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World Journal of Gastroenterology Jun 2024In this editorial we comment on the article published in a recent issue of the . Acute liver failure (ALF) is a critical condition characterized by rapid hepatocellular...
In this editorial we comment on the article published in a recent issue of the . Acute liver failure (ALF) is a critical condition characterized by rapid hepatocellular injury and organ dysfunction, and it often necessitates liver transplant to ensure patient survival. Recent research has elucidated the involvement of distinct cell death pathways, namely ferroptosis and pyroptosis, in the pathogenesis of ALF. Ferroptosis is driven by iron-dependent lipid peroxidation, whereas pyroptosis is an inflammatory form of cell death; both pathways contribute to hepatocyte death and exacerbate tissue damage. This comprehensive review explores the interplay between ferroptosis and pyroptosis in ALF, highlighting the role of key regulators such as silent information regulator sirtuin 1. Insights from clinical and preclinical studies provide valuable perspectives on the dysregulation of cell death pathways in ALF and the therapeutic potential of targeting these pathways. Collaboration across multiple disciplines is essential for translating the experimental insights into effective treatments for this life-threatening condition.
Topics: Animals; Humans; Ferroptosis; Hepatocytes; Iron; Lipid Peroxidation; Liver; Liver Failure, Acute; Liver Transplantation; Pyroptosis; Signal Transduction; Sirtuin 1
PubMed: 38946877
DOI: 10.3748/wjg.v30.i23.2931 -
Precision Clinical Medicine Jun 2024Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response...
BACKGROUND
Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism.
METHODS
MyD88 knockout (MyD88) mice and the MyD88 inhibitor (TJ-M2010-5) were used to investigate the impact of MyD88 on acute dextran sodium sulfate (DSS)-induced colitis. Disease activity index, colon length, histological score, and inflammatory cytokines were examined to evaluate the severity of colitis. RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism.
RESULTS
In an acute DSS-colitis model, the severity of colitis was not alleviated in MyD88 mice and TJ-M2010-5-treated mice, despite significantly lower levels of NF-κB activation being exhibited compared to control mice. Meanwhile, 16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal and an up-regulation of the nucleotide oligomerization domain-like receptors (NLRs) signaling pathway in colitis mice following MyD88 suppression. Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ-M2010-5 ameliorated the disease severity, which was not improved solely by MyD88 inhibition. After treatment with broad-spectrum antibiotics, downregulation of the NLR signaling pathway was observed.
CONCLUSION
Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota, leading to NLR-mediated immune activation and intestinal inflammation.
PubMed: 38946731
DOI: 10.1093/pcmedi/pbae013 -
The Medical Journal of Australia Jul 2024To assess differences between Aboriginal and Torres Strait Islander and non-Indigenous Australian children and young adults in access to and outcomes of kidney...
OBJECTIVES
To assess differences between Aboriginal and Torres Strait Islander and non-Indigenous Australian children and young adults in access to and outcomes of kidney transplantation.
STUDY DESIGN
A cohort study based on prospectively collected data; analysis of Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data.
SETTING, PARTICIPANTS
Children and young adults aged 0-24 years who commenced kidney replacement therapy in Australia during 1963-2020.
MAIN OUTCOME MEASURES
Proportions of children and young adults who received kidney transplants within five years of commencing dialysis; 5- and 10-year death-censored graft survival; and 5- and 10-year survival of children and young adults who received kidney transplants or who remained on dialysis.
RESULTS
During 1963-2020, 3736 children and young adults received kidney replacement therapy in Australia: 213 (5.8%) Aboriginal and Torres Strait Islander and 3523 (94.2%) non-Indigenous children and young adults. During follow-up (median, eight years; interquartile range [IQR], 2.6-15 years), 2762 children and young adults received kidney transplants: 93 Aboriginal and Torres Strait Islander (43.7% of those receiving kidney replacement therapy) and 2669 non-Indigenous children and young adults (75.8%). Smaller proportions of Aboriginal and Torres Strait Islander than of non-Indigenous children and young adults received transplants within five years of commencing dialysis (99, 46% v 2924, 83.0%), received living donor transplants (19, 20% v 1170, 43.9%), or underwent pre-emptive transplantation (one, 1.1% v 363, 13.6%). Five-year graft survival for Aboriginal and Torres Strait Islander recipients was similar to non-Indigenous recipients (61% v 75%; adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 0.02-2.05), but 10-year graft survival was lower (35% v 61%; aHR, 1.69; 95% CI, 1.25-2.28). Five- and 10-year survival after kidney transplantation was similar for Aboriginal and Torres Strait Islander and non-Indigenous people. Among those who remained on dialysis, 10-year survival was poorer for Aboriginal and Torres Strait Islander than non-Indigenous children and young adults (aHR, 1.50; 95% CI, 1.08-2.10).
CONCLUSIONS
Five-year graft and recipient survival were excellent for Aboriginal and Torres Strait Islander children and young adults who received kidney transplants; however, a lower proportion received transplants within five years of dialysis initiation, than non-Indigenous children and young adults. Improving transplant access within five years of dialysis commencement should be a priority.
Topics: Humans; Kidney Transplantation; Native Hawaiian or Other Pacific Islander; Australia; Adolescent; Young Adult; Child; Registries; Female; Male; Child, Preschool; Infant; Graft Survival; Health Services Accessibility; Kidney Failure, Chronic; New Zealand; Infant, Newborn; Renal Dialysis; Cohort Studies; Australian Aboriginal and Torres Strait Islander Peoples
PubMed: 38946656
DOI: 10.5694/mja2.52355 -
Clinical and Molecular Hepatology Jul 2024Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to... (Review)
Review
Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.
PubMed: 38946464
DOI: 10.3350/cmh.2024.0222 -
Medical Science Monitor : International... Jul 2024BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link...
BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link between COVID-19 and thrombosis, the specific association between COVID-19 and thrombosis in this patient population remains unexplored. MATERIAL AND METHODS We conducted a retrospective analysis utilizing data from 394 individuals who underwent kidney transplantation within the period of September 1, 2015, to April 1, 2023. To evaluate overall survival, we employed Kaplan-Meier analysis and utilized a logistic regression model for risk analysis. Furthermore, we developed a prediction model and assessed its accuracy through calibration curves. RESULTS Out of the 394 patients included in our study, a total of 51 individuals experienced thrombosis, resulting in 2 deaths. Our analysis revealed that COVID-19 infection significantly increased the risk of thrombosis (odds ratio [OR] 8.60, 95% confidence interval 3.13-24.74, P<0.01). Additionally, the use of cyclosporine was found to elevate the risk of death (OR 20.86, 95% CI 7.93-59.24, P<0.01) according to multifactorial analysis. Logistic models were employed to screen variables, and predictive models were constructed based on the presence of COVID-19 infection and the usage of cyclosporine. A nomogram was developed, demonstrating promising accuracy in estimating the risk of thrombosis during internal validation, with a corrected C-index of 0.869. CONCLUSIONS Our study suggests that both COVID-19 infection and the use of cyclosporine can serve as reliable predictors of thrombosis risk in patients undergoing renal transplantation. Furthermore, we developed a mortality risk prediction model based on COVID-19 in assessing thrombosis.
Topics: Humans; Kidney Transplantation; COVID-19; Thrombosis; Male; Female; Middle Aged; Retrospective Studies; Incidence; Adult; Prognosis; Risk Factors; Transplant Recipients; SARS-CoV-2; Logistic Models; Aged; Cyclosporine; Kaplan-Meier Estimate
PubMed: 38946121
DOI: 10.12659/MSM.944285 -
Transplantation Jul 2024Antibody-mediated rejection (AMR) is a major cause of renal allograft dysfunction and loss. Targeting B cells and/or donor-specific antibody removal using plasma...
BACKGROUND
Antibody-mediated rejection (AMR) is a major cause of renal allograft dysfunction and loss. Targeting B cells and/or donor-specific antibody removal using plasma exchange and anti-CD20 antibodies are increasingly used in clinical practice, but the efficacy remains limited. Recent studies suggest that targeting purinergic P2X7 receptor/ATP axis can have profound immune regulatory effects in transplant models, but the mechanisms involved remain incompletely defined.
METHODS
Purified B cells were isolated from the spleen of Balb/C mice and cultured with oxidized ATP at different concentrations. Proliferation and differentiation of B cells were examined. Effects of oxidized ATP were examined in a presensitized animal model where kidney allograft rejection mimics aspects of clinical AMR. Histopathology was assessed at the time of rejection or on day 5 after kidney transplantation. Infiltrating immune cells in renal allografts were detected by flow cytometry.
RESULTS
Oxidized ATP inhibited B-cell activation and proliferation in vitro, significantly attenuated histological signs of graft injury and prolonged kidney allograft survival. Mechanistically, oxidized ATP inhibited antibody secretion by activated B cells in response to lipopolysaccharide stimulation and markedly suppressed the production of donor-specific antibody in kidney allograft recipients. Oxidized ATP also reduced graft infiltration by other inflammatory cells.
CONCLUSIONS
These findings provide evidence for the involvement of the purinergic P2X7 receptor pathway in AMR and suggest that targeting this pathways may have important clinical implications.
PubMed: 38946027
DOI: 10.1097/TP.0000000000005118 -
Clinics in Liver Disease Aug 2024Portopulmonary hypertension (POPH), hepatopulmonary syndrome, and hepatic hydrothorax constitute significant complications of portal hypertension, with important... (Review)
Review
Portopulmonary hypertension (POPH), hepatopulmonary syndrome, and hepatic hydrothorax constitute significant complications of portal hypertension, with important implications for management and liver transplantation (LT) candidacy. POPH is characterized by obstruction and remodeling of the pulmonary resistance arterial bed. Hepatopulmonary syndrome is the most common pulmonary vascular disorder, characterized by intrapulmonary vascular dilatations causing impaired gas exchange. LT may improve prognosis in select patients with POPH. LT is the only effective treatment of hepatopulmonary syndrome. Hepatic hydrothorax is defined as transudative pleural fluid accumulation that is not explained by primary cardiopulmonary or pleural disease. LT is the definitive cure for hepatic hydrothorax.
Topics: Humans; Hypertension, Portal; Hepatopulmonary Syndrome; Hydrothorax; Hypertension, Pulmonary; Liver Transplantation
PubMed: 38945638
DOI: 10.1016/j.cld.2024.03.005 -
Clinics in Liver Disease Aug 2024Interventions for portal hypertension are continuously evolving and expanding beyond the realm of medical management. When complications such as varices and ascites... (Review)
Review
Interventions for portal hypertension are continuously evolving and expanding beyond the realm of medical management. When complications such as varices and ascites persist despite conservative interventions, procedures including transjugular intrahepatic portosystemic shunt creation, transvenous obliteration, portal vein recanalization, splenic artery embolization, surgical shunt creation, and devascularization are all potential interventions detailed in this article. Selection of the optimal procedure to address the underlying cause, treat symptoms, and, in some cases, bridge to liver transplantation depends on the specific etiology of portal hypertension and the patient's comorbidities.
Topics: Humans; Hypertension, Portal; Portasystemic Shunt, Transjugular Intrahepatic; Embolization, Therapeutic; Portal Vein; Esophageal and Gastric Varices; Splenic Artery; Portasystemic Shunt, Surgical; Liver Transplantation
PubMed: 38945636
DOI: 10.1016/j.cld.2024.03.003 -
Pharmacological Research Jun 2024Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has...
Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn's disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.
PubMed: 38945379
DOI: 10.1016/j.phrs.2024.107277 -
Clinica Chimica Acta; International... Jun 2024Treprostinil (Remodulin®) is a Food and Drug Administration (FDA) approved prostacyclin analog to treat pulmonary arterial hypertension. Recently, treprostinil has been...
Quantification of treprostinil concentration in rat and human using a novel validated and rapid liquid chromatography-tandem mass spectrometry method: Experimental and clinical applications in ischemia-reperfusion injury.
Treprostinil (Remodulin®) is a Food and Drug Administration (FDA) approved prostacyclin analog to treat pulmonary arterial hypertension. Recently, treprostinil has been investigated to reduce ischemia-reperfusion injury (IRI) during transplantation, which currently has no approved treatment. A validated analytical method is necessary to measure treprostinil concentrations in biological specimens. Here, a novel, sensitive, and specific method to measure treprostinil concentrations in rat serum, human serum, and human plasma has been developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Biological samples were processed by protein precipitation before chromatography and 6-keto Prostaglandin F1α-d4 was used as an internal standard. A gradient method was established with a total run time of 4 min. The assay was linear over the range of 0.25-75.0 ng/ml with accuracy (92.97-107.87 %), intra-assay precision (1.16-3.34 %), and inter-assay precision (1.11-4.58 %) in all biological matrices, which are within FDA acceptance criteria. No significant variation in treprostinil or 6-keto Prostaglandin F1α-d4 concentrations were observed under the investigated storage conditions. This novel, sensitive, and specific LC/MS-MS method is cost-effective and suitable for measuring treprostinil concentrations in animal studies and human biological samples for clinical applications.
PubMed: 38945284
DOI: 10.1016/j.cca.2024.119837