SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease.

Recent evidence shows a close link between Parkinson's disease (PD) and cardiac dysfunction with limited treatment options. Mitophagy plays a crucial role in the control of mitochondrial quantity, metabolic reprogramming and cell differentiation. Mutation of the mitophagy protein Parkin is directly associated with the onset of PD. Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1) for receptor-mediated mitophagy. In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models, and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin. MPTP-induced PD model was established. PD patients and MPTP mice not only displayed pronounced motor defects, but also low plasma FUNDC1 levels, as well as cardiac ultrastructural and geometric anomalies (cardiac atrophy, interstitial fibrosis), functional anomalies (reduced E/A ratio, fractional shortening, ejection fraction, cardiomyocyte contraction) and mitochondrial injury (ultrastructural damage, UCP2, PGC1α, elevated mitochondrial Ca2+ uptake proteins MCU and VDAC1, and mitochondrial apoptotic protein calpain), dampened autophagy, FUNDC1 mitophagy and apoptosis. By Gene set enrichment analysis (GSEA), we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice. Intriguingly, administration of SGLT2 inhibitor empagliflozin (10 mg/kg, i.p., twice per week for 2 weeks) in MPTP-treated mice significantly ameliorated myocardial anomalies (with exception of VDAC1), but did not reconcile the motor defects or plasma FUNDC1. FUNDC1 global knockout (FUNDC1-/- mice) did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult, but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling (atrophy and fibrosis), contractile dysfunction, Ca2+ homeostasis, mitochondrial (including MCU, mitochondrial Ca2+ overload, calpain, PARP1) and apoptotic anomalies. In neonatal and adult cardiomyocytes, treatment with PD neurotoxin preformed fibrils of α-synuclein (PFF) caused cytochrome c release and cardiomyocyte mechanical defects. These effects were mitigated by empagliflozin (10 µM) or MCU inhibitor Ru360 (10 µM). MCU activator kaempferol (10 µM) or calpain activator dibucaine (500 µM) nullified the empagliflozin-induced beneficial effects. These results suggest that empagliflozin protects against PD-induced cardiac anomalies, likely through FUNDC1-mediated regulation of mitochondrial integrity.

Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization.

Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.

PM2.5 exposure increases dry eye disease risks through corneal epithelial inflammation and mitochondrial dysfunctions.

Dry eye disease (DED) is the most common disease affecting vision and quality of life. PM2.5 was a potential risk of DED. Herein, we conducted animal exposure and cell-based studies to evaluate the pathogenic effect of PM2.5 exposure on the ocular surface and DED etiological mechanisms. C57 mice were exposed to filtered air and PM2.5 aerosol. We assessed health conditions and inflammation of the ocular surface by corneal fluorescein staining and immunohistochemistry. In parallel, cultured human corneal epithelial cells (HCETs) were treated with PM2.5, followed by characterization of cell viability, intracellular ATP level, mitochondrial activities, and expression level of DED relevant mRNA and proteins. In mice, PM2.5 exposure induced severe superficial punctate keratopathy and inflammation in their cornea. In HCETs, cell proliferation and ROS generation followed dose-response and time-dependent manner; meanwhile, mitochondrial ROS (mtROS) level increased and mitochondrial membrane potential (MMP) level decreased. Inflammation cascade was triggered even after short-term exposure. The reduction of ATP production was alleviated with Nrf2 overexpression, NF-κB P65 knockdown, or ROS clearance. Nrf2 overexpression and P65 knockdown reduced inflammatory reaction through decreasing expression of P65 and increasing of Nrf2, respectively. They partly alleviated changes of ROS/mtROS/MMP. This research proved that PM2.5 would cause DED-related inflammation reaction on corneal epithelial cells and further explored its mechanism: ROS from mitochondrial dysfunctions of corneal epithelial cells after PM2.5 exposure partly inhibited the expression of anti-inflammatory protein Nrf2 led the activation of inflammatory protein P65 and its downstream molecules, which finally caused inflammation reaction.

LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway.

The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.

Three New Metal Complexes with Imidazole-Containing Tripodal Ligands as Fluorophores for Nitroaromatics- and Ion-Selective Sensing.

Three new metal-organic complexes [Cd(TIPA)(suc)0.5(NO3)·1/2H2O]n (1), [Ni(TIPA)(tda)0.5(H2O)·1/4H2O]n (2) and [Cd(TIPA)(tda)0.5·11/2H2O] (3) were synthesized via rigid tripodal ligand tris(4-(1H-imidazol-1-yl)phenyl)amine (TIPA) and three dicarboxylic acids; either succinic acid (H2suc) or 2,5-thiophenedicarboxylic acid (H2tda). Crystallographic data for 1 - 3 reveal three-dimensional (3D) networks and channels in the structures. The structure of 2 is unique featuring an interpenetrating 2D network, 2D + 2D → 3D, with the two associated 2D networks existing in two opposite spiral channels. TGA plots exhibit a loss of mass corresponding to the loss of the solvated water molecules in the 100 - 200 °C temperature region and begin to lose additional fragments only at T > 300 °C revealing the robust nature of the 3D framework in the complexes. The metal-organic frameworks (MOFs) are screened for their potential application in the detection and removal of environmentally hazardous industrial pollutants. Fluorescence emission spectra for 1 and 2 show that the two MOFs are capable of sensing nitrobenzene (NB), with the nickel complex 2 exhibiting significantly higher sensing ability. Powder XRD data measured for 1 and 2 and those of NB-treated 1 and 2 show significant differences in their patterns, providing further support for the strong interaction between the MOF complexes and NB. The fluorescence emission observed for 1 is more effectively quenched by the presence of Fe3+ than the series of 17 other metal ions investigated. Complex 3 possesses some ability to adsorb inorganic pollutants.

Sublingual allergen immunotherapy with a liquid birch pollen product in patients with seasonal allergic rhinoconjunctivitis with or without asthma.

BACKGROUND: Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both clinically efficacious and safe. However, in line with the current regulatory guidance from the European Medicines Agency, allergen immunotherapy (AIT) products must demonstrate their efficacy and safety in pivotal phase III trials for registration. OBJECTIVE: We sought to investigate the efficacy and safety of sublingual high-dose liquid birch pollen extract (40,000 allergy units native [AUN]/mL) in adults with birch pollen allergy. METHODS: A randomized, double-blind, placebo-controlled, parallel-group multicenter trial was conducted in 406 adult patients with moderate-to-severe birch pollen-induced allergic rhinoconjunctivitis with or without mild-to-moderate controlled asthma. Treatment was started 3 to 6 months before the birch pollen season and continued during the season in 40 clinical study centers in 5 European countries. For primary end point assessment, the recommended combined symptom and medication score of the European Academy of Allergy and Clinical Immunology was used. Secondary end points included quality-of-life assessments, immunologic parameters, and safety. RESULTS: Primary efficacy results demonstrated a significant (P < .0001) and clinically relevant (32%) reduction in the combined symptom and medication score compared with placebo after 3 to 6 months of SLIT. Significantly better rhinoconjunctivitis quality-of-life scores (P < .0001) and the patient's own overall assessment of his or her health status, including the visual analog scale score (Euro Quality of Life Visual Analogue Scale; P = .0025), were also demonstrated. In total, a good safety profile of SLIT was observed. CONCLUSION: This study confirmed both the clinical efficacy and safety of a sublingual liquid birch pollen extract in adults with birch pollen allergy in a pivotal phase III trial (EudraCT: 2013-005550-30; ClinicalTrials.gov: NCT02231307).

Air Pollutants are associated with Dry Eye Disease in Urban Ophthalmic Outpatients: a Prevalence Study in China.

BACKGROUND: Although previous prevalence studies of DED were reported from some countries worldwide, national data are unavailable in China. We aimed to conduct an up-to-date national survey on the prevalence of DED in China and find out the potential risk factors including air pollutant. METHODS: 23,922 eligible outpatients were recruited from ophthalmic clinics of 32 cities in China in 2013 by registration orders. The patients' demographic characteristics, history of keratorefractive surgery, diseases and medication history were collected and the daily air pollutant data in 2013. Multivariate logistic analysis was performed to identify the potential risk factors associated with DED. The association between related factors and dry eye diseases subtypes evaluated as p value and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Among 23,922 outpatients, the prevalence of DED was 61.57%, and that of the male patients was 57.64% and of the female was 65.32% (P < 0.0001). Multivariate logistic regression suggested that the possible risk factors for DED included: female, older age, history of keratorefractive surgery, presence of arthritis, thyroid diseases, and antihistamine, diuretic, duodenal ulcer drugs, diazepam. Air pollutants including O3, PM2.5, and SO2 were also identified as the risk factors. CONCLUSION: The prevalence of DED among ophthalmic outpatients in China was considerably high. Age, gender, history of keratorefractive surgery, diseases, medication history, and air pollutants were associated with DED prevalence.

Guillain-Barré syndrome in southern China: retrospective analysis of hospitalised patients from 14 provinces in the area south of the Huaihe River.

OBJECTIVES: The clinical and epidemiological profiles of Guillain-Barré syndrome (GBS) in southern China have yet to be fully recognised. We aimed to investigate the subtypes of GBS in southern China, compare the clinical features of demyelinating form with that of axonal form and test whether preceding infections and age have influence on the clinical phenotype, disease course and severity of GBS. METHODS: Medical records of patients with a diagnosis of GBS admitted to 31 tertiary hospitals, located in 14 provinces in southern China, from 1 January 2013 to 30 September 2016, were collected and retrospectively reviewed. RESULTS: Finally. 1056 patients, including 887 classic GBS and 169 variants, were enrolled. The 661 classic patients with available electromyographic data were grouped as having acute inflammatory demyelinating polyneuropathy (AIDP, 49.0%), acute motor axonal neuropathy (AMAN, 18.8%), inexcitable (0.9%) and equivocal (31.3%). In contrast to AIDP, patients with AMAN were characterised by earlier nadir (P=0.000), higher Hughes score at nadir (P=0.003) and at discharge (P=0.000). Preceding upper respiratory infections were identified in 369 (34.9%) patients, who were more inclined to develop AIDP (P=0.000) and Miller-Fisher syndrome (P=0.027), whereas gastrointestinal infection were found in 89 (8.4%) patients, who were more prone to develop AMAN (P=0.000), with more severe illness (P=0.001) and longer hospital stay (P=0.009). Children (≤15 years) and the elderly (≥56 years) were more severe at nadir, the elderly had the longest hospital stay (P=0.023). CONCLUSION: AIDP is the predominant form in southern China, which is different from data of northern China. The different subtypes, preceding infection and age of onset can partially determine the disease progression, severity and short-term recovery speed of GBS. CLINICAL TRIAL REGISTRATION: ChiCTR-RRC-17014152.

The influence of comorbid chronic diseases and physical activity on quality of life in lung cancer survivors.

PURPOSE: This study aimed to evaluate the influence of comorbid chronic diseases (CCD) and physical activity (PA) on quality of life (QOL) in lung cancer survivors (LCSs). METHODS: The study used a cross-sectional study design. A total of 701 LCSs were recruited from 17 comprehensive cancer rehabilitation clubs in Shanghai, China. Measurements used included the European Organization for Research and Treatment quality of life version 3 questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy -General version 4 questionnaire (FACT-G). Independent variables were CCD and PA. Multiple linear regression models were used to control for the effect of sociodemographic characteristic. RESULTS: Subjects with CCD generally reported lower scores for most EORTC QLQ-C30 and FACT-G scales when compared to subjects without CCD, indicating poorer QOL. Subjects with PA generally reported higher scores for most EORTC QLQ-C30 and FACT-G scales when compared to subjects without PA, indicating better QOL. The influences of five times and more PA per week were larger than the influence of less than five times PA per week. Subjects without CCD and with PA generally reported similar scores for most EORTC QLQ-C30 and FACT-G scales when compared to others without CCD and PA. Subjects with CCD and PA generally reported higher scores for most EORTC QLQ-C30 and FACT-G scales when compared to other LCSs with CCD and without PA. CONCLUSIONS: CCD have significantly negative influence on QOL. PA has significantly positive influence on QOL among the LCSs with CCD, not among the other LCSs without CCD.

Comorbid chronic diseases and their associations with quality of life among gynecological cancer survivors.

BACKGROUND: Many gynecological cancer survivors (GCS) have comorbid chronic diseases (CCD). This study was to estimate the impacts of CCD on quality of life (QOL) in GCS. METHODS: We collected cross-sectional self-reported survey data from 598 GCS between April and July 2013, in Shanghai, China. All the subjects were asked to complete a questionnaire containing the European Organization for Research and Treatment quality of life version 3 questionnaire (EORTC QLQ-C30) and questions on socio-demographic characteristics and CCD. In order to mitigate the bias caused by confounding factors, multiple linear models were employed to calculate adjusted means of QOL scores. RESULTS: Approximately three-quarters of subjects reported at least one CCD. The highest overall prevalence of all CCD was found in endometrial cancer survivors. Subjects with CCD generally reported lower scores for most EORTC QLQ-C30 scales when compared to subjects without CCD, indicating poorer QOL, particularly for cardiovascular diseases, respiratory diseases, digestive diseases, and musculoskeletal disease. CONCLUSIONS: The CCD are common health problems among GCS. CCD have significantly negative influence on QOL, and GCS with CCD generally reported lower QOL scores. These findings suggested comprehensive cares for GCS.

Patterns of Spatial Variation in Rumen Microbiology, Histomorphology, and Fermentation Parameters in Tarim wapiti (Cervus elaphus yarkandensis).

The rumen is divided into multiple rumen sacs based on anatomical structure, and each has its unique physiological environment. Tarim wapiti preserved roughage tolerance after domestication, and adaptation to the desertified environment led to the development of a unique rumen shape and intraruminal environment. In this work, six Tarim wapiti were chosen and tested for fermentation parameters, microbes, and histomorphology in four rumen areas (Dorsal sac, DS; Ventral sac, VS; Caudodorsal blind sac, CDBS; Caudoventral blind sac, CVBS). Tarim wapiti's rumen blind sac had better developed rumen histomorphology, the ventral sac was richer in VFAs, and the dominant bacteria varied most notably in the phylum Firmicutes, which was enriched in the caudoventral blind sac. The ventral sac biomarkers focused on carbohydrate fermentation-associated bacteria, the dorsal sac focused on N recycling, and the caudoventral blind sac identified the only phylum-level bacterium, Firmicutes; we were surprised to find a probiotic bacterium, Bacillus clausii, identified as a biomarker in the ventral sac. This research provides a better understanding of rumen fermentation parameters, microorganisms, and histomorphology in the Tarim wapiti rumen within a unique ecological habitat, laying the groundwork for future regulation targeting the rumen microbiota and subsequent animal production improvement.

Evaluation of inflammatory hyperreflective foci and plasma EPA as diagnostic and predictive markers for age-related macular degeneration.

Objectives: To detect the plasma polyunsaturated fatty acids (PUFAs) concentrations in age-related macular degeneration (AMD) patients and healthy controls. Additionally, advanced studies were conducted to investigate the relationship between PUFAs concentrations and ophthalmological characteristics, including hyperreflective foci (HRF), visual acuity, and anti-vascular endothelial growth factor (anti-VEGF) response in patients with AMD. Methods: This prospective, single-site study recruited a total of 315 participants, consisting of 105 individuals with dry AMD (early-stage AMD group), 105 individuals with neovascular AMD (late-stage AMD group), and 105 elderly individuals without any fundus diseases (healthy controls). The levels of omega-3 and omega-6 PUFAs in plasma were detected using gas chromatography. Retinal thickness, choroidal thickness, and macular volume were quantified using optical coherence tomography angiography (OCTA) scan with a 6 × 6 mm macular area, and the amounts of HRF were analyzed with OCTA scanning data. Results: Compared to the control group, AMD patients exhibited significantly lower plasma concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha linolenic acid. HRF were observed in various retinal layers of AMD patients, particularly those with late-stage AMD. The correlation coefficient matrix and multiple linear regression models demonstrated that HRF played a crucial role in best corrected visual acuity for both early (p < 0.001) and late-stage AMD patients (p = 0.006), while EPA had an inverse effect on the logarithm of the minimum angle of resolution (logMAR) value in patients with early-stage AMD (p < 0.001). As compared to patients with good responses to anti-VEGF therapy, those with poor responses had significantly lower baseline logMAR (p < 0.001), central retina thickness (p = 0.002), macular volume (p = 0.027), HRF (p = 0.024), and plasma EPA (p < 0.001). This study used a ROC curve analysis to identify the combination of HRF and EPA as a potential biomarker for predicting the response to anti-VEGF treatment in late-stage AMD patients, with an area under the curve (AUC) value of 0.775. Conclusions: Reduced plasma EPA was detected in AMD cases and the lower EPA concentration was related to poorer visual acuity. Additionally, the quantity of HRF combined with concentration of plasma EPA may serve as the prognostic indicator for predicting the effect of anti-VEGF treatment in late-stage AMD patients.

Topical Application of Cell-Penetrating Peptide Modified Anti-VEGF Drug Alleviated Choroidal Neovascularization in Mice.

Background: Age-related macular degeneration (AMD) stands as the foremost cause of irreversible central vision impairment, marked by choroidal neovascularization (CNV). The prevailing clinical approach to AMD treatment relies on intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, this method is encumbered by diverse complications, prompting exploration of non-invasive alternatives such as ocular administration via eye drops for anti-VEGF therapy. Methods: Two complexes, 5-FITC-CPP-Ranibizumab (5-FCR) and 5-FITC-CPP-Conbercept (5-FCC), were synthesized by incorporating the anti-VEGF drugs Ranibizumab (RBZ) or Conbercept (CBC) with cell-penetrating peptide (CPP). Circular dichroism spectrum (CD) facilitated complexes characterization. Eye drops was utilized to address laser-induced CNV in mice. Fluorescein fundus angiography (FFA) observe the CNV lesion, while FITC-dextran and IB4 dual fluorescent staining, along with hematoxylin-eosin (HE) staining, assessed in lesion size. Tissue immunofluorescence examined CD31 and VEGF expression in choroidal/retinal pigment epithelial (RPE) tissues. Biocompatibility and biosafety of 5-FCR and 5-FCC was evaluated through histological examination of various organs or cell experiments. Results: Both 5-FCR and 5-FCC exhibited favorable biocompatibility and safety profiles. VEGF-induced migration of Human umbilical vein endothelial cells (HUVECs) significantly decreased post-5-FCR/5-FCC treatment. Additionally, both complexes suppressed VEGF-induced tube formation in HUVECs. FFA results revealed a significant improvement in retinal exudation in mice. Histological examination unveiled the lesion areas in the 5-FCR and 5-FCC groups showed a significant reduction compared to the control group. Similar outcomes were observed in histological sections of the RPE-choroid-sclera flat mounts. Conclusion: In this study, utilizing the properties of CPP and two anti-VEGF drugs, we successfully synthesized two complexes, 5-FCR and 5-FCC, through a straightforward approach. Effectively delivering the anti-VEGF drugs to the target area in a non-invasive manner, suppressing the progression of laser-induced CNV. This offers a novel approach for the treatment of wet AMD.

Modulating the optoelectronic properties of large, conjugated, high-energy gap, quaternary phosphine oxide hosts: impact of the triplet-excited-state location.

The purposeful modulation of the optoelectronic properties was realised on the basis of a series of the large, conjugated, phosphine oxide hosts 9,9-bis-{4'-[2-(diphenylphosphinoyl)phenoxy]biphenyl-4-yl}-9H-fluorene (DDPESPOF), 9,9-bis-{3'-(diphenylphosphinoyl)-4'-[2-(diphenylphosphinoyl)phenoxy]biphenyl-4-yl}-9H-fluorene (DDPEPOF), 9-[4'-(9-{4'-[2-(diphenylphosphoryl)phenoxy]biphenyl-4-yl}-9H-fluoren-9-yl)biphenyl-4-yl]-9H-carbazole (DPESPOFPhCz) and 9-[4'-(9-{3'-(diphenylphosphoryl)-4'-[2-(diphenylphosphoryl)phenoxy]biphenyl-4-yl}-9H-fluoren-9-yl)biphenyl-4-yl]-9H-carbazole (DPEPOFPhCz). The last two are quaternary with fluorenyls as linking bridges, diphenylphosphine oxide (DPPO) moieties as electron acceptors and diphenylethers and carbazolyls as two different kinds of electron donors. Owing to the fine-organised molecular structures and the mixed indirect and multi-insulating linkages, all of these hosts achieve the same first triplet energy levels (T1) of 2.86 eV for exothermic energy transfer to phosphorescent dopants. The first singlet energy levels (S1) and the carrier injection/transportation ability of the hosts were accurately modulated, so that DPESPOFPhCz and DPEPOFPhCz revealed extremely similar optoelectronic properties. However, the T1 state of the former is localised on fluorenyl, whereas the carbazolyl mainly contributes to the T1 state of the latter. A lower driving voltages and much higher efficiencies of the devices based on DPESPOFPhCz indicated that the chromophore-localised T1 state can suppress the quenching effects through realising independent contributions from the different functional groups to the optoelectronic properties and the embedding and protecting effect on the T1 states by peripheral carrier transporting groups.

Tolerability and Safety of Sublingual Immunotherapy in Patients with Tree Pollen Allergy in Daily Practice-An Open, Prospective, Non-Interventional Study.

To investigate the tolerability and safety of two sublingual tree pollen extracts approved in 2018, a non-interventional study (NIS) was performed. This NIS was an 8-month observational study conducted at 84 sites throughout Germany. Study participants received either a sublingual liquid allergen extract of birch pollen (SBPE) or a liquid allergen extract consisting of a mixture of birch, hazel, and alder tree pollen (STPE). Data from 432 patients were analyzed for the occurrence of adverse events and patient compliance. At least one local reaction occurred in 69 (22.2%) patients, whereas systemic reactions were only observed in 27 (6.3%) patients. STPE-treated patients developed systemic reactions more frequently than SBPE-treated patients (SBPE: 9 (4.3%) vs. STPE: 18 (8.0%)). Only one patient developed a systemic grade III reaction. Severe systemic grade IV reactions were not observed. A total of 348 (98.6%) of the patients who completed all visits were satisfied or very satisfied with the sublingual immunotherapy (SLIT), and 322 (71%) patients completed all visits. Both investigated products were well tolerated by the patients and demonstrated a good safety profile. AEs were observed less frequently than in the preceding clinical phase III trial, and no new safety concerns were identified.

Toward an understanding of the protein interaction network of the human liver.

Proteome-scale protein interaction maps are available for many organisms, ranging from bacteria, yeast, worms and flies to humans. These maps provide substantial new insights into systems biology, disease research and drug discovery. However, only a small fraction of the total number of human protein-protein interactions has been identified. In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins. The data set has a validation rate of over 72% as determined by three independent biochemical or cellular assays. The network includes metabolic enzymes and liver-specific, liver-phenotype and liver-disease proteins that are individually critical for the maintenance of liver functions. The liver enriched proteins had significantly different topological properties and increased our understanding of the functional relationships among proteins in a liver-specific manner. Our data represent the first comprehensive description of a HLPN, which could be a valuable tool for understanding the functioning of the protein interaction network of the human liver.

Development of Proliferative Vitreoretinopathy Is Attenuated by Chicken Ovalbumin Upstream Promoter Transcriptional Factor 1 Via Inhibiting Epithelial-Mesenchymal Transition.

Proliferative vitreoretinopathy (PVR) is an intractable condition after rhegmatogenous retinal detachment (RD), which is the primary cause of failure in retinal reattachment surgery. This study aimed to investigate the effects of chicken ovalbumin upstream promoter transcriptional factor 1 (COUP-TF1) in the development of proliferative vitreoretinopathy (PVR) both in vitro and in vivo. Adult retinal pigment epithelium cell line was used for in-vitro experiments. Immunocytochemistry assay, real-time quantitative polymerase chain reaction, and Western blot were used to measure the expression of COUP-TF1, alpha-smooth muscle actin (α-SMA), and E-cadherin. Epithelial-mesenchymal transition (EMT) was observed through cell counting kit-8 assay, wound healing tests, and the expression changes of related proteins. PVR rabbit models were established and evaluated by the images of fundus and vitreous cavity, pathological sections, and COUP-TF1 expression. As shown by our results, the proliferation and migration of the COUP-TF1 knockdown cells were reduced compared with the control cells with or without transforming growth factor-ß1 (TGF-ß1) treatment. After TGF-ß1 treatment, α-SMA expression was upregulated in ARPE-19 cells but kept the same in COUP-TF1 knockdown cells. E-cadherin expression was down-regulated in all the groups but the extent of the decrease in COUP-TF1 knockdown cells was smaller. EMT was attenuated in ARPE-19 cells after COUP-TF1 was knocked down. In the in-vivo experiment, PVR severity was attenuated and the retinal detachment rate decreased on the 14th and 28th day in COUP-TF1 knockdown group. In conclusion, COUP-TF1 is related to the development of PVR, and COUP-TF1 knockdown attenuates the progression of PVR. This suggests that COUP-TF1 can be a promising candidate for the treatment of PVR.

Impact of primary site on survival in patients with nasopharyngeal carcinoma from 2004 to 2015.

Background: Nasopharynx carcinoma (NPC) is the most common malignant tumor of the nasopharynx. Many studies have shown some factors related with the prognosis of NPC patients. Our study aims to evaluate the differences of prognosis between initial and second primary NPC. Material and methods: The Surveillance, Epidemiology, and End Results (SEER) program was used to perform the population-based analysis in NPC patients who were newly diagnosed between 2004 and 2015. Kaplan-Meier and Cox regressions were used to evaluate the effects of primary site on the overall survival (OS), as well as the cancer-specific survival (CSS). Results: Our study included 5,012 NPC patients: 4,474 initial primary NPC patients and 5,38 s primary NPC patients. Significant differences were observed in sex, age at diagnosis, race, median household income, histological type, American Joint Committee on Cancer (AJCC) stage, N-stage, radiation treatment and chemotherapy between patients with initial and second NPC (P < 0.05). Moreover, the patients with second NPC had longer survival months. In addition, radiation and chemotherapy were recommended both in first and second primary NPC patients. Conclusion: Worse prognosis was observed in patients with second primary NPC compared with those with primary NPC in all subgroups of AJCC stage and age at diagnosis.

Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE.

Senescent cells have been demonstrated to have lower cellular NAD+ levels and are involved in the development of various age-related diseases, including age-related macular degeneration (AMD). Sodium iodate (NaIO3) has been primarily used as an oxidant to establish a model of dry AMD. Results of previous studies have showed that NaIO3 induced retinal tissue senescence in vivo. However, the role of NaIO3 and the mechanism by which it induces retinal pigment epithelium (RPE) senescence remains unknown. In this study, RPE cell senescence was confirmed to be potentially induced by NaIO3. The results showed that the number of senescence-associated-ß-galactosidase (SA-ß-gal-)-positive cells and the protein levels of p16 and p21 increased after NaIO3 treatment. Additionally, the senescent RPE cells underwent oxidative stress and NAD+ depletion. Furthermore, significant DNA damage and mitochondrial dysfunction were also detected in senescent RPE cells. The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD+ levels in cells and tissues.