC12 neuronal-like cells following Mn exposure. Western blot analysis revealed that the expression of Mfn2 was remarkably decreased following different concentrations of Mn exposure. Immunohistochemistry analysis confirmed a remarkable downregulation of Mfn2 in rat striatum after Mn exposure. Immunofluorescent staining showed that Mfn2 was expressed predominantly in neurons, and neuronal loss of Mfn2 was associated with the expression of active caspase-3 following Mn exposure. Importantly, overexpression of Mfn2 apparently attenuated Mn-induced neuronal apoptosis. Notably, treatment with caspase-3 inhibitor Ac-DEVD-CH could not rescue Mn-induced downregulation of Mfn2, suggesting that Mn-induced mfn2 occurs prior to neuronal apoptosis. Taken together, these results indicated that down-regulated expression of Mfn2 might contribute to the pathological processes underlying Mn neurotoxicity.