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Frontiers in Immunology 2024Chronic obstructive pulmonary disease (COPD) is currently listed as the 3 leading cause of death in the United States. Accumulating data shows the association between...
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is currently listed as the 3 leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood.
METHODS
In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics.
RESULTS
ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells.
DISCUSSION
Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung.
Topics: Animals; Ferroptosis; Pulmonary Disease, Chronic Obstructive; Mice; Nicotine; E-Cigarette Vapor; Disease Models, Animal; Cytokines; Mice, Inbred C57BL; Electronic Nicotine Delivery Systems; Male; Mice, Transgenic
PubMed: 38947318
DOI: 10.3389/fimmu.2024.1429946 -
Frontiers in Immunology 2024Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from...
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.
BACKGROUND
Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
METHODS
Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following heme treatment was also examined.
RESULTS
Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
CONCLUSIONS
Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
Topics: Humans; Heme; Burns; Male; Adult; Female; Middle Aged; Cytokines; Wounds and Injuries; Young Adult; Aged; THP-1 Cells; Leukocytes, Mononuclear; Biomarkers; Lipopolysaccharides; Heme Oxygenase-1
PubMed: 38947312
DOI: 10.3389/fimmu.2024.1416820 -
World Journal of Gastroenterology Jun 2024Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, showed a wide spectrum of intestinal and extra-intestinal manifestations, which... (Review)
Review
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, showed a wide spectrum of intestinal and extra-intestinal manifestations, which rendered the patients physically inactive and impaired their quality of life. It has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those patients. Irisin is one member of the myokines secreted by muscle contraction during exercise and could be used as an anti-inflammatory biomarker in assessing the physical activity of IBD patients. In addition, experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental colitis. Furthermore, irisin produces changes in the diversity of the microbiota. Therefore, endogenous or exogenous irisin, its anti-inflammatory effects, will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.
Topics: Humans; Fibronectins; Exercise; Biomarkers; Quality of Life; Intestinal Mucosa; Animals; Inflammatory Bowel Diseases; Crohn Disease; Gastrointestinal Microbiome; Colitis, Ulcerative; Myokines
PubMed: 38947287
DOI: 10.3748/wjg.v30.i22.2923 -
Frontiers in Medicine 2024This scoping review prepared by endocrinology and nephrology experts aimed to address the significance of finerenone, as a novel therapeutic option, in diabetic kidney... (Review)
Review
The significance of finerenone as a novel therapeutic option in diabetic kidney disease: a scoping review with emphasis on cardiorenal outcomes of the finerenone phase 3 trials.
This scoping review prepared by endocrinology and nephrology experts aimed to address the significance of finerenone, as a novel therapeutic option, in diabetic kidney disease (DKD), based on the biological prospect of cardiorenal benefit due to non-steroidal mineralocorticoid receptor antagonist (MRA) properties, and the recent evidence from the finerenone phase 3 program clinical trials. The importance of finerenone in slowing DKD progression was critically reviewed in relation to the role of MR overactivation in the pathogenesis of cardiorenal disease and unmet needs in the current practice patterns. The efficacy and safety outcomes of finerenone phase III study program including FIDELIO-DKD, FIGARO-DKD and FIDELITY were presented. Specifically, perspectives on inclusion of patients with preserved estimated glomerular filtration rate (eGFR) or high albuminuria, concomitant use of sodium-glucose co-transporter-2 inhibitor (SGLT2i) or glucagon-like peptide 1 receptor agonist (GLP-1 RA), baseline glycated hemoglobin (HbA1c) level and insulin treatment, clinically meaningful heart failure outcomes and treatment-induced hyperkalemia were addressed. Finerenone has emerged as a new therapeutic agent that slows DKD progression, reduces albuminuria and risk of cardiovascular complications, regardless of the baseline HbA1c levels and concomitant treatments (SGLT2i, GLP-1 RA, or insulin) and with a favorable benefit-risk profile. The evolving data on the benefit of SGLT2is and non-steroidal MRAs in slowing or reducing cardiorenal risk seem to provide the opportunity to use these pillars of therapy in the management of DKD, after a long-period of treatment scarcity in this field. Along with recognition of the albuminuria as a powerful marker to detect those patients at high risk of cardiorenal disease, these important developments would likely to impact standard-of-care options in the setting of DKD.
PubMed: 38947237
DOI: 10.3389/fmed.2024.1384454 -
The Yale Journal of Biology and Medicine Jun 2024: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal...
: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. : In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4 T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. : The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups ( <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP ( <0.05) and control ( <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control ( <0.001) and CRSwNP ( <0.05) groups. : Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
Topics: Humans; Sinusitis; Suppressor of Cytokine Signaling Proteins; Chronic Disease; Male; Suppressor of Cytokine Signaling 3 Protein; Rhinitis; Female; Adult; Middle Aged; T-Lymphocytes, Helper-Inducer; Cross-Sectional Studies; Nasal Polyps; Cytokines; Suppressor of Cytokine Signaling 1 Protein; Signal Transduction; Rhinosinusitis
PubMed: 38947108
DOI: 10.59249/HZFN2950 -
Research Square Jun 2024Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various...
Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various obesity-related morbidities. Among different metabolic regulatory signals, cytosolic Ca plays pivotal roles in metabolic regulation, including glycolysis, gluconeogenesis, and lipolysis. Recently, intercellular calcium waves (ICWs), the propagation of Ca signaling through tissues, have been found in different systems to coordinate multicellular responses. Nevertheless, our understanding of how ICWs are modulated and operate within living organisms remains limited. In this study, we explore the real-time dynamics, both in organ culture and free-behaving animals, of ICWs in larval and adult adipose tissues. We identified Adipokinetic hormone (AKH), the fly functional homolog of mammalian glucagon, as the key factor driving Ca activities in adipose tissue. Interestingly, we found that AKH, which is released in a pulsatile manner into the circulating hemolymph from the AKH-producing neurosecretory cells (APCs) in the brain, stimulates ICWs in the larval fat by a previously unrecognized gap-junction-independent mechanism to promote lipolysis. In the adult fat body, however, gap-junction-dependent random ICWs are triggered by a presumably uniformly diffused AKH. This highlights the stage-specific interplay of hormone secretion, extracellular diffusion, and intercellular communication in the regulation of Ca dynamics. Additionally, we discovered that specific dietary amino acids activate the APCs, leading to increased intracellular Ca and subsequent AKH secretion. Altogether, our findings identify that dietary amino acids regulate the release of AKH peptides from the APCs, which subsequently stimulates novel gap-junction-independent ICWs in adipose tissues, thereby enhancing lipid metabolism.
PubMed: 38947048
DOI: 10.21203/rs.3.rs-4493132/v1 -
Molecular Therapy. Methods & Clinical... Jun 2024Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the...
Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the introduction of a missing gene into patients' own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.
PubMed: 38946936
DOI: 10.1016/j.omtm.2024.101271 -
International Journal of Nanomedicine 2024Angiogenesis is a physiological process of forming new blood vessels that has pathological importance in seemingly unrelated illnesses like cancer, diabetes, and various... (Review)
Review
Angiogenesis is a physiological process of forming new blood vessels that has pathological importance in seemingly unrelated illnesses like cancer, diabetes, and various inflammatory diseases. Treatment targeting angiogenesis has shown promise for these types of diseases, but current anti-angiogenic agents have critical limitations in delivery and side-effects. This necessitates exploration of alternative approaches like biomolecule-based drugs. Proteins, lipids, and oligonucleotides have recently become popular in biomedicine, specifically as biocompatible components of therapeutic drugs. Their excellent bioavailability and potential bioactive and immunogenic properties make them prime candidates for drug discovery or drug delivery systems. Lipid-based liposomes have become standard vehicles for targeted nanoparticle (NP) delivery, while protein and nucleotide NPs show promise for environment-sensitive delivery as smart NPs. Their therapeutic applications have initially been hampered by short circulation times and difficulty of fabrication but recent developments in nanofabrication and NP engineering have found ways to circumvent these disadvantages, vastly improving the practicality of biomolecular NPs. In this review, we are going to briefly discuss how biomolecule-based NPs have improved anti-angiogenesis-based therapy.
Topics: Humans; Angiogenesis Inhibitors; Theranostic Nanomedicine; Neovascularization, Pathologic; Animals; Liposomes; Nanostructures; Neoplasms; Drug Delivery Systems; Oligonucleotides; Proteins; Lipids; Nanoparticles
PubMed: 38946886
DOI: 10.2147/IJN.S459928 -
World Journal of Gastroenterology Jun 2024Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Animals; Metabolic Syndrome; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Incretins; Intestinal Mucosa; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38946874
DOI: 10.3748/wjg.v30.i23.2964 -
Analytical Cellular Pathology... 2024Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays...
BACKGROUND
Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays a central role in the pathogenesis of hepatic fibrosis. Our study aimed to investigate the pharmacological effect and potential mechanism of pirfenidone (PFD) and andrographolide (AGP) separately and together on liver fibrosis of BA.
MATERIALS AND METHODS
The bile ducts of male C57BL/6J mice were ligated or had the sham operation. The effects of PFD and/or AGP on liver fibrosis of BA were evaluated. Human hepatic stellate cells (LX-2) were also treated with PFD and/or AGP .
RESULTS
PFD and/or AGP ameliorates liver fibrosis and inflammation in the mice model of BA, as evidenced by significant downregulated in the accumulation of collagen fibers, hepatic fibrosis markers (-SMA, collagen I, and collagen IV), and inflammatory markers (IL-1, IL-6, and TNF-). Moreover, compared with monotherapy, these changes are more obvious in the combined treatment of PFD and AGP. Consistent with animal experiments, hepatic fibrosis markers (-SMA, collagen I, and CTGF) and inflammatory markers (IL-1, IL-6, and TNF-) were significantly decreased in activated LX-2 cells after PFD and/or AGP treatment. In addition, PFD and/or AGP inhibited the activation of HSCs by blocking the TGF-/Smad signaling pathway, and the combined treatment of PFD and AGP synergistically inhibited the phosphorylation of Smad2 and Smad3.
CONCLUSION
The combined application of PFD and AGP exerted superior inhibitive effects on HSC activation and liver fibrosis by mediating the TGF-/Smad signaling pathway as compared to monotherapy. Therefore, the combination of PFD and AGP may be a promising treatment strategy for liver fibrosis in BA.
Topics: Hepatic Stellate Cells; Animals; Liver Cirrhosis; Signal Transduction; Diterpenes; Male; Transforming Growth Factor beta; Mice, Inbred C57BL; Smad Proteins; Humans; Pyridones; Cell Line; Mice; Biliary Atresia; Disease Models, Animal; Drug Therapy, Combination
PubMed: 38946862
DOI: 10.1155/2024/2751280