Pathogenesis Of Failure Research Articles

Screening of Herbs with Potential Modulation of NLRP3 Inflammasomes for Acute Liver Failure: A Study Based on the Herb-Compound-Target Network and the ssGSEA Algorithm.

NLRP3 inflammasomes are considered to be key factors in the pathogenesis of Acute Liver Failure (ALF). Some Traditional Chinese Medicines (TCMs) have shown protective and therapeutic effects against ALF by inhibiting NLRP3 inflammasomes. However, the inhibitory effects of most TCMs on ALF remain to be further elucidated. This study aimed to screen potential herbs that can treat ALF based on the inhibition of NLRP3 inflammasomes. Initially, we constructed the target set for 502 herbs. Subsequently, based on the target set and the gene set related to the NLRP3 inflammasome, using the ssGSEA algorithm, we evaluated herb scores and NLRP3 scores in the ALF expression matrix and performed a preliminary herb screening based on score correlations. Through bioinformatics approaches, we identified the key targets for candidate herbs and determined core herbs based on the herb-compound-target network. Furthermore, molecular docking and molecular biology methods validated the screening results of the herbs. A total of 18 crucial targets associated with the inhibition of the NLRP3 inflammasome were identified, which included ALDH2, HMOX1, and VEGFA. Subsequently, based on these key targets, a set of 10 primary herbs was chosen, notably Qinghao, Duzhong, and Gouteng. Moreover, the results were verified through molecular docking and molecular dynamic simulation. Ten key herbs have been identified as potential inhibitors of the NLRP3 inflammasome, offering insights into ALF therapy for drug development.

The STRIPAK associated kinase MST4 is a novel mediator in heart failure pathogenesis

Abstract Heart failure still poses substantial challenges in understanding its underlying molecular pathways. We recently found the mammalian STE20-like kinase 4 (MST4) significantly upregulated in human failing hearts (5.7-fold in DCM and 3.8-fold ICM) as well as in heart failure animal models (i.e. 2.5-fold in Calsarcin-1-KO, 2.5-fold in MLP-KO). MST4 is a member of striatin interacting phosphatases and kinases complexes (STRIPAK), an emerging group of multiprotein complexes responsible for integrating cellular signalling pathways. We provide the first evidence of functional STRIPAK complexes containing MST4 by co-immunoprecipitation and interactomics experiments in cardiomyocytes. Moreover, we found MST4 to interact with several intercalated disc proteins like beta-Catenin or Desmin. Adenoviral overexpression of MST4 in neonatal rat ventricular cardiomyocytes (NRVCM) results in a significant increase in cell size (+13%). This was not accompanied by the activation of fetal genes such as NPPA, NPPB or RCAN1.4, but rather by an increase in phosphorylation of Protein kinase B (PKB/Akt, 3.3-fold). Akt is usually associated with physiological hypertrophy, indicating that MST4 may be involved in protective pathways in cardiomyocytes. In support of this notion, MST4 overexpression reduced apoptotic activity (cleavage of Caspase 3 -69%, Caspase 7 -80%, Parp1 -27%) and improved both contractility (fractional shortening cell +23%, fractional shortening sarcomere +30%, time to max. contraction cell -10%, time to max. contraction sarcomere -12%) and relaxation parameters (time to max. relaxation velocity cell -12%) in isolated adult rat ventricular cardiomyocytes. In order to identify cardiac targets of MST4, we performed a comprehensive analysis of the phosphoproteome of NRVCM overexpressing MST4 compared with control-virus +/- pharmacological inhibitor at two time points. We identified more than 70,000 peptides including more than 20,000 phosphopeptides in more than 4,000 protein groups. Using linear modelling with a reduced data set containing regulated features selected by thresholds for p-value and fold change, we observed a consistent MST4 effect and a number of enriched gene ontology terms. Here, we found several potential MST4 targets and effects on protein expression levels associated with intercalated disc proteins. In human heart samples, MST4 was also localized to the intercalated disc region by immunostaining. Interesting proteins in that context that might help explain some of the observed cardioprotective MST4 effects are Connexin 43, Desmin, Ryanodine receptor, Phospholemman, Junctophilin2, Myozap or Frizzled 1. Taken together, our data imply that MST4 upregulation in human heart failure serves an adaptive role which may offer translational opportunities.Graphical Abstract

Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.

Loss of NAT10 Reduces the Translation of Kmt5a mRNA Through ac4C Modification in Cardiomyocytes and Induces Heart Failure.

In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4-acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N-acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology. Cardiac-specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by invitro data. Activation of the p53 signaling pathway was closely associated with enhanced apoptosis in NAT10-deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome-wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of Kmt5a was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that Kmt5a protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of Kmt5a in cardiomyocytes recapitulated the phenotype of NAT10 deficiency, including increased cardiomyocyte apoptosis and activated p53 signaling. Finally, overexpression of Kmt5a rescued cardiomyocyte apoptosis and p53 activation induced by NAT10 inhibition. Our study highlights the significance of NAT10 in cardiomyocyte physiology, demonstrating that NAT10 loss is sufficient to induce cardiomyocyte apoptosis and heart failure. NAT10 regulates the translational efficiency of Kmt5a, a key mediator, through mRNA ac4C modification during heart failure.

Modulation of Inflammation in Heart Failure: The Role of Ziltivekimab and Canakinumab

This article examines the role of inflammation in heart failure pathogenesis and explores novel therapeutic strategies targeting inflammatory pathways. The increasing prevalence of heart failure, particularly those with preserved ejection fraction (HFpEF), highlights the urgent demand for effective treatments. Canakinumab, a monoclonal antibody targeting interleukin-1β, has shown promise in reducing cardiovascular events by modulating inflammation, while Ziltivekimab, a newer monoclonal antibody targeting interleukin-6, demonstrates potential in heart failure patients with elevated inflammatory markers. The article reviews clinical trials, including CANTOS and RESCUE, providing evidence of the efficacy of patient outcomes. The findings underscore the importance of personalized treatment strategies on heart failure, with a focus on inflammation-driven pathways, positioning anti-inflammatory therapies as a significant advancement in cardiovascular disease management. Future research will determine the broader clinical applicability of these therapies in managing heart failure, its complications, and fostering more favorable outcomes.

6524 Sex-Specific Single Cell Genetic Architecture Of Human Islets With And Without Type 2 Diabetes

Abstract Disclosure: M. Qadir: None. R.M. Elgamal: None. P. Kudtarkar: None. K.J. Gaulton: None. F. Mauvais-Jarvis: None. Type 2 diabetes (T2D) is a heterogeneous disease and biological sex affects its pathogenesis including the development of adiposity, insulin resistance, and β cell failure. For example, ketosis-prone diabetes is a phenotypically-defined form of T2D with acute β cell failure and severe insulin deficiency, predominantly observed in men. However, what mechanisms drive male predominance in β cell failure is unknown. To fully understand the sex-based pathogenesis of islet failure in diabetes, the study of sex differences in human islet biology and dysfunction is essential. To decipher sex differences in human islets genetic architecture and function, we performed an orthogonal series of experiments from 15 islets of non-diabetic (ND) donors, using single cell RNAseq (scRNAseq) and single nucleus assay for transposase-accessible chromatin sequencing (snATACseq). We also leveraged 37 ND and T2D donors for scRNAseq data from the human pancreas analysis program (HPAP) dataset. We studied over 200,000 single cells spanning the accessible genome and transcriptome. It is the largest study of sex-based single-cell genomics and transcriptomics of human islets to date. We observe that in cultured human ND islets, in the absence of the in vivo hormonal environment, islet cell transcriptome, and genome accessibility across coding regions are predominantly limited to sex chromosome genes. Of particular interest are sex differences in gene accessibility and expression of the X-linked KDM6A and Y-linked KDM5D demethylase genes in female (F) and male (M) islet cells respectively. Furthermore, analysis of T2D islets revealed a greater number of autosomal differentially expressed genes (DEGs) in F (721 upregulated and 1164 downregulated, FDR < 0.01) compared to M β cells (111 upregulated and 99 downregulated, FDR < 0.01). M β cell DEGs over-representation analysis revealed suppressed insulin secretion and processing pathways, while F β cell DEGs exhibited suppression of oxidative phosphorylation and electron transport chain pathways. Thus, although, sex differences in gene expression and accessibility of cultured ND human islets are restricted to sex chromosome genes, during the transition from ND to T2D, major sex differences in autosomal DEGs appear, with a greater number of autosomal DEGs in F compared to M T2D islets. Presentation: 6/3/2024

Potential role of peripheral blood mononuclear cell ' s mitochondrial respiratory dysfunction in heart failure severity prediction in patients with cardioverter-defibrillator implantation indications.

It has been reported that the mitochondrial respiratory dysfunction (MRD) is important mechanisms affecting the heart failure (HF) pathogenesis. We sought to evaluate the potential role of MRD of peripheral blood mononuclear cells (PBMC) in HF severity prediction in patients with cardioverter-defibrillator implantation indications. In this single-center study patients with HF of New York Heart Association (NYHA) I-III functional class (FC) and cardioverter-defibrillator implantation indications underwent transthoracic echocardiography (TTE) and MRD assessment using PBMC. Mitochondrial respiration rate (MRR) indicators (pyruvate + malate + adenosine diphosphate; succinate + adenosine diphosphate; pyruvate + malate - adenosine diphosphate [V4.1]; succinate - adenosine diphosphate) were calculated. Correlations between HF NYHA FC, TTE and MRR indicators were evaluated. Based on our data, we developed a risk model regarding HF severity. Of 53 (100.0%) HF patients, 33 (62.3%) had mild exercise intolerance (1st group) and 20 (37.7%) had moderate-to-severe exercise intolerance (2nd group). Patients with mild exercise intolerance were likely to have a higher V4.1 (P < 0.001) values. V4.1 was independently associated with moderate-to-severe exercise intolerance in univariate and multivariate logistic regression (OR = 0.932, 95% CI: 0.891-0.975, P < 0.001). The severity of HF is associated with PBMC mitochondrial respiratory dysfunction in patients with cardioverter-defibrillator implantation indications. Our HF severity risk model including V4.1 parameters is able to distinguish patients with mild and moderate-to-severe exercise intolerance. Further investigations of their predictive significance are warranted.

IDH1/MDH1 deacetylation promotes NETosis by regulating OPA1 and autophagy

BackgroundAs a heterogeneous and life-threatening disease, the pathogenesis of acute liver failure (ALF) is complex. Our previous study has shown that IDH1/MDH1 deacetylation promotes ALF by regulating NETosis (a novel mode of cell death). In this article, we explore the manners of IDH1/MDH1 deacetylation regulates NETosis. MethodsIn vitro experiments, the formation of NETs was detected by immunofluorescence staining and Western blotting. LC3 fluorescence staining was used to detect autophagosome formation. To observe mitochondrial morphology, cells were stained by Mito-Tracker Red. Western blotting was used to detect the levels of autophagy protein and mitochondrial dynamin. In vivo experiments, the ALF model in mouse was established with LPS/D-gal, and the formation of NETs was detected by immunofluorescence staining and Western blotting. The autophagy levels were detected by Western blotting in liver samples. ResultsIn dHL-60 cells, Western blotting results showed that the expression of OPA1 was higher in the IDH1/MDH1 deacetylated group compared with the IDH1/MDH1 WT group. And histone deacetylase inhibitor 6 (HDAC6i, ACY1215) decreased the expression level of OPA1 in IDH1/MDH1 deacetylated group. IDH1/MDH1 deacetylation increased the expression levels of both LC3B-II and Beclin 1, while decreasing the expression level of P62. It was reversed by ACY1215. Combined with our previous experiments, IDH1/MDH1 deacetylation upregulated autophagy concomitant with the increased expression of the markers of NETs formation. In a mouse model of ALF, ACY1215 further decreased the expression levels of LC3B-II and Beclin 1, while increasing the expression level of P62 in IDH1/MDH1 deacetylated mice. ConclusionsIDH1/MDH1 deacetylation promoted NETosis by regulating autophagy and OPA1 in vitro. The regulation of neutrophil autophagy on NETosis during IDH1/MDH1 deacetylation might be masked in mice. ACY1215 might attenuate NETosis by regulating neutrophil autophagy, which alleviated ALF aggravated by IDH1/MDH1 deacetylation.

Pathogenesis of respiratory failure in COVID-19 due to coagulopathy and endothelial dysfunction

Respiratory failure is known to be the main clinical manifestation of COVID-19. However, the mechanism of its development has not been sufficiently studied. The originality of the study is that for the first time, coagulation, fibrinolysis and endothelial dysfunction indicators were studied depending on the SpO2/FiO2 index in patients with COVID-19.The aim of the work. To assess the role of impaired activity of the blood coagulation system and the development of endothelial dysfunction in patients with COVID-19 in the pathogenesis of respiratory failure.Methods. The study included 134 patients infected with SARS-CoV-2 virus having varying severity of the clinical picture. They were divided into three groups according to the SpO2/FiO2 index. We determined the number of venous blood cells and studied the level of transferrin (TF), D-dimer, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the blood serum.Results. The study revealed that the tissue factor content increased by 24 % in patients of the third group compared to the first. The PAI-1 level was high in the second group and significantly decreased in the third (p &lt; 0.001). An increase in the D-dimer level was recorded in the second and third groups. The levels of ICAM-1 and VCAM-1 molecules increased significantly in the third group of patients (p = 0.021 and p = 0.028, respectively). A moderate positive correlation was found between the SpO2/FiO2 index and the VCAM-1 level (p &lt; 0.001), a weak positive correlation with PAI-1 (p = 0.012), and a weak negative correlation with TF (p = 0.027).Conclusion. Respiratory failure in patients with COVID-19 is caused by disorders in the hemostasis and fibrinolysis systems, as evidenced by an increase in the level of tissue factor and D-dimer, “consumption” of tissue activator and plasminogen activator inhibitor. Developing endothelial dysfunction, accompanied by increased secretion of adhesion molecules, aggravates the pathogenesis of respiratory failure.

Desensitization Strategies for Donor-Specific Antibodies in HLA-Mismatched Stem Cell Transplantation Recipients: What We Know and What We Do Not Know.

In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application.

Decoding the pathogenesis of spermatogenic failure in cryptorchidism through single-cell transcriptomic profiling

Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor β1 (TGF-β1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.

Vaginal and endometrial microbiome dysbiosis associated with adverse embryo transfer outcomes

BackgroundAssisted reproductive technology (ART) is the most effective method to treat infertility and the pathogenesis of implantation failure after in vitro fertilization-embryo transfer (IVF-ET) is a challenging filed in infertility. Microbes in the female reproductive tract are considered to be associated with gynecological and obstetric diseases. However, its effects on embryo implantation failure are unsured.PurposeThis study aimed to investigate reproductive tract dysbiosis, identify different bacteria in reproductive tract as potential biomarkers of embryo implantation failure and demonstrate the pathogenesis through metabolites analysis.MethodsWe compared the data from 16S rRNA gene and metagenome in reproductive tracts through QIIME2 and HUMAnN2 by the times of embryo implantation failure on 239 infertile patients and 17 healthy women.ResultsOur study revealed a strong positive correlation between Lactobacillus abundance and embryo implantation success (IS) after IVF-ET. The microbial community composition and structure in reproductive tract showed substantially difference between the embryo implantation failure (IF) and healthy control. Moreover, we established a diagnostic model through receiver operating characteristic (ROC) with 0.913 area under curve (AUC) in IS and multiple implantation failures (MIF), verified its effectiveness with an AUC = 0.784 demonstrating microbial community alterations could efficiently discriminate MIF patients. Metagenome functional analyses of vaginal samples from another independent infertile patients after IVF-ET revealed the L-lysine synthesis pathway enriched in IF patients, along with ascended vaginal pH and decreased Lactobacillus abundance.ConclusionsThis study clarifies several independent relationships of bacteria in vagina and endometrial fluid on embryo implantation failure and undoubtedly broadens the understanding about female reproductive health.

Abstract Or120: CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2 + macrophages and CD8 T-cells

Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leveraged genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2 + macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2 + macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

The ADVanced Organ Support (ADVOS) hemodialysis system removes IL-6: an in vitro proof-of-concept study

BackgroundIL-6 is a pleiotropic cytokine modulating inflammation and metabolic pathways. Its proinflammatory effect plays a significant role in organ failure pathogenesis, commonly elevated in systemic inflammatory conditions. Extracorporeal blood purification devices, such as the Advanced Organ Support (ADVOS) multi hemodialysis system, might offer potential in mitigating IL-6's detrimental effects, yet its efficacy remains unreported.MethodsWe conducted a proof-of-concept in vitro study to assess the ADVOS multi system's efficacy in eliminating IL-6. Varying concentrations of IL-6 were introduced into a swine blood model and treated with ADVOS multi for up to 12 h, employing different blood and concentrate flow rates. IL-6 reduction rate, clearance, and dynamics in blood and dialysate were analyzed.ResultsIL-6 clearance rates of 0.70 L/h and 0.42 L/h were observed in 4 and 12-h experiments, respectively. No significant differences were noted across different initial concentrations. Reduction rates ranged between 40 and 46% within the first 4 h, increasing up to 72% over 12 h, with minimal impact from flow rate variations. Our findings suggest that an IL-6-albumin interaction and convective filtration are implicated in in vitro IL-6 elimination with ADVOS multi.ConclusionsThis study demonstrates for the first time an efficient and continuous in vitro removal of IL-6 by ADVOS multi at low blood flow rates. Initial concentration-dependent removal transitions to more consistent elimination over time. Further clinical investigations are imperative for comprehensive data acquisition.

TRIM35: A Proposed Gateway to p53-Induced Heart Failure Pathogenesis.

TRIM35: A Proposed Gateway to p53-Induced Heart Failure Pathogenesis.

Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER.

Detections of Chemicals and Migratory Plastics in Peritoneal Dialysis Fluids

Background: Peritoneal dialysis (PD) is an important modality of renal replacement therapy (RRT). Peritonitis and ultrafiltration failure are complications that have a long-term impact on PD patients. Besides touch contamination, procedural errors and clinical reasons of peritonitis, contaminants, and constituents of peritoneal dialysis fluids (PDFs) have been implicated in causing peritonitis and ultrafiltration failure. This study was aimed to test the PDFs in India for the presence of migratory plastics. Materials and Methods: PDFs from the two manufacturers in India were tested using liquid chromatography mass spectrometry (LCMS) and gas chromatography mass spectrometry (GCMS) with headspace analysis (volatile compounds) and pyrolysis of plastics (polymer compounds). The storage conditions and handling were uniform. Results: The results revealed impurities of acetate compounds and aldehyde derivatives of glucose degradation products (GDPs) with contaminants and leachable plastics. There were high levels of GDP derivative in the form of 5-hydroxymethylfurfural compounds (5-HMF). The analysis revealed the presence of plastic softeners in very high concentrations. Conclusion: The study unmasks the presence of chemicals and GDPs that can be implicated in pathogenesis of sterile peritonitis and ultrafiltration failure. The study demonstrated the presence of leachable plastics. In conclusion, LCMS and GCMS studies can be used to test PDFs for unwanted chemicals prior to human use.

Leukocyte-platelet aggregates in the pathogenesis of respiratory failure in patients with COVID-19 with varying degrees of oxygen support

Leukocyte-platelet aggregates in the pathogenesis of respiratory failure in patients with COVID-19 with varying degrees of oxygen support

Pathophysiological features of acute liver failure caused by cholestasis [

Acute liver failure is a syndrome that occurs in 20-59% of patients with liver pathology and is one of the main causes of death in 40% of patients with mechanical jaundice of benign origin and in more than 70% of cases of tumor obstruction of the biliary tract and cancer of caput pancreas. In most cases, the syndrome is a consequence of acute liver damage (viral or drug-induced). Still, it can occur with longterm obstructive jaundice, be the first manifestation of Wilson’s disease, autoimmune chronic hepatitis, or superinfection of the hepatitis D virus against the background of chronic hepatitis B. The aim of the work was to study the pathophysiological features of the development of acute liver failure in patients with bile outflow disorders. The pathogenesis of acute liver failure caused by cholestasis is based on the damage and death of hepatocytes due to impaired blood circulation in the liver, as well as the toxic effect on the parenchyma of both the etiological factors themselves and their metabolites. The first week from the onset of symptoms is very important and usually accompanied by a systemic inflammatory response syndrome with significant consequences. At the same time, the main factors influencing the results of treatment of patients at different points in time are the combination of the critical functional reserve of the liver and the nature and severity of liver damage. In the case of the development of a systemic inflammatory response syndrome, there is a further increase in inflammation, which has a systemic nature and leads to the failure of other organs. Under these circumstances, understanding the pathophysiological features of the course of acute liver failure makes it possible to carry out the necessary diagnostic measures on time and offer appropriate therapy.

IRGM/Irgm1 increases autophagy to inhibit activation of NLRP3 inflammasome in inflammatory injury induced acute liver failure

Immune-related GTPase M (IRGM) induces autophagy and suppresses inflammation, but its putative role and signaling mechanism remain undefined in the pathogenesis of liver failure. This study aimed to address how IRGM attenuates inflammatory injury by regulating autophagy in liver failure. In this study, a total of 10 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and 10 healthy controls were prospectively enrolled. Intrahepatic expression of IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, and caspase-1), autophagy-related proteins (LC3II, P62), and inflammatory cytokines (IL-1β, TNF-α) were measured. Autophagy was activated by rapamycin (4 mg/kg) in an acute liver failure (ALF) mouse model, which was used to further study the expression of Irgm1, NLRP3 inflammasome, autophagy-related proteins, and inflammatory cytokines using both qRT-PCR and Western blot analyses. Irgm1 expression was knocked down using Irgm1 short hairpin RNA (shRNA) in lipopolysaccharide (LPS)-induced AML12 cells to investigate the effects of Irgm1 deletion on autophagy and inflammation. We found that the expression of IRGM and autophagy-related proteins was significantly downregulated while the NLRP3 inflammasome was significantly upregulated in the livers of HBV-ACLF patients and the ALF mouse model (all P < 0.05). Rapamycin-induced autophagy ameliorated intrahepatic NLRP3 inflammasome activation and decreased inflammation and necrosis in the ALF mice. Irgm1 knockdown decreased autophagy and significantly upregulated NLRP3 inflammasome activation in AML12 cells (all P < 0.05). Rapamycin-induced autophagy also protected against hepatocyte injury following LPS stimulation in vitro by inhibiting NLRP3 inflammasome activation. Thus, IRGM/Irgm1 alleviates inflammation-mediated hepatocyte injury by regulating autophagy. This study provides new insight into potential molecular targets to treat liver failure.