Therapy For Acute Liver Failure Research Articles

Multimodal Tetrahedral DNA Nanoplatform for Surprisingly Rapid and Significant Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a life-threatening disease associated with the rapid development of inflammatory storms, level elevation of reactive oxygen species (ROS), and hepatocyte necrosis, which results in high short-term mortality. Except for liver transplantation, no effective strategies are available for ALF therapy due to the rapid disease progression and narrow window of therapeutic time. Therefore, there is an urgent demand to explore the fast and effective modalities for ALF treatment. Herein, a multifunctional tetrahedral DNA nanoplatform (TDN) is constructed by incorporating tumor necrosis factor-α siRNA (siTNF-α) through DNA hybridization and antioxidant manganese porphyrin (MnP4) via π-π stacking interaction with G-quadruplex (G4) for surprisingly rapid and significant ALF therapy. TDN-siTNF-α/-G4-MnP4 silences TNF-α of macrophages by siTNF-α and polarizes them to the anti-inflammatory M2 phenotype, providing appropriate microenvironments for hepatocyte viability. Additionally, TDN-siTNF-α/-G4-MnP4 scavenges intracellular ROS by MnP4, protecting hepatocytes from oxidative-stress-associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation by modulating the cell cycle. TDN-siTNF-α/-G4-MnP4 shows almost complete liver accumulation after intravenous injection and exhibits excellent therapeutic efficacy of ALF within 2h. The multifunctional DNA nanoformulation provides an effective strategy for rapid ALF therapy, expanding its application for innovative treatments of liver diseases.

Macrophages in necrotic liver lesion repair: opportunities for therapeutical applications.

Healthy livers contain 80% of body resident macrophages known as Kupffer cells. In diseased livers, the number of Kupffer cells usually drops but is compensated by infiltration of monocyte-derived macrophages, some of which can differentiate into Kupffer-like cells. Early studies suggest that Kupffer cells play important roles in both promoting liver injury and liver regeneration. Yet, the distinction between the functionalities of resident and infiltrating macrophages is not always made. By using more specific macrophage markers and targeted cell depletion and single-cell RNA sequencing, recent studies revealed several subsets of monocyte-derived macrophages that play important functions in inducing liver damage and inflammation as well as in liver repair and regeneration. In this review, we discuss the different roles that hepatic macrophages play in promoting necrotic liver lesion resolution and dead cell clearance, as well as the targeting of these cells as potential tools for the development of novel therapies for acute liver failure and acute-on-chronic liver failure.

Extra-corporeal non-liver transplant therapies for acute liver failure: Focus on plasma exchange and continuous renal replacement therapy.

The acute inflammatory milieu in patients with acute liver failure (ALF) results in 'toxic' blood in these patients. In vitro experiments have shown that the plasma obtained from ALF patients is toxic to rabbit hepatocytes and inhibits regeneration of rat hepatocytes. Treatments such as plasma exchange and continuous renal replacement therapy to cleanse the blood have improved survival in ALF patients. In the liver microcirculation, the exchange of fluid across fenestrae in liver sinusoidal endothelial cells (LSECs) is vital for proper functioning of hepatocytes. Clogging of the liver filter bed by inflammatory debris and cells ('traffic jam hypothesis') impeding blood flow in sinusoids may in turn reduce the exchange of fluid across LSEC fenestrae and cause dysfunction and necrosis of hepatocytes in ALF patients. In mouse model of paracetamol overdose, disturbances in microcirculation in the liver preceded the development of injury and necrosis of hepatocytes. This may represent a reversible pathophysiological mechanism in ALF which may be improved by the anti-inflammatory effect of plasma exchange. Wider access to urgent plasma exchange is a major advantage compared to urgent liver transplantation to treat ALF patients worldwide, especially so in resource constrained settings. Continuous hemo-filtration or dialysis is used toreduce ammonia levels and treat cerebral edema in ALF patients. In this review, we discuss the different modalities to cleanse the blood in ALF patients, with an emphasis on plasma exchange, from a hepatology perspective.

Recipient Survival among Living Donor vs. Deceased Donor Liver Transplants for Acute Liver Failure in the United States.

Objectives: Acute liver failure (ALF) is associated with high morbidity and mortality. Timely liver transplantation (LT) is the only universally accepted therapy for ALF that is non-responsive to medical therapy. Data regarding the use of living donor LT (LDLT) for this indication in the US is scarce. Materials and Methods: United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) data from January 2002 to December 2020 were reviewed. Adult and pediatric recipients listed as status 1 were included. Demographics, clinical and laboratory data, and post-LT survival rates were compared for LDLT vs. DDLT recipients. Results: There were 180 LDLT (3.6%) and 4779 DDLT (96.4%) recipients with a diagnosis of ALF. The majority of recipients in the LDLT group were pediatric (n = 164, 91%) compared to the DDLT group (n = 1455, 30%), p < 0.001. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients (p = 0.15). Five-year post-LT survival was higher for pediatric recipients compared to adults in the LDLT group (84.2% vs. 62.5%, respectively, p < 0.001) and the DDLT group (82.8% vs. 78.7%, respectively, p < 0.001). Adults had a higher hazard of death compared to pediatric recipients in the LDLT group (HR = 3.560, 95% CI 1.612-7.844, p = 0.002) and the DDLT group (HR = 1.472, 95% CI 1.290-1.679, p < 0.001). In multivariate analysis results, the type of LT and age group were not associated with higher post-LT mortality. Conclusions: In the US, LDLT constitutes 3.6% of LTs for ALF. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients. Overall, there were superior post-LT outcomes for pediatric recipients compared to adults for LDLT and DDLT.

Dihydroquercetin improves experimental acute liver failure by targeting ferroptosis and mitochondria-mediated apoptosis through the SIRT1/p53 axis

BackgroundFerroptosis and mitochondria-mediated apoptosis are both involved in the pathogenesis of acute liver failure (ALF). Ferroptosis-produced reactive oxygen species (ROS) trigger the chain oxidation of polyunsaturated phospholipids and promote mitochondrial apoptosis. Dihydroquercetin (DHQ) also plays an important protective role against liver injury. PurposeHere, we aimed to investigate the protective effects of DHQ on ALF. We also explored the underlying mechanism. MethodsWe established a Lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced ALF mouse model and tumor necrosis factor-α (TNF-α)/D-Gal-induced ALF LO2 cell model. 2′,7′-Dichlorofluorescein diacetate (DCFH-DA) and Dihydroethidium (DHE) were used to detect total ROS levels. Lipid ROS was assessed using C11-BODIPY flow cytometry. Lipid peroxidative products levels were detected using MDA ELISA assay and 4-hydroxynonenal (4-HNE) immunohistochemistry. QRT-PCR and western blots were used to test mRNA and protein expression levels, respectively. Cell viability was evaluated with CCK8 assay, and apoptosis was analyzed using flow cytometry. ResultsDHQ treatment improved LPS/D-Gal-induced ALF, as well as TNF-α/D-Gal-induced reductions in LO2 viability and increased sirtuin 1 (SIRT1) expression. DHQ pretreatment also reduced the accumulation of ROS, reduced lipid peroxidation, elevated mitochondrial membrane potentials (ΔΨm), and decreased liver cell apoptosis both in vivo and in vitro. Additionally, the knockdown of SIRT1 and p53 activator (Tenovin-6) treatment reversed DHQ's inhibitory effects on ferroptosis and mitochondria-mediated apoptosis in vitro. DHQ enhanced p53 deacetylation by both up-regulating SIRT1 expression and directly bonding to SIRT1. We also found that Tenovin-6′s stimulatory effects on ferroptosis and mitochondria-mediated apoptosis in the DHQ-treated LO2 ALF cell model were partially attenuated by overexpression of solute carrier family 7member 11 (SLC7A11), as well as by apoptotic protease activating factor 1 (Apaf-1) knockdown. ConclusionOur results suggest that DHQ alleviated ALF by inhibiting both ferroptosis and mitochondria-mediated apoptosis by regulating the SIRT1/p53 axis. Thus, DHQ may serve as a novel therapy for ALF.

Microfluidic Fabrication of MicroRNA-Induced Hepatocyte-Like Cells/Human Umbilical Vein Endothelial Cells-Laden Microgels for Acute Liver Failure Treatment.

Acute liver failure (ALF) is a critical life-threatening disease that occurs due to a rapid loss in hepatocyte functions. Hepatocyte transplantation holds great potential for ALF treatment, as it rapidly supports liver biofunctions and enhances liver regeneration. However, hepatocyte transplantation is still limited by renewable and ongoing cell sources. In addition, intravenously injected hepatocytes are primarily trapped in the lungs and have limited efficacy because of the rapid clearance in vivo. Here, we designed a Y-shaped DNA nanostructure to deliver microRNA-122 (Y-miR122), which could induce the hepatic differentiation and maturation of human mesenchymal stem cells. mRNA sequencing analysis revealed that the Y-miR122 promoted important hepatic biofunctions of the induced hepatocyte-like cells including fat and lipid metabolism, drug metabolism, and liver development. To further improve hepatocyte transplantation efficiency and therapeutic effects in ALF treatment, we fabricated protective microgels for the delivery of Y-miR122-induced hepatocyte-like cells based on droplet microfluidic technology. When cocultured with human umbilical vein endothelial cells in microgels, the hepatocyte-like cells exhibited an increase in hepatocyte-associated functions, including albumin secretion and cytochrome P450 activity. Notably, upon transplantation into the ALF mouse model, the multiple cell-laden microgels effectively induced the restoration of liver function and enhanced liver regeneration. Overall, this study presents an efficient approach from the generation of hepatocyte-like cells to hepatocyte transplantation in ALF therapy.

Molecular Adsorbent Recirculating System for Acute Liver Failure in a New Pediatric-Based Extracorporeal Liver Support Program.

Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent. We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center. Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022. Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test. Five pediatric and two adult patients underwent MARS for ALF. Ages ranged from 2 to 29 years. Overall, 21 MARS runs were performed (median 3 runs per patient, 12.4 hr per run [interquartile range, IQR 10.1-17]). Overall survival was 85.7%, and transplant-free survival was 71.4%. There was a statistically significant reduction in HE score with MARS therapy (median 3 [IQR 3-4] to 1 [IQR 0-1], p = 0.03), and in ALF biomarkers including ammonia (256 µL/dL [195-265] to 75 µL/dL [58-101], p = 0.02), aspartate aminotransferase (6,362 U/L [920-8,305] to 212 U/L [72-431], p = 0.02), alanine aminotransferase (8,362 U/L [3,866-9,189] to 953 U/L [437-1,351], p = 0.02), and international normalized ratio (4.5 [3.3-6.7] to 1.3 [1.2-1.4], p = 0.02). MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts.

Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure.

Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.

A 15-Year Retrospective Study of Supportive Extracorporeal Therapies Including Plasma Exchange and Continuous Venovenous Hemodiafiltration of 114 Adults with Acute Liver Failure Awaiting Liver Transplantation.

BACKGROUND Recently, there has been a recommendation to utilize a combination of supportive extracorporeal therapies, specifically plasma exchange and continuous venovenous hemodiafiltration, in patients with acute liver failure. This 15-year retrospective study aimed to evaluate supportive extracorporeal therapy, including plasma exchange and continuous venovenous hemodiafiltration, for 114 adults with acute liver failure awaiting liver transplant. MATERIAL AND METHODS In this retrospective study, the medical records of 1288 adult patients who underwent liver transplantation and 161 adult patients who received alternative therapy were analyzed; 114 patients who received combined supportive extracorporeal therapy for acute liver failure were included in the study. Biochemical laboratory data were compared before and after therapy. RESULTS The study included 50 male and 64 female patients. The first group (34 patients) recovered with liver transplantation, and 4 patients died in the first year after liver transplantation. In the second group (80 patients), 66 patients recovered without liver transplantation, while 14 patients died within the first 2 weeks after therapy. All patients showed significant reductions in serum hepatic function tests (alanine transaminase, aspartate transaminase, and total bilirubin), ammonia, and prothrombin time/international normalized ratio after discontinuation of combined supportive extracorporeal therapy (P<0.01). There was also a significant improvement in the hemodynamic parameter. CONCLUSIONS This combined extracorporeal therapy can be used as a supportive treatment for both recovery and bridge to liver transplantation in patients with acute liver failure. In addition, treatment can be continued until liver regeneration and until a usable donor is found.

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Reactive oxygen species (ROS)-associated oxidative stress, inflammation storm, and massive hepatocyte necrosis are the typical manifestations of acute liver failure (ALF), therefore specific therapeutic interventions are essential for the devastating disease. Here, we developed a platform consisting of versatile biomimetic copper oxide nanozymes (Cu NZs)-loaded PLGA nanofibers (Cu NZs@PLGA nanofibers) and decellularized extracellular matrix (dECM) hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells (hADMSCs-derived HLCs) (HLCs/Cu NZs@fiber/dECM). Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF, and reduce the massive accumulation of pro-inflammatory cytokines, herein efficiently preventing the deterioration of hepatocytes necrosis. Moreover, Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs. Meanwhile, HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy. The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs. In addition, the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver. Hence, HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice. This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

Mesenchymal Stem Cell Therapy in Acute Liver Failure.

Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.

Integrated Analysis of Gut Microbiome and Liver Metabolome to Evaluate the Effects of Fecal Microbiota Transplantation on Lipopolysaccharide/D-galactosamine-Induced Acute Liver Injury in Mice

Acute liver failure (ALF) refers to the occurrence of massive hepatocyte necrosis in a short time, with multiple complications, including inflammatory response, hepatic encephalopathy, and multiple organ failure. Additionally, effective therapies for ALF are lacking. There exists a relationship between the human intestinal microbiota and liver, so intestinal microbiota modulation may be a strategy for therapy of hepatic diseases. In previous studies, fecal microbiota transplantation (FMT) from fit donors has been used to modulate intestinal microbiota widely. Here, we established a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-gal) induced ALF to explore the preventive and therapeutic effects of FMT, and its mechanism of action. We found that FMT decreased hepatic aminotransferase activity and serum total bilirubin levels, and decreased hepatic pro-inflammatory cytokines in LPS/D-gal challenged mice (p < 0.05). Moreover, FMT gavage ameliorated LPS/D-gal induced liver apoptosis and markedly reduced cleaved caspase-3 levels, and improved histopathological features of the liver. FMT gavage also restored LPS/D-gal-evoked gut microbiota dysbiosis by modifying the colonic microbial composition, improving the abundance of unclassified_o_Bacteroidales (p < 0.001), norank_f_Muribaculaceae (p < 0.001), and Prevotellaceae_UCG-001 (p < 0.001), while reducing that of Lactobacillus (p < 0.05) and unclassified_f_Lachnospiraceae (p < 0.05). Metabolomics analysis revealed that FMT significantly altered LPS/D-gal induced disordered liver metabolites. Pearson's correlation revealed strong correlations between microbiota composition and liver metabolites. Our findings suggest that FMT ameliorate ALF by modulating gut microbiota and liver metabolism, and can used as a potential preventive and therapeutic strategy for ALF.

Pharmacokinetic profile of acyclovir in a child receiving continuous kidney replacement therapy for acute liver failure.

Continuous venovenous hemodiafiltration (CVVHDF) is one of the treatments of critically ill children presenting severe acute liver failure. This affliction might be induced by HSV infection requiring a treatment by acyclovir. Continuous kidney replacement therapy (CKRT) can alter its pharmacokinetics, according to its physicochemical properties and CVVHDF settings. The patient was a 21-month-old female presenting liver failure with hyperammonemia treated by acyclovir with presumed HSV infection. CKRT was initiated on day 1 with substantial replacement and dialysate flow rates (respectively 75 and 220mL/kg/h). Acyclovir was intravenously administered every 8h with a 1-h infusion of 500mg/m2. Plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry assay to estimate the area under a curve (AUC) and CKRT clearance by 2 methods (one based on pre- and post-filter concentrations and the other one on dialysate flow rates). Clearance was estimated between 19.2 and 26.3mL/min with the first method and between 27.6 and 44.3mL/min with the second one. Concentrations were highly above the therapeutic index (peak concentration was measured at 28mg/L), but AUC was appropriate. This case describes acyclovir pharmacokinetics during CKRT in a pediatric patient treated by acyclovir. The patient was treated with adapted exposure with the usual dosing, but lower dosing should be investigated with complementary studies. ClinicalTrials.gov NCT02539407.

Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b

SummaryThe conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.

HNF4α overexpression enhances the therapeutic potential of umbilical cord mesenchymal stem/stromal cells in mice with acute liver failure.

Human umbilical cord mesenchymal stem/stromal cells (hUMSCs) hold promise for treating acute liver failure (ALF). Here, we investigated the therapeutic effect of hUMSCs overexpressing hepatocyte nuclear factor 4α (HNF4α), a transcription factor important for maintaining hepatocyte identity and hepatic functions, in ALF, compared with hUMSCs without overexpression of HNF4α (CON-hUMSCs). The cells were administered into mice via the tail vein for 24 h before exposure to lipopolysaccharide/d-galactosamine (LPS/d-GalN) for 6 h by intraperitoneal injection. HNF4α-hUMSCs ameliorated liver injury in ALF better than CON-hUMSCs. The overexpression of HNF4α enhanced the transcription of interleukin (IL)-10 and promoted M2 macrophage polarization through the IL-10/signal transducer and activator of transcription 3 (STAT3) pathway. HNF4α-hUMSCs could exert a more pronounced therapeutic effect on ALF than CON-hUMSCs, providing a novel therapy for ALF.

Sulfated Alginate Reduces Pericapsular Fibrotic Overgrowth on Encapsulated cGMP-Compliant hPSC-Hepatocytes in Mice.

Intra-peritoneal placement of alginate encapsulated human induced pluripotent stem cell-derived hepatocytes (hPSC-Heps) represents a potential new bridging therapy for acute liver failure. One of the rate-limiting steps that needs to be overcome to make such a procedure more efficacious and safer is to reduce the accumulation of fibrotic tissue around the encapsulated cells to allow the free passage of relevant molecules in and out for metabolism. Novel chemical compositions of alginate afford the possibility of achieving this aim. We accordingly used sulfated alginate and demonstrated that this material reduced fibrotic overgrowth whilst not impeding the process of encapsulation nor cell function. Cumulatively, this suggests sulfated alginate could be a more suitable material to encapsulate hPSC-hepatocyte prior to human use.

CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure

BackgroundMesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs.MethodsBy evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2 compared to those of the MSCvector control.ResultsIn vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2 rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2 exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration.ConclusionsAltogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF.

A ROS-Sensitive Nanozyme-Augmented Photoacoustic Nanoprobe for Early Diagnosis and Therapy of Acute Liver Failure.

Early diagnosis of acute liver failure (ALF) is critical for curable treatment of patients, because most existing ALF therapies have narrow therapeutic time windows after disease onset. Reactive oxygen species (ROS), which lead to the sequential occurrences of hepatocyte necrosis and the leakage of alanine aminotransferase (ALT), represent early biomarkers of ALF. Photoacoustic imaging is emerging as a powerful tool for in vivo imaging of ROS. However, high-performance imaging probes that can boost the photoacoustic signals of the short-lived ROS of ALF are yet to be developed, and there remains a great challenge for ROS-based imaging of ALF. Herein, a ROS-sensitive nanozyme-augmented photoacoustic nanoprobe for successful in vivo imaging of ALF is presented. The deep-penetrating photoacoustic signals of the nanoprobe can be activated by the overexpressed ROS in ALF due to the synergy between nanocatalytic bubbles generation and thermoelastic expansion. Impressively, the nanozyme-augmented ROS imaging enables earlier diagnosis of ALF than the clinical ALT method, and the ROS-activated catalytic activity of nanoprobe permits timely nanocatalytic therapy of ALF.

5-((7-Chloro-6-fluoro-1h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione as a RIP1 inhibitor protects LPS/D-galactosamine-induced liver failure

AimsNecroptosis, an inflammatory form of regulated necrosis mediated by receptor-interacting kinase 1 (RIP1), RIP3, and pseudokinase mixed lineage kinase domain-like protein (MLKL) is extensively implicated in liver inflammatory disease. Thus identification small-molecule inhibitor of necroptosis has emerged as a potential therapeutic strategy to prevent liver damage. In this study, we identified 5-((7-chloro-6-fluoro-1 h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione (F-nec) as a novel potent necroptosis inhibitor. Main methodsTo find out the potent chemical inhibitors of necroptosis, human monocytic U937 cells were treated with a combination of tumor necrosis factor alpha (TNFα) and a pan-caspase inhibitor z-VAD-fmk. LPS and D-galactosamine (LPS/GalN) were further employed to simulate acute liver failure to explore therapeutic potency of F-nec in vivo. In addition, a specific inhibitor of c-Jun NH (2)-terminal kinases (JNK) SP600125 and its activator anisomycin are used to elucidate its mechanisms in acute liver failure therapy. Necroptosis pathway related proteins were tested by western blot. Key findingsIn this study, we identified F-nec as a novel potent RIP1 inhibitor which efficiently blocked TNFα-induced necroptosis in human and mice cells. Furthermore, pre-treatment of F-nec could prevent hepatic necrosis by reducing RIP1-mediated necroptosis also effectively ameliorated LPS/GalN induced acute liver failure by attenuating cell death signaling-stimulated JNK pathway activation and then suppressing JNK-triggered inflammation. SignificanceAltogether, this study demonstrates that F-nec is a potent inhibitor of RIP1 and highlights its great potential for use in the treatment of RIP1-driven inflammatory liver diseases.

Plasma Exchange as a Rescue Therapy for Acute Liver Failure

Acute Liver Failure (ALF) is a life-threatening condition and often necessitates Liver Transplantation (LT). However, LT is not available to most patients in developing countries due to resource constraints. Here, authors presents a case of 30-year-old female with ALF and fulfilled the criteria for LT. The aetiology of ALF could not be diagnosed in her. Due to the lack of LT facilities, she was offered plasma exchange as a therapeutic option, which resulted in improvement in sensorium and Liver Function Tests (LFT) {bilirubin, International Normalised Ratio (INR), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT)} over a period of two weeks. She was discharged and was doing well during follow-up. Plasma exchange is a less studied but potential treatment option for ALF when LT is not feasible.