Cyclophilin B, a molecule chaperone, promotes adipogenesis in 3T3­L1 preadipocytes via AKT/mTOR pathway.

Cyclophilin is known to act as a molecular chaperone in the endoplasmic reticulum. Recent studies have reported that the expression of cyclophilin B (CypB) is increased in ob/ob mice and its inhibitor suppresses adipocyte differentiation. However, the mechanism of action of CypB in adipocytes remains to be elucidated. The present study investigated the role of CypB in 3T3­L1 adipocyte differentiation. It showed that the expression level of CypB was increased during 3T3­L1 adipocyte differentiation by reverse transcription­quantitative PCR and western blotting analysis. CypB knockdown using short interfering RNA delayed cell cycle progression from the G1/S to G2/M phase through the mammalian target of rapamycin (mTOR) signaling pathway and inhibited the expression levels of adipogenic transcription factors including peroxisome proliferator­activated receptor Î³ (PPARγ) and CCAAT­enhancer binding protein (C/EBP)α. Additionally, the accumulation of lipid droplets was inhibited by CypB knockdown. Conversely, overexpression of CypB promoted cell cycle progression from the G1/S to G2/M phase by the mTOR signaling pathway and enhanced the expression levels of adipogenic transcription factors including PPARγ and C/EBPα. Finally, the present study showed that CypB downregulated the expression of CHOP, a well­known negative regulator of adipogenesis. Taken together, the data suggested that CypB might serve important physiological regulatory roles in 3T3­L1 adipocyte differentiation.

Discovery of Dual-Functional Amorphous Titanium Suboxide to Promote Polysulfide Adsorption and Regulate Sulfide Growth in Li-S Batteries.

Lithium-sulfur (Li-S) batteries are promising as next-generation energy storage systems. Adsorbents for sulfide species are favorably applied to the cathode, but this substrate often results in a surface-passivating lithium sulfide(Li2 S) film with a strong adsorption of Li2 S. Here, an amorphous titanium suboxide (a-TiOx) is presented that strongly adsorbs lithium polysulfides (Li2 Sx , x < 6) but relatively weakly adsorbs to Li2 S. With these characteristics, the a-TiOx achieves high conversion of Li2 Sx and high sulfur utilization accompanying the growth of particulate Li2 S. The DFT calculations present a mechanism for particulate growth driven by the promoted diffusion and favorable clustering of Li2 S. The a-TiOx -coated carbon nanotube-assembled film (CNTF) cathode substrate cell achieves a high discharge capacity equivalent to 90% sulfur utilization at 0.2 C. The cell also delivers a high capacity of 850 mAh g-1 even at the ultra-high-speed of 10 C and also exhibits high stability of capacity loss of 0.0226% per cycle up to 500 cycles. The a-TiOx /CNTF is stacked to achieve a high loading of 7.5 mg S cm-2 , achieving a practical areal capacity of 10.1 mAh cm-2 .

2-O-Methylhonokiol Suppresses HCV Replication via TRAF6-Mediated NF-kB Activation.

Hepatitis C virus (HCV) is associated with various liver diseases. Chronic HCV infection is characterized by an abnormal host immune response. Therefore, it is speculated that to suppress HCV, a well-regulated host immune response is necessary. 2-O-methylhonokiol was identified by the screening of anti-HCV compounds using Renilla luciferase assay in Huh 7.5/Con 1 genotype 1b replicon cells. Here, we investigated the mechanism by which 2-O-methylhonokiol treatment inhibits HCV replication using real-time PCR. Our data shows that treatment with 2-O-methylhonokiol activated innate immune responses via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. Additionally, the immunoprecipitation result shows that treatment with 2-O-methylhonokiol augmented tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) by preventing p62 from binding to TRAF6, resulting in reduced autophagy caused by HCV. Finally, we reproduced our data with the conditioned media from 2-O-methylhonokiol-treated cells. These findings strongly suggest that 2-O-methylhonokiol enhances the host immune response and suppresses HCV replication via TRAF6-mediated NF-kB activation.

2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes.

BACKGROUND: The 96 weeks' assessment from the VIEW studies provided insights into the long-term efficacy of intravitreal aflibercept (IVT-AFL) in neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2. The aim of this analysis was to perform a literature review and meta-analysis assessing the use of IVT-AFL and real-world outcomes in treatment-naïve patients with nAMD treated with IVT-AFL for 2 years, as per label. METHODS: A literature review and meta-analysis were performed to provide an overview of the baseline characteristics of the population, the 2-year outcomes, the associated treatment burden, and safety. RESULTS: Eleven publications providing data from patients with nAMD who had treatment initiated with IVT-AFL between 2012 and 2016 were identified. The mean baseline age of patients was 78.62 years, with a baseline best-corrected visual acuity (BCVA) of 57.73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients reported a mean BCVA at 2 years of 62.55 ETDRS letters, with 47.39% of patients having a BCVA ≥ 70 ETDRS letters. Mean gain in BCVA versus baseline was + 4.49 ETDRS letters for the combined population (+ 5.91 letters for patients treated with a treat-and-extend regimen). Over the 2 years of the study, patients received an average of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. The qualitative assessment of the safety data suggested that no new safety signals were identified. CONCLUSION: Patients treated with IVT-AFL reported significant gains in visual acuity versus baseline after 2 years. The evidence identified indicates that the visual gains achieved during the first year of treatment are maintained through the second year and that these were achieved with a reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.

Honokiol inhibits hepatoma carcinoma cell migration through downregulated Cyclophilin B expression.

Hepatocellular carcinoma (HCC) is the fifth common types of cancer with poor prognosis in the world. Honokiol (HNK), a natural biphenyl compound derived from the magnolia plant, has been reported to exert anticancer effects, but its mechanism has not been elucidated exactly. In the present study, HNK treatment significantly suppressed the migration ability of HepG2 and Hep3B human hepatocellular carcinoma. The treatment reduced the expression levels of the genes associated with cell migration, such as S100A4, MMP-2, MMP-9 and Vimentin. Interestingly, treatment with HNK significantly reduced the expression level of Cyclophilin B (CypB) which stimulates cancer cell migration. However, overexpressed CypB abolished HNK-mediated suppression of cell migration, and reversed the apoptotic effects of HNK. Altogether, we concluded that the suppression of migration activities by HNK was through down-regulated CypB in HCC. These finding suggest that HNK may be a promising candidate for HCC treatment via regulation of CypB.

Real-World Effectiveness and Real-World Cost-Effectiveness of Intravitreal Aflibercept and Intravitreal Ranibizumab in Neovascular Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Real-World Studies.

INTRODUCTION: Treatment of neovascular age-related macular degeneration (nAMD) has evolved with the advent of anti-vascular endothelial growth factor agents such that intravitreally administered aflibercept and ranibizumab (RBZ) have become the standard of care. Randomized clinical trials (RCTs) have demonstrated the benefits of these agents in nAMD; however, results achieved under RCT protocols may not always be replicated in clinical practice. Assessing real-world outcomes is important to estimate the effectiveness and cost-effectiveness of these two agents. Our objective was to assess the real-world effectiveness of intravitreally administered aflibercept and RBZ in treatment-naive patients with nAMD and determine the cost-effectiveness of intravitreally administered aflibercept versus RBZ in a real-world setting. METHODS: A multistage approach was undertaken. A systematic literature review (SLR) was completed to identify studies describing real-world outcomes in patients with nAMD treated intravitreally with aflibercept or RBZ. A meta-analysis of data identified in the SLR generated a pooled estimate of the effectiveness of intravitreally administered aflibercept and RBZ at 52 weeks and an estimate of treatment burden (injection frequency and monitoring). The impact of treatment effect modifiers, such as baseline visual acuity (VA) and age, were corrected through a multivariable meta-regression. A Markov state transition model was developed to estimate the real-world cost-effectiveness of intravitreally administered aflibercept using results from the pooled estimates for effectiveness and treatment burden as primary inputs. The analysis considered the perspective of the French National Healthcare System. RESULTS: Patients treated intravitreally with aflibercept had a mean age of 79.52 years and mean baseline VA of 55.80 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. At week 52, mean VA gain was 5.30 ETDRS letters in patients reporting an average of 7.10 intravitreal injections of aflibercept and 8.65 visits (injection and/or monitoring). RBZ-treated patients were younger (77.28 years), with a lower mean baseline VA (52.81 ETDRS letters). At week 52, mean VA gain from baseline was 4.24 ETDRS letters, with an average of 5.88 injections and 10.10 visits (injection and/or monitoring). After correcting for differences in age (77.28 years) and baseline VA (52.81 ETDRS letters) and considering the current clinical practice with aflibercept and RBZ, the mean VA gain was 6.57 ETDRS letters for patients treated intravitreally with aflibercept and 4.42 ETDRS for patients treated intravitreally with RBZ. The cost-effectiveness analysis showed that intravitreally administered aflibercept is a more effective treatment option with an incremental gain in quality-adjusted life years (QALYs) (4.918 versus 4.880) and an incremental cost-effectiveness ratio (ICER) of €27,087 per QALY. CONCLUSIONS: The analysis identified differences in the overall treatment approach and how ophthalmologists use intravitreally administered aflibercept and RBZ in clinical practice. These differences ultimately influence the mean real-world effectiveness of the two agents. Intravitreal treatment with aflibercept (injection frequency and patients follow-up) was consistent and in line with the European label recommendations. Patients treated intravitreally with aflibercept in clinical practice reported a mean gain in VA of similar magnitude to the mean VA gain reported in the pivotal RCT. Conversely, treatment with RBZ varied significantly across the different studies. On average, RBZ-treated patients reported a low injection frequency and a frequent follow-up, driven in part by the high number of patients treated with pro re nata (PRN) regimens. RBZ-treated patients reported gains in VA versus baseline; however, the magnitude of the gain in VA was not comparable to the VA gains reported in the RBZ pivotal RCT. Intravitreal treatment with aflibercept was associated with better mean VA outcomes and an incremental gain in QALYs compared with RBZ and can be considered cost-effective for the treatment of nAMD in patients in France despite a higher price for each individual intravitreal injection of aflibercept compared with RBZ. FUNDING: Bayer AG, Basel.