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BMJ Paediatrics Open Jun 2024A low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more...
OBJECTIVE
A low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The present study aimed to investigate if low levels of CC16, proinflammatory cytokines and vascular endothelial growth factors (VEGF) in tracheal aspirate early after birth were associated with lung function impairment at school age.
PATIENTS AND METHODS
Participants were 20 children, born very preterm (median gestational age 25+3 weeks+days, IQR: 24+1-27+0 weeks+days), who had tracheal aspirates collected during mechanical ventilation in their first day of life. CC16, cytokines, VEGF and matrix metalloproteinase-9 were measured in the tracheal aspirate and later correlated to results from advanced lung function measurements at 12 years of age.
RESULTS
Low levels of CC16 and high levels of the proinflammatory cytokines IL-1β and TNF-α in tracheal aspirate were associated with airway obstruction at school age but not with other lung function parameters. The correlation with airway obstruction was even stronger when the ratio between the respective proinflammatory cytokine and CC16 was used. In addition, low levels of VEGF and CC16 were associated with impaired diffusion capacity of the lung.
CONCLUSIONS
An imbalance in inflammatory mediators and growth factors in the lungs at birth may have consequences for airway function and vasculature at school age in preterm born children.
Topics: Humans; Male; Trachea; Female; Infant, Newborn; Airway Obstruction; Uteroglobin; Child; Infant, Extremely Premature; Vascular Endothelial Growth Factor A; Cytokines; Matrix Metalloproteinase 9; Cohort Studies; Respiratory Function Tests
PubMed: 38862162
DOI: 10.1136/bmjpo-2024-002643 -
Redox Report : Communications in Free... Dec 2024Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We...
Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.
Topics: Animals; Emodin; Carcinoma, Hepatocellular; Rats; Thioacetamide; Liver Neoplasms; Antioxidants; ADAMTS4 Protein; Male; Protein Kinase C; Oxidative Stress; Antineoplastic Agents; Signal Transduction; Cell Proliferation
PubMed: 38861483
DOI: 10.1080/13510002.2024.2365590 -
ELife Jun 2024The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development...
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.
Topics: ADAM17 Protein; Animals; Humans; Langerhans Cells; Mice; Skin; Lupus Erythematosus, Systemic; Ultraviolet Rays; Female; Disease Models, Animal; Photosensitivity Disorders; Interferons; Mice, Inbred MRL lpr
PubMed: 38860651
DOI: 10.7554/eLife.85914 -
BMC Pregnancy and Childbirth Jun 2024Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of...
Maternal serum biomarkers of placental insufficiency at 24-28 weeks of pregnancy in relation to the risk of delivering small-for-gestational-age infant in Sylhet, Bangladesh: a prospective cohort study.
BACKGROUND
Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA.
METHODS
Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders.
RESULTS
The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025).
CONCLUSIONS
This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.
Topics: Humans; Female; Pregnancy; Infant, Small for Gestational Age; Placenta Growth Factor; Biomarkers; Prospective Studies; Adult; Vascular Endothelial Growth Factor Receptor-1; Pregnancy-Associated Plasma Protein-A; Placental Insufficiency; Infant, Newborn; Pregnancy Trimester, Second; Bangladesh; Young Adult; Gestational Age; Risk Factors
PubMed: 38858611
DOI: 10.1186/s12884-024-06588-8 -
Scientific Reports Jun 2024This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p < 0.001 and 0.026, respectively), and corneal (p < 0.001 and 0.001, respectively) and conjunctival (p = 0.017 and 0.042, respectively) staining after 4 weeks of treatment. An increase in Schirmer test scores was observed only after rebamipide treatment (p = 0.007). No significant changes were detected in tear osmolarity, MMP-9, and LLT following both treatments. The patients' preference was slightly greater for diquafosol (46.4%) than rebamipide (36.7%), presumably due to rebamipide's bitter taste. The self-efficacy of both drugs and overall satisfaction scores were comparable. These findings indicate that two mucin secretagogues showed comparable effects in ameliorating symptoms and improving signs (TBUT, corneal and conjunctival staining) in patients with DED.
Topics: Humans; Dry Eye Syndromes; Female; Male; Middle Aged; Quinolones; Prospective Studies; Mucins; Uracil Nucleotides; Alanine; Aged; Tears; Cross-Over Studies; Ophthalmic Solutions; Polyphosphates; Treatment Outcome; Adult; Matrix Metalloproteinase 9
PubMed: 38858411
DOI: 10.1038/s41598-024-63784-4 -
PLoS Neglected Tropical Diseases Jun 2024Leishmania donovani surface glycoprotein 63 (GP63) is a major virulence factor involved in parasite escape and immune evasion. In this study, we generated virus-like...
Leishmania donovani surface glycoprotein 63 (GP63) is a major virulence factor involved in parasite escape and immune evasion. In this study, we generated virus-like particles (VLPs) expressing L. donovani GP63 using the baculovirus expression system. Mice were intramuscularly immunized with GP63-VLPs and challenged with L. donovani promastigotes. GP63-VLP immunization elicited higher levels of L. donovani antigen-specific serum antibodies and enhanced splenic B cell, germinal center B cell, CD4+, and CD8+ T cell responses compared to unimmunized controls. GP63-VLPs inhibited the influx of pro-inflammatory cytokines IFN-γ and IL-6 in the livers, as well as thwarting the development of splenomegaly in immunized mice. Upon L. donovani challenge infection, a drastic reduction in splenic parasite burden was observed in VLP-immunized mice. These results indicate that GP63-VLPs immunization conferred protection against L. donovani challenge infection by inducing humoral and cellular immunity in mice.
Topics: Animals; Leishmania donovani; Mice; Vaccines, Virus-Like Particle; Mice, Inbred BALB C; Female; Leishmaniasis, Visceral; Antibodies, Protozoan; Leishmaniasis Vaccines; Vaccine Efficacy; Immunity, Cellular; Spleen; CD8-Positive T-Lymphocytes; B-Lymphocytes; Immunity, Humoral; Membrane Glycoproteins; Cytokines; Metalloendopeptidases
PubMed: 38857253
DOI: 10.1371/journal.pntd.0012229 -
JCI Insight Jun 2024In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known....
In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.
Topics: Animals; Cadherins; Sphingosine-1-Phosphate Receptors; Mice; Arthritis, Experimental; Antigens, CD; Endothelial Cells; Humans; Arthritis, Rheumatoid; ADAM10 Protein; Amyloid Precursor Protein Secretases; Signal Transduction; Mice, Knockout; Membrane Proteins; Male; Sphingosine; Lysophospholipids; Capillary Permeability; Female
PubMed: 38855867
DOI: 10.1172/jci.insight.171467 -
Theranostics 2024In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the... (Review)
Review
In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [F]DCFPyL (PYLARIFY, Lantheus Holdings), [F]rhPSMA-7.3 (POSLUMA, Blue Earth Diagnostics) and [Ga]Ga-PSMA-11 (Locametz, Novartis/ ILLUCCIX, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [Lu]Lu-PSMA-617 (Pluvicto, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.
Topics: Humans; Prostatic Neoplasms; Glutamate Carboxypeptidase II; Male; Antigens, Surface; Radiopharmaceuticals; Nuclear Medicine; Theranostic Nanomedicine; Radioisotopes; History, 21st Century; History, 20th Century
PubMed: 38855174
DOI: 10.7150/thno.92612 -
TheScientificWorldJournal 2024This paper explores the role of botulinum neurotoxin in aiding fracture recovery through temporary muscle paralysis. Specifically, it investigates the effects of...
This paper explores the role of botulinum neurotoxin in aiding fracture recovery through temporary muscle paralysis. Specifically, it investigates the effects of botulinum neurotoxin-induced paralysis of the sternocleidomastoid muscle on clavicle fractures in rats. The research aims to assess safety, effectiveness, and the impact on fracture healing. Healthy male Albino Wistar rats were divided into four groups: clavicle fracture, botulinum neurotoxin injection, both, and control. Surgeries were conducted under anaesthesia, and postoperatively, animals were monitored for 28 days. Euthanasia and radiological assessment followed, examining fracture healing and muscle changes, while tissues were histopathologically evaluated. The modified Lane-Sandhu scoring system was used for the radiographic evaluation of clavicle fractures, and the results varied from complete healing to nonunion. Histopathological examination at 28 days postfracture showed fibrous tissue, mesenchymal cells, and primary callus formation in all groups. Despite varied callus compositions, botulinum neurotoxin administration did not affect clavicle healing, as evidenced by similar scores to the control group. Several studies have explored botulinum neurotoxin applications in fracture recovery. Research suggests its potential to enhance functional recovery in certain types of fractures. Theoretical benefits include managing muscle spasticity, aiding reduction techniques, and preventing nonunion. However, botulinum neurotoxin's transient effect and nonuniversal applications should be considered. The present study found that botulinum toxin had no clear superiority in healing compared to controls, while histological evaluation showed potential adverse effects on muscle tissue. Further research is essential to understand its risk-benefit balance and long-term effects.
Topics: Animals; Botulinum Toxins, Type A; Rats; Male; Rats, Wistar; Fracture Healing; Fractures, Bone; Conservative Treatment; Clavicle; Disease Models, Animal
PubMed: 38854678
DOI: 10.1155/2024/7446251 -
Human Vaccines & Immunotherapeutics Dec 2024Among all natural and synthetic toxins, botulinum neurotoxins (BoNTs), produced by in an anaerobic environment, are the most toxic polymer proteins. Currently, the most...
Among all natural and synthetic toxins, botulinum neurotoxins (BoNTs), produced by in an anaerobic environment, are the most toxic polymer proteins. Currently, the most effective modalities for botulism prevention and treatment are vaccination and antitoxin use, respectively. However, these modalities are associated with long response time for active immunization, side effects, and donor limitations. As such, the development of more promising botulism prevention and treatment modalities is warranted. Here, we designed an mRNA encoding B9-hFc - a heavy-chain antibody fused to VHH and human Fc that can neutralize BoNT serotype B (BoNT/B) effectively - and assessed its expression in vitro and in vivo. The results confirmed that our mRNA demonstrates good expression in vitro and in vivo. Moreover, a single mRNA lipid nanoparticle injection effectively prevents BoNT/B intoxication in vivo, with effects comparable to those of protein antibodies. In conclusion, we explored and clarified whether mRNA drugs encoding neutralizing antibodies prevent BoNT/B intoxication. Our results provide an efficient strategy for further research on the prevention and treatment of intoxication by botulinum toxin.
Topics: Antibodies, Neutralizing; Animals; Botulism; Botulinum Toxins, Type A; RNA, Messenger; Mice; Humans; Female; Nanoparticles; Mice, Inbred BALB C; Antibodies, Bacterial; Vaccines, Synthetic; Liposomes
PubMed: 38853516
DOI: 10.1080/21645515.2024.2358570