Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study.

PURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study. PARTICIPANTS: Male patients ≥10 years of age with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 1010 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 1011 vector genomes/eye) or to be an untreated control participant. MAIN OUTCOME MEASURES: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12. RESULTS: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group. CONCLUSIONS: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Enhanced Biphasic Reactions in Amphiphilic Silica Mesopores.

In this study, we investigated the effect of the pore volume and mesopore size of surface-active catalytic organosilicas on the genesis of particle-stabilized (Pickering) emulsions for the dodecanal/ethylene glycol system and their reactivity for the acid-catalyzed biphasic acetalization reaction. To this aim, we functionalized a series of fumed silica superparticles (size 100-300 nm) displaying an average mesopore size in the range of 11-14 nm and variable mesopore volume, with a similar surface density of octyl and propylsulfonic acid groups. The modified silica superparticles were characterized in detail using different techniques, including acid-base titration, thermogravimetric analysis, TEM, and dynamic light scattering. The pore volume of the particles impacts their self-assembly and coverage at the dodecanal/ethylene glycol (DA/EG) interface. This affects the stability and the average droplet size of emulsions and conditions of the available interfacial surface area for reaction. The maximum DA-EG productivity is observed for A200 super-SiNPs with a pore volume of 0.39 cm3·g-1 with an interfacial coverage by particles lower than 1 (i.e., submonolayer). Using dissipative particle dynamics and all-atom grand canonical Monte Carlo simulations, we unveil a stabilizing role of the pore volume of porous silica superparticles for generating emulsions and local micromixing of immiscible dodecanal and ethylene glycol, allowing fast and efficient solvent-free acetalization in the presence of Pickering emulsions. The micromixing level is interrelated to the adsorption energy of self-assembled particles at the DA/EG interface.

Three-dimensional modelling and hemodynamic simulation of the closure of multiple entry tears in type B aortic dissection.

BACKGROUND: Stanford type B aortic dissection (TB-AD) is a life-threatening vascular condition with high rates of morbidity and mortality. Currently, thoracic endovascular aortic repair (TEVAR) is widely performed to treat TB-AD, and some studies have analyzed the influence of stents on hemodynamics using computational fluid dynamics (CFD) models. However, the accuracy of TB-AD simulation models are not satisfactory, they are often constructed as a regular ideal model. Furthermore, it is unclear which tear should be closed for the best treatment when there are multi entry tears. PURPOSE: The aims of this paper were to provide an assessment method for the selection of the surgical closure location for type B aortic dissection. Five 3D models of multiple entry tears in type B aortic dissection were produced using real patient computed tomography (CT) images to perform hemodynamic analyses of flow velocity streamlines, wall pressure, and wall shear stress. METHODS: A Boolean operation was adopted to establish 3D models with multiple entry tears in type B aortic dissection based on patient-specific CT images. The Mimics and Ansys plug-in The Integrated Computer Engineering and Manufacturing code for Computational Fluid Dynamics (ICEM CFD) software were applied to mesh the 3D models. The flow velocity streamlines, wall pressures, and wall shear stresses were then analyzed in the finite element analysis software Fluent. Five 3D models were produced to compare the hemodynamic characteristics of different entry tear numbers, as well as the changes of different closure positions before and after closure. RESULTS: The false lumen of the model with two entry tears had a higher wall pressure than that of model with multiple entry tears, which may tend to squeeze the true lumen and expand the false lumen. The load distribution of the vessel in the model with multiple entry tears had a more balanced flow velocity, and its wall pressure and shear stress were lower than that of model with two entry tears. For aortic dissection with two entry tears, the closure of the proximal entry tear was recommended, which helped to isolate and thrombose the false lumen, thereby improving the blood supply function of the true lumen. Because the postoperative vascular flow velocity and mechanical load performance of the vascular wall were still higher than those of normal blood vessels, the postoperative blood vessels remained pathological, and TEVAR did not restore the blood vessels to their original healthy state. CONCLUSIONS: Type B aortic dissection with two entry tears tend to squeeze the true lumen and expand the false lumen, resulting in a new entry tear and deterioration into multiple entry type B aortic dissection. The model of the vessel with multiple entry tears had a more balanced distribution in flow velocity and a smaller wall pressure and shear stress than that of the vessel with two entry tears. The closure of the proximal entry tear was considered an ideal solution for type B aortic dissection with two entry tears.

Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial.

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .

Inhalable siRNA Nanoparticles for Enhanced Tumor-Targeting Treatment of KRAS-Mutant Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma (KRAS) is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of KRAS-mutant NSCLC and other respiratory diseases.

Controllable EIT-like mode splitting in a chiral microcavity.

Two coupled resonance modes can lead to exotic transmission spectra due to internal interference processes. Examples include electromagnetically induced transparency (EIT) in atoms and mode splitting in optics. The ability to control individual modes plays a crucial role in controlling such transmission spectra for practical applications. Here we experimentally demonstrate a controllable EIT-like mode splitting in a single microcavity using a double-port excitation. The mode splitting caused by internal coupling between two counter-propagating resonances can be effectively controlled by varying the power of the two inputs, as well as their relative phase. Moreover, the presence of asymmetric scattering in the microcavity leads to chiral behaviors in the mode splitting in the two propagating directions, manifesting itself in terms of a Fano-like resonance mode. These results may offer a compact platform for a tunable device in all-optical information processing.

A Phase IIb Randomized Clinical Study of an Anti-αvß6 Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge.

Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.

A Facile Synthesis of Novel Amorphous TiO2 Nanorods Decorated rGO Hybrid Composites with Wide Band Microwave Absorption.

Amorphous structures may play important roles in achieving highly efficient microwave absorption performance due to the polarization losses induced by the disorders, vacancies and other functional groups existed in them. Herein, a kind of amorphous TiO2/rGO composite (a-TiO2/rGO) was successfully fabricated via a facile one-step solvothermal method. The complex permittivity of the composites can be regulated by adjusting the addition of precursor solution. The minimum reflection loss of a-TiO2/rGO composites reached -42.8 dB at 8.72 GHz with a thickness of 3.25 mm, and the widest efficient absorption bandwidth (EAB) was up to 6.2 GHz (11.8 to 18 GHz) with a thickness of only 2.15 mm, which achieved the full absorption in Ku band (12 to 18 GHz). Furthermore, the EAB was achieved ranging from 3.97 to 18 GHz by adjusting the thickness of the absorber, covering 87.7% of the whole radar frequency band. It is considered that the well-matched impedance, various polarization processes, capacitor-like structure and conductive networks all contributed to the excellent microwave absorption of a-TiO2/rGO. This study provides reference on constructing amorphous structures for future microwave absorber researches and the as-prepared a-TiO2/rGO composites also have great potential owing to its facile synthesis and highly efficient microwave absorption.

Quantitative proteomics analysis of Fructus Psoraleae-induced hepatotoxicity in rats.

Fructus Psoraleae, which is commonly consumed for the treatment of osteoporosis, bone fracture, and leucoderma, induces liver injury. This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae (EEFP)-induced liver injury in rats. EEFP (1.35, 1.80, and 2.25 g·kg-1) was administrated to Sprague Dawley (SD) rats for 30 d. We measured liver chemistries, histopathology, and quantitative isobaric tags for relative and absolute quantitation (iTRAQ)-based protein profiling. EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion, bile flow rate, and liver histopathology. iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats. Among these proteins, 81 were upregulated and 32 were downregulated in the treatment group. KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450, glutathione metabolism, glycerolipid metabolism, and bile secretion were enriched with differentially expressed proteins. The expression of key proteins related to the farnesoid X receptor (FXR), i.e., the peroxisome proliferators-activated receptor alpha (PPAR-α), were downregulated, and multidrug resistance-associated protein 3 (MRP3) was upregulated in the EEFP-treated rats. Our results provide evidence that EEFP may induce hepatotoxicity through various pathways. Furthermore, our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.

Imbalanced insulin substrate-1 and insulin substrate-2 signaling trigger hepatic steatosis in vitamin D deficient rats: 8-methoxypsoralen, a vitamin D receptor ligand with a promising anti-steatotic action.

The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde. Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl- CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.

Neurofilament as a potential biomarker for spinal muscular atrophy.

OBJECTIVE: To evaluate plasma phosphorylated neurofilament heavy chain (pNF-H) as a biomarker in spinal muscular atrophy (SMA). METHODS: Levels of pNF-H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. RESULTS: Median pNF-H plasma level was 167.0 pg/mL (7.46-7,030; n = 34) in children without SMA (aged 7 weeks-18 years) and was higher in those aged < 1 versus 1-18 years (P = 0.0002). In ENDEAR participants with infantile-onset SMA, median baseline pNF-H level (15,400 pg/mL; 2390-50,100; n = 117) was ~10-fold higher than that of age-matched infants without SMA (P < 0.0001) and ~90-fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF-H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF-H levels: nusinersen-treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control-treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. INTERPRETATION: Plasma pNF-H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF-H levels followed by relative stabilization. Together these data suggest plasma pNF-H is a promising marker of disease activity/treatment response in infants with SMA.

Adaptive homeostasis of the vitamin D-vitamin D nuclear receptor axis in 8-methoxypsoralen-induced hepatotoxicity.

8-methoxypsoralen (8-MOP) with ultraviolet A radiation therapy (PUVA) is the standard therapy for patients with psoriasis, despite the reported potential risks of 8-MOP-induced cholestatic liver injury in both humans and animals. Usually, patients with chronic cholestasis exhibit lower serum 25-hydroxy vitamin D (25(OH)D) levels. But those patients receiving PUVA for psoriasis showed an increase in serum 25(OH)D levels, probably highlighting that the vitamin D-vitamin D nuclear receptor (VD-VDR) axis play a protective role in 8-MOP-induced hepatotoxicity. The present study confirmed 8-MOP could increase serum 25(OH)D levels in conventional lighting and diet (CLD) and vitamin D deficient (VDD) Sprague-Dawley rats. Potential liver risks were also found in CLD and VDD rats after 8-MOP treatment. We proved that 8-MOP could be a potent ligand for VDR using molecular docking and luciferase report assay. Effect of 8-MOP on VDR subcellular distribution was determined using human liver cell line L02. We found 8-MOP could increase VDR protein expression in the nuclear and cytosol extracts and also total cell extracts in L02. siRNAs for VDR were used to determine the role of VDR in protecting 8-MOP-induced cholestasis and potential cellular mechanisms. The results showed 8-MOP could affect the CYP7A1, SHP and MRP3 expression via VDR, and such effects could be reversed by knockdown of VDR expression, suggesting a vital role of VDR involved in 8-MOP-regulated bile acid synthesis and transportation. In conclusion, these results revealed activation of VD-VDR axis may play a beneficial role in 8-MOP-mediated regulation of bile acid synthesis and transportation.

Mitochondrial dysfunction and inhibition of myoblast differentiation in mice with high-fat-diet-induced pre-diabetes.

Pre-diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre-diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre-diabetes, in which 6-week-old male C57BL6/J mice were fed either normal diet or high-fat diet (HFD) for 8 or 16 weeks. Both non-fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8-week HFD developed pre-diabetes with IGT; whereas mice fed a 16-week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG-IGT). Mice at both stages of pre-diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG-IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG-IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid-induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre-diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage.

Nanomixing Effects in Glycerol/Dodecanol Pickering Emulsions for Interfacial Catalysis.

Pickering emulsions offer a promising platform for conducting interfacial reactions between immiscible reagents. Despite the significant progress in the engineering of amphiphilic catalysts for such reactions, the mechanism behind their enhanced activity is still poorly understood. Herein, using the glycerol/dodecanol system as a case study, we conducted a combined meso- and microscale study of Pickering emulsions stabilized by amphiphilic silica nanoparticles bearing acid centers by marrying dissipative particle dynamics simulations with emulsification experiments. The optimal surface properties of the silica particles in terms of length and density of alkyl chains were identified, matching the experimental results. The local distribution of glycerol and dodecanol near the acid centers was ascertained, unraveling potential reactivity zones near the catalytic acid centers due to an enhanced nanomixing between glycerol and dodecanol.

Psoralen Induced Liver Injury by Attenuating Liver Regenerative Capability.

Psoralen is a major component of the common traditional Chinese medicine Fructus Psoraleae (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest in vivo. The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by Fructus Psoraleae.

A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis.

AIMS: Enhancing myogenesis has been identified as a possible target to improve insulin sensitivity and protect against metabolic diseases. Catalpol, an iridoid glycoside, has been shown to exert a hypoglycaemic effect by improvement of insulin sensitivity; however, the underlying mechanism remains unknown. In this study, we tested whether catalpol has the potential to improve insulin sensitivity by augmenting myogenesis. MAIN METHODS: We examined the hypoglycaemic mechanism of catalpol in db/db mice and C2C12 cells. db/db mice were treated with catalpol (200 mg/kg) for 8 consecutive weeks. Serum analysis, skeletal muscle performance and histology, and gene and protein expression were performed. In vitro glucose uptake, gene and protein expression were determined, and small interfering RNA was used to identify the underlying hypoglycaemic mechanism of catalpol. KEY FINDINGS: In this study, we tested whether catalpol has the potential to improve skeletal insulin sensitivity by augmenting myogenesis, in which we found that, catalpol treatment in db/db mice lowered blood glucose and improved insulin sensitivity via activation of phosphatidylinositol­3­Kinase (PI3K)/protein kinase B (AKT) pathway. Moreover, catalpol-treated mice exhibited enhanced myogenesis, as evidenced by increased myogenic differentiation (MyoD), myogenin (MyoG) and myosin heavy chain (MHC) expressions. The in vitro experimental results showed that both catalpol and metformin enhanced glucose uptake via activation of PI3K/AKT pathway. However, unlike metformin, the PI3K/AKT pathway activation by catalpol was dependent on enhanced MyoD/MyoG-mediated myogenesis. SIGNIFICANCE: Improvement of insulin sensitivity by enhancing MyoD/MyoG-mediated myogenesis may constitute a new therapeutic approach for treating type 2 diabetes.

Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 µg, ethinyl estradiol 35 µg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification.

Experimental demonstration of a reconfigurable electro-optic directed logic circuit using cascaded carrier-injection micro-ring resonators.

We experimentally demonstrate a reconfigurable electro-optic directed logic circuit which can perform any combinatorial logic operation using cascaded carrier-injection micro-ring resonators (MRRs), and the logic circuit is fabricated on the silicon-on-insulator (SOI) substrate with the standard commercial Complementary Metal-Oxide-Semiconductor (CMOS) fabrication process. PIN diodes embedded around MRRs are employed to achieve the carrier injection modulation. The operands are represented by electrical signals, which are applied to the corresponding MRRs to control their switching states. The operation result is directed to the output port in the form of light. For proof of principle, several logic operations of three-operand with the operation speed of 100 Mbps are demonstrated successfully.