TY  - JOUR
AB  - INTRODUCTION: Observational studies have identified associations between hematological traits and type-2 diabetes mellitus (T2D). However, it is difficult to infer causal effects due to the potential of confounding. Our study utilizes the Mendelian randomization (MR) approach to address the above limitation and investigate the causal effect of hematological traits such as white blood cell (WBC), platelets (PLT), and red blood cell (RBC) on T2D in individuals of African ancestry. METHODS: The participating cohorts included participants of African ancestry in the Blood Cell consortium and the Million Veteran Program dataset. Using GWAS summary statistics, we applied a univariable and multivariable Two-sample MR to estimate the causal relationship between hematological traits and T2D. RESULTS: In the main IVW MR estimates, genetically predicted levels of mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) were associated with decreased risk of T2D. We also observed a decreased risk of T2D with genetically predicted total WBC count and neutrophil count (NEU), for the WBC traits. The multivariable analysis further supported the direct associations of genetically predicted MCH, MCHC, and MCV levels with a decreased risk of T2D. For the European ancestry, a similar pattern of association was observed for MCH and MCV. DISCUSSION: These findings indicate that hematological traits may differentially play a role in the development of T2D and be affected by T2D. However, further research is needed to validate and explore the biological pathways and mechanisms involved in these associations.
AU  - Soremekun, C.
AU  - Jjingo, D.*
AU  - Kateete, D.*
AU  - Nash, O.*
AU  - Nitsch, D.*
AU  - Nyirenda, M.*
AU  - Gill, D.*
AU  - Zeggini, E.
AU  - Grallert, H.
AU  - Peters, A.
AU  - Chikowore, T.*
AU  - Batini, C.*
AU  - Soremekun, O.
AU  - Fatumo, S.*
C1  - 74093
C2  - 57332
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Mendelian randomization study highlights the role of hematological traits on Type-2 diabetes mellitus in African ancestry individuals.
JO  - Front. Pharmacol.
VL  - 16
PB  - Frontiers Media Sa
PY  - 2025
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - IMPORTANCE: Clinical trials in recent years have shown significant effectiveness of complement inhibitors for geographic atrophy (GA) treatment. Two complement inhibitor drugs have been approved by the Food and Drug Administration (FDA). OBJECTIVE: to compare and rank the different complement inhibitors in the treatment of GA secondary to age-related macular degeneration (AMD). DATA SOURCES: A systematic literature search was conducted in the Cochrane Central, Web of Science Core Collection, PubMed, LWW Medical Journals, ClinicalTrials.gov, and WHO ICTRP from inception to October 2023. STUDY SELECTION: All randomized clinical trials evaluating the effectiveness of complement inhibitors in patients diagnosed with secondary GA in AMD were identified. DATA EXTRACTION AND SYNTHESIS: This study followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) network meta-analysis Checklist of Items and the Cochrane Risk of Bias Assessment Tool for assessing the study quality. Multiple authors independently coded all titles and abstracts, reviewed full-text articles against the inclusion and exclusion criteria, and resolved all discrepancies by consensus. Random-effects network meta-analyses were applied. Bayesian network meta-analysis was performed using the BUGSnet package in R (4.2.0). MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the change in GA lesion size (mm2) from baseline to month 12. The secondary efficacy outcome was the mean change in best-corrected visual acuity (BCVA) from baseline to month 12. Safety outcome measures included the number of subjects with serious adverse events (SAEs) and macular neovascularization (MNV). RESULTS: Ten randomized controlled trials including 4,405 participants and five complement inhibitors were identified. Comparison with sham and SUCRA analysis showed that avacincaptad pegol 2 mg (MD: -0.58, 95% CrI: -0.97 to -0.18, SUCRA: 93.55), pegcetacoplan monthly (MD: -0.38, 95% CrI: -0.57 to -0.20, SUCRA: 81.37), and pegcetacoplan every other month (MD: -0.30, 95% CrI: -0.49 to -0.11, SUCRA: 70.16) have significant changes in GA lesion reduction. No treatments showed significant changes in BCVA and SAE compared with sham. Pegcetacoplan monthly (OR: 4.30, 95% CrI: 1.48-16.72) increased the risk of MNV. Avacincaptad pegol 2 mg demonstrated favorable outcomes in terms of SAE and MNV. CONCLUSION AND RELEVANCE: Avacincaptad pegol 2 mg is the most effective complement inhibitor with better safety for the treatment of GA secondary to AMD. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351515, Identifier PROSPERO CRD42022351515.
AU  - Wang, H.*
AU  - Zheng, J.
AU  - Zhang, Q.*
AU  - Tian, Z.*
AU  - Sun, Y.*
AU  - Zhu, T.*
AU  - Bi, Y.*
AU  - Zhang, L.*
C1  - 72542
C2  - 56647
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: A network meta-analysis of randomized controlled trials.
JO  - Front. Pharmacol.
VL  - 15
PB  - Frontiers Media Sa
PY  - 2024
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - Background: Different asthma phenotypes are driven by molecular endotypes. A Th1-high phenotype is linked to severe, therapy-refractory asthma, subclinical infections and neutrophil inflammation. Previously, we found neutrophil granulocytes (NGs) from asthmatics exhibit decreased chemotaxis towards leukotriene B4 (LTB4), a chemoattractant involved in inflammation response. We hypothesized that this pattern is driven by asthma in general and aggravated in a Th1-high phenotype. Methods: NGs from asthmatic nd healthy children were stimulated with 10 nM LTB4/100 nM N-formylmethionine-leucyl-phenylalanine and neutrophil migration was documented following our prior SiMA (simplified migration assay) workflow, capturing morphologic and dynamic parameters from single-cell tracking in the images. Demographic, clinical and serum cytokine data were determined in the ALLIANCE cohort. Results: A reduced chemotactic response towards LTB4 was confirmed in asthmatic donors regardless of inhaled corticosteroid (ICS) treatment. By contrast, only NGs from ICS-treated asthmatic children migrate similarly to controls with the exception of Th1-high donors, whose NGs presented a reduced and less directed migration towards the chemokines. ICS-treated and Th1-high asthmatic donors present an altered surface receptor profile, which partly correlates with migration. Conclusions: Neutrophil migration in vitro may be affected by ICS-therapy or a Th1-high phenotype. This may be explained by alteration of receptor expression and could be used as a tool to monitor asthma treatment.
AU  - Lemmel, S.*
AU  - Weckmann, M.*
AU  - Wohlers, A.*
AU  - Jirmo, A.C.*
AU  - Grychtol, R.*
AU  - Ricklefs, I.*
AU  - Nissen, G.*
AU  - Bachmann, A.*
AU  - Singh, S.*
AU  - Caicedo, J.C.*
AU  - Bahmer, T.*
AU  - Hansen, G.*
AU  - ALLIANCE Study Group (von Mutius, E.
AU  - Illi, S.
AU  - Maison, N.
AU  - Schmidt-Weber, C.B.
AU  - Zissler, U.M.)
AU  - Rabe, K.F.*
AU  - Fuchs, O.*
AU  - Dittrich, A.M.*
AU  - Schaub, B.*
AU  - Happle, C.*
AU  - Carpenter, A.E.*
AU  - Kopp, M.V.*
AU  - Becker, T.*
C1  - 66532
C2  - 53205
TI  - In vitro neutrophil migration is associated with inhaled corticosteroid treatment and serum cytokines in pediatric asthma.
JO  - Front. Pharmacol.
VL  - 13
PY  - 2022
SN  - 1663-9812
ER  - 

TY  - JOUR
AU  - Puljung, M.*
AU  - Haythorne, E.*
AU  - Rohm, M.
AU  - Vedovato, N.*
C1  - 66167
C2  - 53103
TI  - Editorial: Ion channels and transporters in diabetes and metabolic diseases.
JO  - Front. Pharmacol.
VL  - 13
PY  - 2022
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - The nasal olfactory region is a potential route for non-invasive 
      delivery of drugs directly from the nasal epithelium to the brain, 
      bypassing the often impermeable blood-brain barrier. However, efficient 
      aerosol delivery to the olfactory region is challenging due to its 
      location in the nose. Here we explore aerosol delivery with 
      bi-directional pulsatile flow conditions for targeted drug delivery to 
      the olfactory region using a computational fluid dynamics (CFD) model on
       the patient-specific nasal geometry. Aerosols with aerodynamic diameter
       of 1 µm, which is large enough for delivery of large enough drug doses 
      and yet potentially small enough for non-inertial aerosol deposition due
       to, e.g., particle diffusion and flow oscillations, is inhaled for 
      1.98 s through one nostril and exhaled through the other one. The 
      bi-directional aerosol delivery with steady flow rate of 4 L/min results
       in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity 
      and olfactory region, respectively. Pulsatile flow with average flow 
      rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 
      0.12%, respectively, and it mitigates the non-uniformity of right-left 
      deposition in both the cavity (from 1.77- to 1.33-fold) and the 
      olfactory region (from 624- to 53.2-fold). The average drug dose 
      deposited in the nasal cavity and the olfactory epithelium region is 
      very similar in the right nasal cavity independent of pulsation 
      conditions (inhalation side). In contrast, the local aerosol dose in the
       olfactory region of the left side is at least 100-fold lower than that 
      in the nasal cavity independent of pulsation condition. Hence, while 
      pulsatile flow reduces the right-left (inhalation-exhalation) imbalance,
       it is not able to overcome it. However, the inhalation side (even with 
      pulsation) allows for relatively high olfactory epithelium drug doses 
      per area reaching the same level as in the total nasal cavity. Due to 
      the relatively low drug deposition in olfactory region on the exhalation
       side, this allows either very efficient targeting of the inhalation 
      side, or uniform drug delivery by performing bidirectional flow first 
      from the one and then from the other side of the nose.
AU  - Farnoud, A.
AU  - Tofighian, H.*
AU  - Baumann, I.*
AU  - Martin, A.R.*
AU  - Rashidi, M.M.*
AU  - Menden, M.P.
AU  - Schmid, O.
C1  - 63379
C2  - 51466
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Pulsatile bi-directional aerosol flow affects aerosol delivery to the intranasal olfactory region: A patient-specific computational study
JO  - Front. Pharmacol.
VL  - 12
PB  - Frontiers Media Sa
PY  - 2021
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - Müller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Müller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Müller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Müller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Müller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, VEGF, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Müller cells and the human Müller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Müller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Müller cells resulted in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Müller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Müller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation.
AU  - Schmalen, A.
AU  - Lorenz, L.*
AU  - Grosche, A.*
AU  - Pauly, D.*
AU  - Deeg, C.A.*
AU  - Hauck, S.M.
C1  - 63551
C2  - 51583
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity.
JO  - Front. Pharmacol.
VL  - 12
PB  - Frontiers Media Sa
PY  - 2021
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - Background The anticancer potential of pharmacologic ascorbic acid (AA) has been detected in a number of cancer cells. However,in vivostudy suggested a strongly reduced cytotoxic activity of AA. It was known that pH could be a critical influencing factor for multiple anticancer treatments. In this study, we explored the influence of pH on the cytotoxicity of ascorbic acid. We employed castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145 to observe the therapeutic effect of AA on PCa cells that were cultured with different pHin vitro. We also analyzed the influence of pH and extracellular oxidation on cytotoxicity of AA in cancer cells using reactive oxygen species (ROS) assay, cellular uptake of AA, and NADPH assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to AA with or without bicarbonatein vivo. The cellular uptake of AA in PCa xenografts was detected using positron emission tomography (PET). Small animal PET/CT scans were performed on mice after the administration of 6-deoxy-6-[F-18] fluoro-L-ascorbic acid (F-18-DFA). Results Ourin vitrostudies demonstrate that acidic pH attenuates the cytotoxic activity of pharmacologic ascorbic acid by inhibiting AA uptake in PCa cells. Additionally, we found that the cancer cell-selective toxicity of AA depends on ROS.In vivo, combination of AA and bicarbonate could provide a significant better therapeutic outcome in comparison with controls or AA single treated mice.F-18-DFA PET imaging illustrated that the treatment with NaHCO(3)could significantly increase the AA uptake in tumor. Conclusions The alkalinity of tumor microenvironment plays an important role in anticancer efficiency of AA in CRPC.F-18-DFA PET/CT imaging could predict the therapeutic response of PCa animal model through illustration of tumoral uptake of AA.F-18-DFA might be a potential PET tracer in clinical diagnosis and treatment for CRPC.
AU  - Li, Z.*
AU  - He, P.*
AU  - Luo, G.*
AU  - Shi, X.*
AU  - Yuan, G.*
AU  - Zhang, B.*
AU  - Seidl, C.*
AU  - Gewies, A.
AU  - Wang, Y.*
AU  - Zou, Y.*
AU  - Long, Y.*
AU  - Yue, D.*
AU  - Zhang, X.*
C1  - 60287
C2  - 49134
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Increased tumoral microenvironmental pH improves cytotoxic effect of pharmacologic ascorbic acid in castration-resistant prostate cancer cells.
JO  - Front. Pharmacol.
VL  - 11
PB  - Frontiers Media Sa
PY  - 2020
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - We present two unrelated Chinese patients with CAD deficiency manifesting with a triad of infantile-onset psychomotor developmental delay with regression, drug-refractory epilepsy, and anaemia with anisopoikilocytosis. Timely translation into uridine supplementation, within 2-months of disease onset, allowed us to stop conventional anti-epileptic drugs and led to dramatic improvement in the clinical symptoms, with prompt cessation of seizures, resolution of anaemia, developmental progress, and prevention of development of severe and non-reversible manifestations. The remarkable recovery and prevention of advanced disease with prompt treatment, highlights the need to act immediately upon genetic diagnosis of a treatable disease. This further reinforces CAD deficiency as a treatable neurometabolic disorder and emphasises the need for a biomarker or genetic new born screening for early identification.
AU  - Zhou, L.*
AU  - Deng, J.*
AU  - Stenton, S.
AU  - Zhou, J.*
AU  - Li, H.*
AU  - Chen, C.*
AU  - Prokisch, H.
AU  - Fang, F.*
C1  - 60865
C2  - 49656
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Case Report: Rapid treatment of uridine-responsive epileptic encephalopathy caused by CAD deficiency.
JO  - Front. Pharmacol.
VL  - 11
PB  - Frontiers Media Sa
PY  - 2020
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - In recent animal experiments with suspensions of radiolabeled TiO2 nanoparticles large and highly variable radioactivity fractions were retained in disposable plastic syringes. After unloading between 10% and up to 70% of the loaded dose were still present in the syringes. As a consequence the effectively delivered nanoparticle dose to the animals was frequently much smaller than the nominal dose of the nanoparticles loaded into the syringe. The high variability of this nanoparticle retention challenges the application of a precise, predefined dose and creates a major error source when normalizing organ and tissue contents to the dose loaded into the syringe, which is usually set as the applied dose. A control study was performed employing six commonly used syringe types with seven types of radiolabeled oxide and metallic nanoparticles. For this purpose the syringes were loaded with a given volume of nanoparticle suspension, the radioactivity was measured, the syringe was unloaded and the activity measurement was repeated with the empty syringe. The highest retention values were found when using TiO2 nanoparticle suspensions with Tuberkulin type syringes. In the worst case between 6.6% and 79.1% of the nanoparticles were retained in the syringe. When using the same nanoparticle suspension with an insulin-type syringe the retention was reduced to 1.4% to 20.6%. For amorphous silica nanoparticles the maximum observed retention was 8% and for Au nanoparticles it was 5.1%. Further data gathered from in vivo animal imaging studies show that nanoparticle retention in syringes also affects experiments with nanoparticles such as exosomes, polymersomes, and protein-based nanoparticles investigated for possible applications in nanomedicine. Since the retention is highly variable the effectively applied dose cannot be determined by applying a simple syringe retention factor. The present work shall alert to the problem and illustrate its possible magnitude and unpredictable variability. As mitigation strategy adequate checks with different syringe types are proposed in order to find out whether a given combination of syringe type and nanoparticle suspension is affected by nanoparticle retention and, if necessary, to select a different syringe type that minimizes retention.
AU  - Holzwarth, U.*
AU  - Cossio, U.*
AU  - Llop, J.*
AU  - Kreyling, W.G.
C1  - 57432
C2  - 47764
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Unpredictable nanoparticle retention in commonly used plastic syringes introduces dosage uncertainties that may compromise the accuracy of nanomedicine and nanotoxicology studies.
JO  - Front. Pharmacol.
VL  - 10
PB  - Frontiers Media Sa
PY  - 2019
SN  - 1663-9812
ER  - 

TY  - JOUR
AB  - Background and Purpose: Radiotherapy is an essential tool for cancer treatment. In order to spare normal tissues and to reduce the risk of normal tissue complications, particle therapy is a method of choice. Although a large part of healthy tissues can be spared due to improved depth dose characteristics, little is known about the biological and molecular mechanisms altered after particle irradiation in healthy tissues. Elucidation of these effects is also required in the context of long term space flights, as particle radiation is the main contributor to the radiation effects observed in space. Endothelial cells (EC), forming the inner layer of all vascular structures, are especially sensitive to irradiation and, if damaged, contribute to radiation-induced cardiovascular disease. Materials and Methods: Transcriptomics, proteomics and cytokine analyses were used to compare the response of ECs irradiated or not with a single 2 Gy dose of X-rays or Fe ions measured one and 7 days post-irradiation. To support the observed inflammatory effects, monocyte adhesion on ECs was also assessed. Results: Experimental data indicate time- and radiation quality-dependent changes of the EC response to irradiation. The irradiation impact was more pronounced and longer lasting for Fe ions than for X-rays. Both radiation qualities decreased the expression of genes involved in cell-cell adhesion and enhanced the expression of proteins involved in caveolar mediated endocytosis signaling. Endothelial inflammation and adhesiveness were increased with X-rays, but decreased after Fe ion exposure. Conclusions: Fe ions induce pro-atherosclerotic processes in ECs that are different in nature and kinetics than those induced by X-rays, highlighting radiation quality-dependent differences which can be linked to the induction and progression of cardiovascular diseases (CVD). Our findings give a better understanding of the underlying processes triggered by particle irradiation in ECs, a crucial aspect for the development of protective measures for cancer patients undergoing particle therapy and for astronauts in space.
AU  - Baselet, B.*
AU  - Azimzadeh, O.
AU  - Erbeldinger, N.*
AU  - Bakshi, M.V.
AU  - Dettmering, T.*
AU  - Janssen, A.*
AU  - Ktitareva, S.*
AU  - Lowe, D.J.*
AU  - Michaux, A.*
AU  - Quintens, R.*
AU  - Raj, K.*
AU  - Durante, M.J.*
AU  - Fournier, C.*
AU  - Benotmane, M.A.*
AU  - Baatout, S.*
AU  - Sonveaux, P.*
AU  - Tapio, S.
AU  - Aerts, A.L.*
C1  - 52048
C2  - 43688
TI  - Differential impact of single-dose Fe ion and X-ray irradiation on endothelial cell transcriptomic and proteomic responses.
JO  - Front. Pharmacol.
VL  - 8
IS  - SEP
PY  - 2017
SN  - 1663-9812
ER  -