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Experimental Biology and Medicine... 2024Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of rheumatoid arthritis (RA). Toll-like receptor 3 (TLR3) is...
Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of rheumatoid arthritis (RA). Toll-like receptor 3 (TLR3) is upregulated in RFLS; its activation leads to the production of interferon-β (IFN-β), a type I IFN. IFN-stimulated gene 56 (ISG56) is induced by IFN and is involved in innate immune responses; however, its role in RA remains unknown. Therefore, the purpose of this study was to investigate the role of TLR3-induced ISG56 in human RFLS. RFLS were treated with polyinosinic-polycytidylic acid (poly I:C), which served as a TLR3 ligand. ISG56, melanoma differentiation-associated gene 5 (MDA5), and C-X-C motif chemokine ligand 10 (CXCL10) expression were measured using quantitative reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Using immunohistochemistry, we found that ISG56 was expressed in synovial tissues of patients with RA and osteoarthritis. Under poly I:C treatment, ISG56 was upregulated in RFLS. In addition, we found that the type I IFN-neutralizing antibody mixture suppressed ISG56 expression. ISG56 knockdown decreased CXCL10 expression and MDA5 knockdown decreased ISG56 expression. In addition, we found that ISG56 was strongly expressed in the synovial cells of patients with RA. TLR3 signaling induced ISG56 expression in RFLS and type I IFN was involved in ISG56 expression. ISG56 was also found to be associated with CXCL10 expression, suggesting that ISG56 may be involved in TLR3/type I IFN/CXCL10 axis, and play a role in RA synovial inflammation.
Topics: Humans; Toll-Like Receptor 3; Arthritis, Rheumatoid; Poly I-C; Signal Transduction; Synoviocytes; Chemokine CXCL10; Interferon-Induced Helicase, IFIH1; Cells, Cultured; Synovial Membrane; Adaptor Proteins, Vesicular Transport; RNA-Binding Proteins; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins
PubMed: 38881847
DOI: 10.3389/ebm.2024.10122 -
Journal of Microbiology and... Jun 2024Fungi employ diverse mechanisms for iron uptake to ensure proliferation and survival in ironlimited environments. Siderophores are secondary metabolite small molecules... (Review)
Review
Fungi employ diverse mechanisms for iron uptake to ensure proliferation and survival in ironlimited environments. Siderophores are secondary metabolite small molecules with a high affinity specifically for ferric iron; these molecules play an essential role in iron acquisition in fungi and significantly influence fungal physiology and virulence. Fungal siderophores, which are primarily hydroxamate types, are synthesized via non-ribosomal peptide synthetases (NRPS) or NRPSindependent pathways. Following synthesis, siderophores are excreted, chelate iron, and are transported into the cell by specific cell membrane transporters. In several human pathogenic fungi, siderophores are pivotal for virulence, as inhibition of their synthesis or transport significantly reduces disease in murine models of infection. This review briefly highlights siderophore biosynthesis and transport mechanisms in fungal pathogens as well the model fungi and Understanding siderophore biosynthesis and transport in pathogenic fungi provides valuable insights into fungal biology and illuminates potential therapeutic targets for combating fungal infections.
PubMed: 38881181
DOI: 10.4014/jmb.2405.05020 -
Nature Communications Jun 2024Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac...
Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca release channel, the ryanodine receptor, at physiologically relevant [Ca] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators.
Topics: Ryanodine Receptor Calcium Release Channel; Calmodulin; Calcium; Myocardium; Kinetics; Animals; Muscle, Skeletal; Fluorescence Resonance Energy Transfer; Humans; Protein Conformation; Protein Binding; Sarcoplasmic Reticulum
PubMed: 38879623
DOI: 10.1038/s41467-024-48951-5 -
Journal of the American Heart... Jun 2024Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a... (Review)
Review
Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a major shift in the focus of care for people with type 2 diabetes, from control of hyperglycemia to managing cardiovascular risk. Multiple international cardiology and diabetes society guidelines and recommendations now endorse sodium-glucose cotransporter-2 inhibitors and glucagon-like protein-1 receptor agonists as first-line therapies to mitigate cardiovascular risk. The most recent publication is the 2023 European Society of Cardiology guideline on the management of cardiovascular disease in those with type 2 diabetes that, for the first time, recommends use of both classes of medications for the mitigation of cardiovascular risk for those with or at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Here, we review the evidence behind contemporary society guidelines and recommendations for the management of type 2 diabetes and cardiovascular risk.
Topics: Humans; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Hypoglycemic Agents; Heart Disease Risk Factors; Practice Guidelines as Topic; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor
PubMed: 38879449
DOI: 10.1161/JAHA.123.034053 -
JACC. Heart Failure May 2024Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused...
BACKGROUND
Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns.
OBJECTIVES
The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk).
METHODS
REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]).
RESULTS
Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily.
CONCLUSIONS
REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone; NCT04676646).
PubMed: 38878009
DOI: 10.1016/j.jchf.2024.05.003 -
Scientific Reports Jun 2024Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2... (Randomized Controlled Trial)
Randomized Controlled Trial
Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.
Topics: Male; Humans; Benzhydryl Compounds; Glucosides; Adult; Sodium-Glucose Transporter 2 Inhibitors; Double-Blind Method; Testis; Testosterone; Inhibins; Middle Aged; Sodium-Glucose Transporter 2; Androgens; Leydig Cells; Sertoli Cells
PubMed: 38877312
DOI: 10.1038/s41598-024-64684-3 -
Scientific Reports Jun 2024Apolipoprotein E (ApoE) is involved in cholesterol transport among cells and also plays an important role in amyloid formation, co-depositing with amyloid fibrils in...
Apolipoprotein E (ApoE) is involved in cholesterol transport among cells and also plays an important role in amyloid formation, co-depositing with amyloid fibrils in various types of amyloidosis. Although the in vivo amyloidogenicity of ApoE has not been previously demonstrated, this study provides evidence of ApoE amyloidogenicity in leopard geckos (Eublepharis macularius), belonging to the class Reptilia. Histologically, amyloid deposits were localized within cholesterol granulomas and exhibited positive Congo red staining, with yellow to green birefringence under polarized light. On mass spectrometry-based proteomic analysis, ApoE was detected as a dominant component of amyloid; of the full length of the 274 amino acid residues, peptides derived from Leu185-Arg230 were frequently detected with non-tryptic truncations. Immunohistochemistry with anti-leopard gecko ApoE antibody showed positive reactions of amyloid deposits. These results show that ApoE is an amyloid precursor protein within the cholesterol granulomas of leopard geckos. Although further investigations are needed, the C-terminal region of ApoE involved in amyloid formation is a lipid-binding region, and there should be a relationship between amyloidogenesis and the development of cholesterol granulomas in leopard geckos. This study provides novel insights into the pathogenesis of ApoE-related diseases.
Topics: Animals; Lizards; Cholesterol; Apolipoproteins E; Amyloid; Granuloma; Proteomics
PubMed: 38877049
DOI: 10.1038/s41598-024-64643-y -
Biomedicine & Pharmacotherapy =... Jul 2024Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but...
Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFβ. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFβ. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFβ induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Pyridones; Indoles; Adenosine Triphosphate; Receptors, Purinergic P2X7; Male; Lung; Female; Cytokines; Aged; Leukocytes, Mononuclear; Middle Aged; Transforming Growth Factor beta; Macrophages; Signal Transduction
PubMed: 38876049
DOI: 10.1016/j.biopha.2024.116896 -
Redox Biology Aug 2024The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability...
Glucose-6-phosphate dehydrogenase alleviates epileptic seizures by repressing reactive oxygen species production to promote signal transducer and activator of transcription 1-mediated N-methyl-d-aspartic acid receptors inhibition.
The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability and inhibition. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway, which is primarily involved in deoxynucleic acid synthesis and antioxidant defense mechanisms and exhibits increased expression during the chronic phase of epilepsy, predominantly colocalizing with neurons. G6PD overexpression significantly reduces the frequency and duration of spontaneous recurrent seizures. Furthermore, G6PD overexpression enhances signal transducer and activator of transcription 1 (STAT1) expression, thus influencing N-methyl-d-aspartic acid receptors expression, and subsequently affecting seizure activity. Importantly, the regulation of STAT1 by G6PD appears to be mediated primarily through reactive oxygen species signaling pathways. Collectively, our findings highlight the pivotal role of G6PD in modulating epileptogenesis, and suggest its potential as a therapeutic target for epilepsy.
Topics: Glucosephosphate Dehydrogenase; Reactive Oxygen Species; Animals; Receptors, N-Methyl-D-Aspartate; Seizures; STAT1 Transcription Factor; Epilepsy; Signal Transduction; Mice; Humans; Neurons; Male; Rats; Disease Models, Animal
PubMed: 38875958
DOI: 10.1016/j.redox.2024.103236 -
PloS One 2024The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process...
The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process in which metabolic events and ionic channel activity are finely coupled. GLUT2 and glucokinase (GK) play central roles in GSIS by regulating the rate of the glycolytic pathway. The biphasic release of insulin upon glucose stimulation characterizes mature adult beta cells. On the other hand, beta cells obtained from neonatal, suckling, and weaning rats are considered immature because they secrete low levels of insulin and do not increase insulin secretion in response to high glucose. The weaning of rats (at postnatal day 20 in laboratory conditions) involves a dietary transition from maternal milk to standard chow. It is characterized by increased basal plasma glucose levels and insulin levels, which we consider physiological insulin resistance. On the other hand, we have observed that incubating rat beta cells with NGF increases GSIS by increasing calcium currents in neonatal cells. In this work, we studied the effects of NGF on the regulation of cellular distribution and activity of GLUT2 and GK to explore its potential role in the maturation of GSIS in beta cells from P20 rats. Pancreatic islet cells from both adult and P20 rats were isolated and incubated with 5.6 mM or 15.6 mM glucose with and without NGF for 4 hours. Specific immunofluorescence assays were conducted following the incubation period to detect insulin and GLUT2. Additionally, we measured glucose uptake, glucokinase activity, and insulin secretion assays at 5.6 mM or 15.6 mM glucose concentrations. We observed an age-dependent variation in the distribution of GLUT2 in pancreatic beta cells and found that glucose plays a regulatory role in GLUT2 distribution independently of age. Moreover, NGF increases GLUT2 abundance, glucose uptake, and GSIS in P20 beta cells and GK activity in adult beta cells. Our results suggest that besides increasing calcium currents, NGF regulates metabolic components of the GSIS, thereby contributing to the maturation process of pancreatic beta cells.
Topics: Animals; Glucose Transporter Type 2; Glucokinase; Insulin-Secreting Cells; Rats; Nerve Growth Factor; Glucose; Insulin; Rats, Wistar; Male; Insulin Secretion; Cells, Cultured
PubMed: 38875221
DOI: 10.1371/journal.pone.0303934