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Frontiers in Cardiovascular Medicine 2023Cardiac repair after myocardial infarction (MI) is orchestrated by multiple intrinsic mechanisms in the heart. Identifying cardiac cell heterogeneity and its effect on... (Review)
Review
Cardiac repair after myocardial infarction (MI) is orchestrated by multiple intrinsic mechanisms in the heart. Identifying cardiac cell heterogeneity and its effect on processes that mediate the ischemic myocardium repair may be key to developing novel therapeutics for preventing heart failure. With the rapid advancement of single-cell transcriptomics, recent studies have uncovered novel cardiac cell populations, dynamics of cell type composition, and molecular signatures of MI-associated cells at the single-cell level. In this review, we summarized the main findings during cardiac repair by applying single-cell transcriptomics, including endogenous myocardial regeneration, myocardial fibrosis, angiogenesis, and the immune microenvironment. Finally, we also discussed the integrative analysis of spatial multi-omics transcriptomics and single-cell transcriptomics. This review provided a basis for future studies to further advance the mechanism and development of therapeutic approaches for cardiac repair.
PubMed: 37920179
DOI: 10.3389/fcvm.2023.1237208 -
World Journal of Clinical Pediatrics Sep 2023Neuromuscular diseases (NMDs) affect the development and growth of the neuromuscular system in children. The pathology can occur anywhere along the neuromuscular... (Review)
Review
Neuromuscular diseases (NMDs) affect the development and growth of the neuromuscular system in children. The pathology can occur anywhere along the neuromuscular pathway, from the brain to the nerves to the muscle fibers. These diseases have a profound impact on the quality of life not only of children but also of their families. The predominant manifestation in NMDs is hypotonia, which leads to muscle weakness and fatigue, reduced mobility, and decreased physical performance. However, multiple organ systems can be affected, with resulting orthopedic, cardiac, infectious, respiratory, and nutritional problems. Children with NMD present an increased risk for several dietary and feeding difficulties because of their neuromuscular diagnosis, presentation, and severity. These problems include chronic gastrointestinal issues (constipation, dysphagia, gastroesophageal reflux, and diarrhea), dysphagia, malnutrition, and body composition alterations. As a result, compared to the overall pediatric population, infants and children with NMD are more likely to be malnourished, ranging from failure to thrive to overweight or obesity. Disease-specific guidelines vary in level of detail and recommendations for dietary management. Overall, nutritional data available are sparse, with the exception of Duchenne muscular dystrophy, spinal muscular atrophy, and congenital muscular dystrophy. The purpose of this review is to describe the spectrum of nutritional challenges in children with NMD and to summarize the main dietary and gastrointestinal recommendations for each neuromuscular disorder to provide guidance for daily clinical practice.
PubMed: 37753494
DOI: 10.5409/wjcp.v12.i4.197 -
Cell Death & Disease Jul 2023Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of...
Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of vascular dysfunction is of the essence. ATP-citrate lyase (ACLY) directs glucose metabolic fluxes to de novo lipogenesis by generating acetyl-Co-enzyme A (acetyl-CoA), which facilitates transcriptional priming via protein acetylation. It is well illustrated that ACLY participates in promoting cancer metastasis and fatty liver diseases. Its biological functions in ECs during sepsis remain unclear. We found that plasma levels of ACLY were increased in septic patients and were positively correlated with interleukin (IL)-6, soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), and lactate levels. ACLY inhibition significantly ameliorated lipopolysaccharide challenge-induced EC proinflammatory response in vitro and organ injury in vivo. The metabolomic analysis revealed that ACLY blockade fostered ECs a quiescent status by reducing the levels of glycolytic and lipogenic metabolites. Mechanistically, ACLY promoted forkhead box O1 (FoxO1) and histone H3 acetylation, thereby increasing the transcription of c-Myc (MYC) to facilitate the expression of proinflammatory and gluco-lipogenic genes. Our findings revealed that ACLY promoted EC gluco-lipogenic metabolism and proinflammatory response through acetylation-mediated MYC transcription, suggesting ACLY as the potential therapeutic target for treating sepsis-associated EC dysfunction and organ injury.
Topics: Humans; Lipogenesis; ATP Citrate (pro-S)-Lyase; Inflammation; Adenosine Triphosphate
PubMed: 37414769
DOI: 10.1038/s41419-023-05932-8 -
Nature Communications Dec 2023Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone... (Randomized Controlled Trial)
Randomized Controlled Trial
Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071.
Topics: Adult; Humans; Critical Illness; Pilot Projects; Intensive Care Units; Ketone Bodies; Ketosis
PubMed: 38102152
DOI: 10.1038/s41467-023-42659-8 -
Seminars in Liver Disease Nov 2023Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute... (Review)
Review
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
Topics: Humans; Acute-On-Chronic Liver Failure; Liver Cirrhosis; Liver Transplantation; Multiple Organ Failure; Syndrome; Prognosis
PubMed: 38101419
DOI: 10.1055/s-0043-1776773 -
Endocrinology, Diabetes & Metabolism... Jan 2024Myxoedema coma is a severe form of hypothyroidism with multiple organ dysfunction, characterised by an altered state of consciousness and hypothermia. Intravenous...
SUMMARY
Myxoedema coma is a severe form of hypothyroidism with multiple organ dysfunction, characterised by an altered state of consciousness and hypothermia. Intravenous thyroid hormone replacement therapy is the preferred treatment for myxoedema. The mortality rate associated with this disease is high, and early detection and intervention are essential. Supraglottal myxoedema is a rare form of periglottic oedema and can be fatal. A previously healthy 66-year-old man presented with impaired consciousness, hypothermia, and nonpitting oedema. Blood tests revealed the presence of hypothyroidism and respiratory acidosis. He was intubated for type 2 respiratory failure; however, severe laryngeal oedema made the procedure difficult to perform. Oral thyroid hormone therapy was initiated under the diagnosis of myxoedema coma. Tracheostomy was performed because of prolonged type 2 respiratory failure and laryngeal oedema. Three weeks after admission, the patient was weaned off the ventilator. Approximately a week later, laryngeal oedema improved, and the tracheostomy tube was removed. The patient was discharged and remained stable for 3 months. This case report describes a patient with comatose myxoedema and supraglottic oedema who was successfully treated with oral medication alone. This case shows that supraglottic oedema should be considered even in the absence of wheezing or other signs of upper airway obstruction.
LEARNING POINTS
Myxoedema coma is a differential diagnosis of respiratory acidosis. In myxoedematous coma, the possibility of difficult intubation due to supraglottic oedema should be considered. Tracheostomy should be considered for supraglottic myxoedema, which often results in prolonged ventilator use. Supraglottic myxoedema can be treated with oral medications.
PubMed: 38377682
DOI: 10.1530/EDM-23-0078 -
International Journal of Molecular... Dec 2023Sepsis‑induced cardiomyopathy (SIC) is a manifestation of multiple organ failure as a result of sepsis and is a serious threat to life. Here, the effect and mechanisms...
Sepsis‑induced cardiomyopathy (SIC) is a manifestation of multiple organ failure as a result of sepsis and is a serious threat to life. Here, the effect and mechanisms of quercetin (QUE) in SIC were assessed. It was found that patients with SIC expressed lower serum levels of glutathione peroxidase 4 (GPX4) and SIRT1 but higher levels of CK‑MB, cTnI, TNF‑α, and IL‑6 compared with healthy individuals. A dose of 80 µM QUE increased the viability and reduced the ferroptosis of H9C2 cells treated with 1.0 µg/ml LPS . The administration of QUE decreased the levels of MDA, NADPH, lipid peroxidation and cytoplasmic cytochrome C and upregulated the levels of GSH and TOM 20, thus exerting an anti‑oxidative effect via mediating SIRT1 expression. It also activated the SIRT1/p53/SLC7A11 signaling pathway to reduce cellular Fe and PTGS2 levels, decreased cell apoptosis rate, and upregulated the levels of GPX4 and ferritin to inhibit ferroptosis of H9C2 cells . Injection of QUE into rats activated the SIRT1/p53/SLC7A11 signaling pathway, reduced the levels of CK‑MB, cTnI, inflammatory cell infiltration, MDA, NADPH, cytoplasmic cytochrome C, cellular Fe, and PTGS2 but upregulated the levels of GSH, TOM 20, GPX4, and ferritin to alleviate SIC in a dose‑dependent manner . To conclude, QUE exerted an anti‑ferroptotic effect via activation of the SIRT1/p53/SLC7A11 signaling pathway to dampen SIC both and . These findings highlighted a potential therapeutic strategy for the management of SIC.
Topics: Humans; Animals; Rats; Myocytes, Cardiac; Ferroptosis; Sirtuin 1; Quercetin; Tumor Suppressor Protein p53; Cyclooxygenase 2; Cytochromes c; NADP; Sepsis; Cardiomyopathies; Ferritins; Membrane Transport Proteins; Signal Transduction
PubMed: 37859612
DOI: 10.3892/ijmm.2023.5319 -
Respiratory Research Jul 2023Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a...
BACKGROUND
Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the AR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to ARs in regulating the host's response to T/HS.
METHODS
T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, AR) and conditional knockout (intestinal epithelial cell-specific deficient Villin-AR) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury.
RESULTS
T/HS upregulated the expression of CD39, CD73, and the AR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and AR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and AR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and AR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient Villin-AR mice showed increased intestinal injury compared to their wild-type Villin controls.
CONCLUSION
In conclusion, the CD39-CD73-AR axis protects against T/HS-induced multiple organ failure.
Topics: Animals; Mice; Adenosine; Multiple Organ Failure; Adenosine Triphosphate; Signal Transduction; Bronchoalveolar Lavage Fluid
PubMed: 37438813
DOI: 10.1186/s12931-023-02486-3 -
Frontiers in Immunology 2023Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated... (Review)
Review
Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated with elevated mortality rates and a poorer prognosis. The development of sepsis involves hyperactive inflammation, immune disorder, and disrupted microcirculation. It is crucial to identify targets within these processes to develop therapeutic interventions. One such potential target is Panx1 (pannexin-1), a widely expressed transmembrane protein that facilitates the passage of molecules smaller than 1 KDa, such as ATP. Accumulating evidence has implicated the involvement of Panx1 in sepsis-associated MODS. It attracts immune cells via the purinergic signaling pathway, mediates immune responses via the Panx1-IL-33 axis, promotes immune cell apoptosis, regulates blood flow by modulating VSMCs' and vascular endothelial cells' tension, and disrupts microcirculation by elevating endothelial permeability and promoting microthrombosis. At the level of organs, Panx1 contributes to inflammatory injury in multiple organs. Panx1 primarily exacerbates injury and hinders recovery, making it a potential target for sepsis-induced MODS. While no drugs have been developed explicitly against Panx1, some compounds that inhibit Panx1 hemichannels have been used extensively in experiments. However, given that Panx1's role may vary during different phases of sepsis, more investigations are required before interventions against Panx1 can be applied in clinical. Overall, Panx1 may be a promising target for sepsis-induced MODS. Nevertheless, further research is needed to understand its complex role in different stages of sepsis fully and to develop suitable pharmaceutical interventions for clinical use.
Topics: Humans; Endothelial Cells; Multiple Organ Failure; Apoptosis; Inflammation; Membrane Proteins
PubMed: 37711629
DOI: 10.3389/fimmu.2023.1217366