Acute liver injury (ALI) is a prevalent inflammatory disease with no currently available effective targeted therapies that characterized by high mortality and morbidity. Dihydroartemisinin (DHA), a derivative of the renowned antimalarial compound artemisinin, has garnered attention for its anti-inflammatory property. However, the precise anti-inflammatory mechanisms underlying its efficacy in treating ALI remain unclear. Notably, the excessive inflammatory cytokines secreted by macrophages represents a critical factor of liver damage. In our comprehensive study, transcriptome and proteomic analysis of M1 macrophages after DHA treatment was performed to unearth the potential anti-inflammatory targets for ALI treatment. Transcriptomics analysis indicated that DHA significantly mitigated inflammation, primarily by downregulating the expressions of CCL1, CCL2, CCL7, CCL13, and CXCL13. Concurrently, proteomics analysis identified six proteins, such as CYBA and CYBB, that were consistently downregulated in the DHA intervention groups compared to the M1 group. Intriguingly, a protein-protein interaction network analysis highlighted the close association of CYBA and CYBB with the aforementioned chemokine genes. Through meticulous screening, DHA curtailed the production of reactive oxygen species (ROS) by targeting CYBA and CYBB, subsequently suppressing the secretion of several chemokines and dampening the inflammatory response in M1 macrophages. More importantly, DHA not only reduced ROS and chemokine levels but also restored liver function by downregulating CYBA and CYBB to inhibit NF-κB pathway in ALI mice, demonstrating strong anti-inflammatory effects. In conclusion, our findings throw novel light into the underlying anti-inflammatory mechanism of DHA in ALI management, offering valuable insights for future clinical research and therapeutic strategies for inflammatory diseases.

The role of tryptophan 2,3-dioxygenase2 (TDO2), a key enzyme in the L-tryptophan (Trp)-kynurenine (Kyn) pathway, in liver transplant immunity is unclear. This study aims to explore the role of TDO2 in liver transplant rejection.

We used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to construct a TDO2 knockout rat model for liver transplant rejection. We validated the effects of TDO2 on acute rejection and survival, assessed TDO2 expression, and measured Trp and Kyn levels. We studied how TDO2 deficiency affects inflammatory cytokines, analyzed immune cell subtypes and their spatial distribution, and examined programmed death 1 and programmed cell death-ligand 1 (PDL1) spatial distribution and expression using multiplex immunohistochemistry. We also validated the regulatory mechanism of TDO2 on transplant-related immune cells in vivo and in vitro.

TDO2 deficiency in the allograft liver worsens acute rejection and reduces survival rates. During transplant rejection, TDO2 expression increases, enhancing Trp metabolism and elevating serum Kyn levels. TDO2 knockout mitigates this process. The TDO2-Kyn-aryl hydrocarbon receptor pathway regulates acute rejection. TDO2 knockout reprograms immune cell distribution, decreasing regulatory T cells and M2 macrophages in the intermediate region while increasing CD8+ T cells and M1 macrophages in the portal area, leading to M1 polarization. Additionally, TDO2 deficiency raises programmed death 1 and programmed cell death-ligand 1 expression, varying with the spatial distribution and quantity of immune cells. TDO2 can regulate the proliferation and differentiation of various immune cells through the Kyn-aryl hydrocarbon receptor pathway.

Collectively, we elucidated the mechanism of TDO2 in liver transplant immune rejection and used spatial immunity to reveal the impact of TDO2 on liver transplantation.

Succinate regulates inflammation through its receptor, succinate receptor 1 (SUCNR1). However, the effects of this interaction on Kupffer cell (KC)-driven inflammation during liver ischemia-reperfusion injury (IRI) remain unclear. Herein, we investigated the succinate/SUCNR1 axis in the progression of liver IRI. In this study, succinate levels and SUCNR1 expression were analyzed in mice underwent segmental liver IRI. Sucnr1 deficiency (Sucnr1-/-) and Wild-type mice were treated with or without clodronate before liver IRI modeling, and a co-culture system was established to assess the impact of Sucnr1 deficiency in KCs on hepatocyte viability and apoptosis. KC activation status and polarization were determined, in vivo and in vitro. Furthermore, the downstream pathways in regulating KC polarization were investigated. We observed a significant increase in succinate levels in the serum and liver, and SUCNR1 expression in KCs after IRI. Sucnr1 deletion alleviated liver IRI and hepatocyte apoptosis either in vivo or in vitro. However, the aforementioned hepatoprotective effects were abolished by the depletion of KCs with clodronate. Sucnr1 deletion inhibited KC activation and M1 polarization, and dampened proinflammatory cytokine release after liver IRI. In addition, Sucnr1 knockout reversed the increasing phosphorylation of ERK and NF-κB p65 in KCs following liver IRI. The phosphorylation of ERK/NF-κB p65 and M1 polarization in KCs were also inhibited by the SUCNR1 antagonist Compound 4C or ERK inhibitor SCH772984. Together, these findings suggest that SUCNR1 deficiency protects against liver IRI by modulating KC activation and polarization probably through the ERK/NF-κB pathway.

Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated.

We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models.

LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT.

In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone.

Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages.

Myocardial ischemia-reperfusion (IR) injury is a critical complication following revascularization therapy for ischemic heart disease. Itaconate, a macrophage-derived metabolite, has been implicated in inflammation and metabolic regulation. This study investigates the protective role of itaconate derivatives against IR injury. Using a mice model of IR injury, the impact of 7-day 4-Octyl itaconate (4-OI) administration on cardiac function is assessed. Exogenous administration of 4-OI significantly reduces myocardial damage, enhances angiogenesis, and alleviates myocardial hypoxia injury during reperfusion. RNA sequencing and molecular docking techniques are used to find the target of itaconate, and changes in cardiac function are observed in Immune-Responsive Gene1 (IRG1) global knockout mice. In cell culture studies, 4-OI promotes endothelial cell proliferation and migration, mediated by Mitogen-Activated Protein Kinases (MAPK) signaling pathway activation, particularly through Extracellular Signal-Regulated Kinase (ERK) signaling. Inhibition of ERK blocks these beneficial effects on endothelial cells. Furthermore, itaconate synthesis inhibition worsens myocardial damage, which is mitigated by 4-OI supplementation. The results indicate that 4-OI promotes angiogenesis by activating MAPK signaling via FMS-like tyrosine kinase 1 (Flt1), highlighting its potential as a therapeutic strategy for myocardial IR injury.

Diverse liver diseases are characterised by late diagnosis and rapid progression and have become one of the major threats to human health. To delay the transition from benign tissue lesions to a substantial organ injury, scientists have gradually applied natural compounds derived from plants as a complementary therapy in the field of hepatology. Ginseng (Panax ginseng C. A. Meyer) is a tonic traditional Chinese herbal medicine, and natural products, including ginsenoside Rg1 (G-Rg1), which is a kind of 20(S)-protopanaxatriol saponin with a relatively high biological activity, can be isolated from the roots or stems of ginseng. Given these information, this review aimed to summarise and discuss the metabolic mechanisms of G-Rg1 in the regulation of diverse liver diseases and the measures to improve its bioavailability. As a kind of monomer in Chinese medicine with multitarget pharmacological effects, G-Rg1 can provide significant therapeutic benefits in the alleviation of alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, viral hepatitis, etc., which mainly rely on the inhibition of apoptosis, strengthening endogenous anti-inflammatory and antioxidant mechanisms, activation of immune responses and regulation of efflux transport signals, to improve pathological changes in the liver caused by lipid deposition, inflammation, oxidative stress, accumulation of hepatotoxic product, etc. However, the poor bioavailability of G-Rg1 must be overcome to improve its clinical application value. In summary, focusing on the hepatoprotective benefits of G-Rg1 will provide new insights into the development of natural Chinese medicine resources and their pharmaceutical products to target the treatment of liver diseases.

Using autologous orthotopic liver transplantation (AOLT) model in rats, the effect of lipid reactive oxygen species (L-ROS) inhibitor Ferrostain-1 on ferroptosis signal pathway was observed to determine whether ferroptosis occurred in rat liver injury after cold ischemia-reperfusion (I/R). Thirty-two healthy adult SPF male SD rats, 8 ~ 10 weeks old, weight 240 ~ 260 g, were divided into four groups by the method of random number table (n = 8): sham group, I/R group, I/R + Fer-1 group, I/R + DFO group. In the I/R + Fer-1 group, ferristatin-1(5 mg /kg) was intraperitoneally injected 30 min before surgery; in the I/R + DFO group, DFO 100 mg/kg was injected intraperitoneally 1 h before operation and 12 h after operation. Blood samples were taken from the inferior hepatic vena cava 24 h after reperfusion. After anesthesia, the rats were killed and part of their liver tissue was removed. The pathological changes of liver tissue sections were observed under a high-power microscope, and the liver injury was evaluated. Serum malondialdehyde (MDA) and serum levels of ALT, AST and IL-6 were determined by the ELISA method, Reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), MDA, Fe2 + and superoxide dismutase (SOD) were determined in the liver tissue. Compared with the sham group, the serum levels of the IL-6,MDA, AST and ALT in I/R group were obviously higher (P < 0.05); The levels of MDA and Fe2+ in liver tissue were significantly increased (P < 0.05).The levels of SOD, GSH and GPX4 in liver tissue were decreased. The levels of serum MDA, IL-6, AST, and ALT in the I/R + Fer-1 and I/R + DFO groups were significantly lower than those in the I/R group at 24 h after reperfusion. In the I/R + Fer-1 group, the level of MDA in liver tissue decreased significantly, while the level of SOD, GSH and GPX4 in intestinal tissue increased (P < 0.05). In The I/R + DFO group, the levels of MDA and Fe2+ in liver tissue decreased significantly, while the level of SOD in intestinal tissue increased (P < 0.05). Ferroptosis is involved in pathophysiological process of liver injury after cold ischemia-reperfusion in AOLT rats.

Hepatic ischemia-reperfusion injury (IRI) triggers macrophage activation, which in turn mediates inflammatory responses and affects tissue repair and injury severity. Pentraxin 3 (PTX3) is vital in immune regulation and inflammatory processes. In this study, we aim to investigate the potential role of PTX3 in macrophage-mediated hepatic IRI.

Gene expression profiles and single-cell data were obtained from the Gene Expression Omnibus (GEO) database. Immunohistochemistry was used to evaluate the expression levels of PTX3, CD68, and CD86 in samples from the human and mouse hepatic IRI models. The effects of PTX3 knockdown or overexpression on macrophage polarization were assessed in Raw264.7. PTX3 knockdown/ overexpression in Raw264.7 and co-culturing with AML12 were performed under conditions of hypoxia-reoxygenation (H/R) to examine pyroptosis and injury in AML12.

PTX3 expression was significantly upregulated in both human and mouse hepatic IRI model samples. Bulk and single-cell RNA-seq data analyses revealed that PTX3 is associated with inflammatory response pathways and macrophage activation. Macrophages with high PTX3 expression exhibit M1-like characteristics. Similarly, overexpression of PTX3 promotes M1 polarization of Raw264.7 after H/R, while the knockdown group exhibits reduced M1 polarization. Co-culture results indicated that pyroptosis in AML12 was significantly reduced after H/R in the PTX3 knockdown group, whereas the PTX3 overexpression group exhibited the opposite outcome.

PTX3 regulates macrophage polarization during hepatic IRI, consequently influencing hepatocellular pyroptosis.

Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) is a cytosolic pattern recognition receptor that recognizes multiple pathogen-associated molecular patterns and damage-associated molecular patterns. It is a cytoplasmic immune factor that responds to cellular stress signals, and it is usually activated after infection or inflammation, forming an NLRP3 inflammasome to protect the body. Aberrant NLRP3 inflammasome activation is reportedly associated with some inflammatory diseases and metabolic diseases. Recently, there have been mounting indications that NLRP3 inflammasomes play an important role in liver injuries caused by a variety of diseases, specifically hepatic ischemia/reperfusion injury, hepatitis, and liver failure. Herein, we summarize new research pertaining to NLRP3 inflammasomes in hepatic injury, hepatitis, and liver failure. The review addresses the potential mechanisms of action of the NLRP3 inflammasome, and its regulation in these liver diseases.

Acute liver failure (ALF) is a devastating liver disease characterized by the rapid deterioration of hepatocytes, which causes a series of clinical complications, including hepatic dysfunction, coagulopathy, encephalopathy, and multiorgan failure. Cell-based therapy is a promising alternative as it can bridge patients until their livers regenerate, releasing immunomodulatory molecules to suppress inflammation. This study reports an iPSCs-derived long-term expanded hepatic progenitor cell (LTHepPCs), which can differentiate into hepatocyte-like cells (HLCs) in vivo. When introduced into drug-induced ALF models, LTHepPCs mitigate liver damage by modulating the local immune microenvironment. This is achieved by shifting macrophages/Kupffer cells towards an anti-inflammatory state, resulting in a decrease in the expression of inflammatory cytokines such as TNF-a, IL-1β, and IL-8, and an increase in the expression of anti-inflammatory cytokines such as IL-10 and ARG-1. In vitro co-culturing of THP-1 or mBMDMs with LTHepPCs suggested that LTHepPCs could activate the anti-inflammatory state of macrophages/Kupffer cells via the IL-10/JAK2/STAT3 signaling pathway. Therefore, LTHepPC transplantation is a promising therapy for ALF patients.

Hepatic ischemia and reperfusion (I/R) injury is a common problem faced by patients undergoing clinical liver transplantation and hepatectomy, but the specific mechanism of liver I/R injury has not been fully elucidated. The protein degradation complex 11S proteasome is involved in apoptosis, proliferation and cell cycle regulation by regulating the 11S proteasome regulatory complex (REG)γ. The main objective of this study is to explore the role and specific mechanism of REGγ in liver I/R.

By constructing a model of in vivo hepatic I/R injury in mice and a model of hypoxia and reoxygenation (H/R) in isolated hepatocytes. First, the REGγ expression were detected during hepatic I/R in mice. Second, to investigate the effects of REGγ knockout (KO) on liver necrosis, inflammatory response, apoptosis and mitochondrial function. Finally, mouse liver Src homology collagen (p66shc) mitochondrial translocation was detected.

The expression of REGγ was up-regulated during hepatic I/R. REGγ KO had significantly reduced liver tissue infarct size, liver transaminases, inflammatory cells infiltration, inflammatory cytokine and activation of nuclear factor kappa-B (NF-κB) signaling pathway and cell apoptosis. REGγ KO had significantly alleviated the mitochondrial damage, decreased the up-regulated level of cytochrome C, reactive oxygen species (ROS). REGγ KO had significantly reduced p66shc mitochondrial translocation in mice.

The experimental results of this study indicated that REGγ has an important role in preventing liver I/R injury and may play a role through the mitochondrial p66shc signaling pathway.

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.

Hepatic ischemia-reperfusion (IR) injury is a major complication of liver transplantation and gravely affects patient prognosis. Icaritin (ICT), the primary plasma metabolite of icariin (ICA), plays a critical role in anti-inflammatory and immunomodulatory processes. However, the role of ICT in hepatic IR injury remains largely undefined. In this study, we aimed to elucidate the role of ICT in hepatic IR injury.

We established hepatic IR injury models in animals, as well as an oxygen-glucose deprivation/reperfusion (OGD/R) cell model. Liver injury in vivo was assessed by measuring serum alanine aminotransferase (ALT) levels, necrotic areas by liver histology and local hepatic inflammatory responses. For in vitro analyses, we implemented flow-cytometric and western blot analyses, transmission electron microscopy, and an mRFP-GFP-LC3 adenovirus reporter assay to assess the effects of ICT on OGD/R injury in AML12 and THLE-2 cell lines. Signaling pathways were explored in vitro and in vivo to identify possible mechanisms underlying ICT action in hepatic IR injury.

Compared to the mouse model group, ICT preconditioning considerably protected the liver against IR stress, and diminished the levels of necrosis/apoptosis and inflammation-related cytokines. In additional studies, ICT treatment dramatically boosted the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR proteins in hepatic cells following OGD/R damage. We also applied LY294002 (a PI3K inhibitor) and RAPA (rapamycin, an mTOR inhibitor), which blocked the protective effects of ICT in hepatocytes subjected to OGD/R.

This study indicates that ICT attenuates ischemia-reperfusion injury by exerting anti-inflammation, anti-oxidative stress, and anti-autophagy effects, as demonstrated in mouse livers. We thus posit that ICT could have therapeutic potential for the treatment of hepatic IR injury.

Hepatic ischemia reperfusion injury (IRI) is a common liver surgery complication. This study aims to explore the effect and potential mechanism of Sunitinib - a multi-target tyrosine kinase inhibitor - on hepatic IRI.

We established a hepatic IRI model using C57BL/6 mice, and integrated 40 mg/kg of Sunitinib, solely or combined with 100 μg/kg of coumermycin A1 (C-A1), in the treatment strategy. H&E staining, TUNEL assay, and detection of serum ALT and AST activities were used to assess liver damage. Further, ELISA kits and Western Blots were utilized to determine IL-1β, TNF-α, IL-6, CXCL10, and CXCL2 levels. Primary macrophages, once isolated, were cultured in vitro with either 2 nM of Sunitinib, or Sunitinib in conjunction with 1 μM of C-A1, to gauge their influence on macrophage polarization. qPCR and Western blot were conducted to examine the level of p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2, and M1/M2 polarization markers. To quantify immune cell infiltration, we applied Immunofluorescence.

Sunitinib pretreatment significantly alleviated liver injury and reduced p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2 levels. In vitro, Sunitinib treatment curbed M1 polarization induced by LPS + IFN-γ and bolstered M2 polarization triggered by IL-4. C-A1 application upregulated JAK2/STAT pathway phosphorylation and promoted LPS + IFN-γ-induced M1 polarization, which was reversed by Sunitinib treatment. In IL-4-stimulated macrophages, application of C-A1 activated the JAK2/STAT pathway and decreased M2-type macrophages, which was reversed by Sunitinib treatment either.

Sunitinib is capable of guiding the polarization of macrophages toward an M2-type phenotype via the inhibition of the JAK2/STAT pathway, thereby exerting a protective effect on hepatic IRI.

Ischemia-reperfusion injury (IRI) poses a significant challenge to liver transplantation (LT). The underlying mechanism primarily involves overactivation of the immune system. Heat shock protein 110 (HSP110) functions as a molecular chaperone that helps stabilize protein structures.

An IRI model was established by performing LT on Sprague-Dawley rats, and HSP110 was silenced using siRNA. Hematoxylin-eosin staining, TUNEL, immunohistochemistry, ELISA and liver enzyme analysis were performed to assess IRI following LT. Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular changes.

Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT (P < 0.05). However, when rats were injected with siRNA-HSP110, IRI subsequent to LT was notably reduced (P < 0.05). Additionally, the levels of liver enzymes and inflammatory chemokines in rat serum were significantly reduced (P < 0.05). Silencing HSP110 with siRNA resulted in a marked decrease in M1-type polarization of Kupffer cells in the liver and downregulated the NF-κB pathway in the liver (P < 0.05).

HSP110 in the liver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer cells. Targeting HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

Piperine, the major active substance in black pepper, has been shown to have anti-inflammatory and antioxidant effects in several ischemic diseases. However, the role of piperine in hepatic ischemia/reperfusion injury (HIRI) and its underlying mechanisms remain unclear. In this study, the mice were administered piperine (30 mg/kg) intragastric administration before surgery. After 24 h of hepatic ischemia-reperfusion, liver histopathological evaluation, serum transaminase measurements, and TUNEL analysis were performed. The infiltration of inflammatory cells and production of inflammatory mediators in the liver tissue were determined by immunofluorescence and immunohistochemical staining. The protein levels of toll-like receptor 4 (TLR4) and related proteins such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin-1 receptor-associated kinase 1 (IRAK1), p65, and p38 were detected by western blotting. The results showed that plasma aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte apoptosis, oxidative stress, and inflammatory cell infiltration significantly increased in HIRI mice. Piperine pretreatment notably repaired liver function, improved the histopathology and apoptosis of liver cells, alleviated oxidative stress injury, and reduced inflammatory cell infiltration. Further analysis showed that piperine attenuated tumor necrosis factor-a (TNF-α) and interleukin 6 (IL-6) production and reduced TLR4 activation and phosphorylation of IRAK1, p38, and NF-κB in HIRI. Piperine has a protective effect against HIRI through the TLR4/IRAK1/NF-κB signaling pathway and may be a safer option for future clinical treatment and prevention of ischemia-related diseases.

Ischemia-reperfusion (I/R) injury, resulting from blood flow interruption and its subsequent restoration, is a prevalent complication in liver surgery. The liver, as a crucial organ for carbohydrate and lipid metabolism, exhibits decreased tolerance to hepatic I/R in patients with diabetes mellitus (DM), resulting in a significant increase in hepatic dysfunction following surgery. This may be attributed to elevated oxidative stress and inflammation. Our prior research established sinomenine's (SIN) protective role against hepatic I/R injury. Nevertheless, the impact of SIN on hepatic I/R injury in DM rats remains unexplored.

This study aimed to investigate the therapeutic potential of SIN in hepatic I/R injury in DM rats and elucidate its mechanism. Diabetic and hepatic I/R injury models were established in rats through high-fat/sugar diet, streptozotocin injection, and hepatic blood flow occlusion. Liver function, oxidative stress, inflammatory reaction, histopathology, and Nrf-2/HO-1 signaling pathway were evaluated by using UV spectrophotometry, biochemical assays, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Western blot analysis.

High-dose SIN (300 mg/kg) significantly attenuated hepatic I/R injury in DM rats, reducing serum activities of ALT and AST, decreasing the AST/ALT ratio, enhancing tissue contents of SOD and GSH-Px, suppressing the levels of TNF-α and IL-6, improving the liver histopathology, and activating Nrf-2/HO-1 signaling by promoting Nrf-2 trans-location from cytoplasm to nucleus. Low-dose SIN (100 mg/kg) was ineffective.

This study demonstrates that high-dose sinomenine's mitigates hepatic I/R-induced inflammation and oxidative stress in diabetes mellitus (DM) rats via Nrf-2/HO-1 activation, suggesting its potential as a preventive strategy for hepatic I/R injury in DM patients.

Ischemia-reperfusion injury (IRI) remains an unavoidable challenge in liver surgery, with macrophages playing a critical role in its pathogenesis. However, the mechanisms by which macrophages regulate the pathogenesis of IRI are not well understood. Through a target-guided screening approach, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected mice against liver IRI by promoting M2 macrophage polarization, and this protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages from the SjDX5-271 treatment group. We further identified that SjDX5-271 promoted M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and alleviated hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibited some promising therapeutic effects in IRI and represented a novel therapeutic approach, potentially applicable to other immune-related diseases. The current study demonstrates the potential of new biologics from the parasite, enhances our understanding of host-parasite interplay, and provides a blueprint for future therapies for immune-related diseases.

Background and Objectives: The aim of this study is to evaluate the clinical and laboratory changes of ischemia and reperfusion injury in the remnant livers of donors with and without Pringle maneuver. Furthermore, we evaluated the recipients who have been transplanted with liver grafts from these donors. Methods and Materials: A total of 108 patients (54 living liver donors and 54 liver recipients) who underwent donor hepatectomy and recipients who living donor liver transplantation, were included in this randomized double-blind study between February 2021 and June 2021. The donors were divided into two groups: Pringle maneuver applied (n = 27) and Pringle maneuver not applied (n = 27). Similarly, recipients with implanted liver obtained from these donors were divided into two groups as the Pringle maneuver was performed (n = 27) and not performed (n = 27). Blood samples from donors and recipients were obtained on pre-operative, post-operative 0 h day (day of surgery), post-operative 1st day, post-operative 2nd day, post-operative 3rd day, post-operative 4th day, post-operative 5th day, and liver tissue was taken from the graft during the back table procedures. Liver function tests and complete blood count, coagulation tests, IL-1, IL-2, IL-6, TNF-α, and β-galactosidase measurements, and histopathological findings were examined. Results: There was no statistically significant difference in the parameters of biochemical analyses for ischemia-reperfusion injury at all periods in the donors with and without the Pringle maneuver. Similarly, there was no statistically significant difference between in the recipients in who received liver grafts harvested with and without the Pringle maneuver. There was no statistically significant difference between the two recipient groups in terms of perioperative bleeding and early bile duct complications (p = 0.685). In the histopathological examinations, hepatocyte damage was significantly higher in the Pringle maneuver group (p = 0.001). Conclusions: Although the histological scoring of hepatocyte damage was found to be higher in the Pringle maneuver group, the Pringle maneuver did not augment ischemia-reperfusion injury in donors and recipients that was evaluated by clinical and laboratory analyses.

Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI).

The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes.

Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues.

Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

In bone tissue engineering, the bone immunomodulatory properties of biomaterials are critical for bone regeneration, which is a synergistic process involving physiological activities like immune response, osteogenesis, and angiogenesis. The effect of the macrophage immune microenvironment on the osteogenesis and angiogenesis of various material extracts was examined in this experiment using Mg2+and Nano-hydroxyapatite/collagen (nHAC) in both a single application and a combined form. This studyin vitrorevealed that the two compounds combined significantly inhibited the NF-κB signaling pathway and reduced the release of inflammatory factors from macrophages when compared with the extraction phase alone. Additionally, by contributing to the polarization of macrophages towards the M2 type, the combined effects of the two materials can significantly improve osteogenesis/angiogenesis. The results ofin vivoexperiments confirmed that Mg2+/nHAC significantly promoted bone regeneration and angiogenesis. This study offers a promising method for enhancing bone graft material osseointegration.

Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.

Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.

Sepsis-associated liver dysfunction (SALD) aggravates the disease progression and prognosis of patients. Macrophages in the liver play a crucial role in the occurrence and development of SALD. Human umbilical cord mesenchymal stem cells (MSCs), by secreting extracellular vesicles (EVs), show beneficial effects in various inflammatory diseases. However, whether MSC-derived EVs (MSC-EVs) could ameliorate the inflammatory response in liver macrophages and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis induced by lipopolysaccharide (LPS) challenge was used to investigate the immunomodulatory functions of MSC-EVs in SALD. LPS-stimulated primary Kupffer cells (KCs) and Raw264.7 were used to further explore the potential mechanisms of MSC-EVs in regulating the inflammatory response of macrophages. The results showed that MSC-EVs alleviated liver tissue injury and facilitated the polarization of M1 to M2 macrophages. Further in vitro studies confirmed that MSC-EVs treatment significantly downregulated the expression of several enzymes related to glycolysis and reduced the glycolytic flux by inhibiting hypoxia-inducible factor 1α (HIF-1α) expression, thus effectively inhibiting the inflammatory responses of macrophages. These findings reveal that the application of MSC-EVs might be a potential therapeutic strategy for treating SALD.

Hepatic ischemia-reperfusion injury (HIRI) often occurs in liver surgery, such as partial hepatectomy and liver transplantation, in which myeloid macrophage-mediated inflammation plays a critical role. Cell division cycle 42 (Cdc42) regulates cell migration, cytoskeleton rearrangement, and cell polarity. In this study, we explore the role of myeloid Cdc42 in HIRI.

Mouse HIRI models were established with 1-hour ischemia followed by 12-hour reperfusion in myeloid Cdc42 knockout (Cdc42mye) and Cdc42flox mice. Myeloid-derived macrophages were traced with RosamTmG fluorescent reporter under LyzCre-mediated excision. The experiments for serum or hepatic enzymic activities, histologic and immunologic analysis, gene expressions, flow cytometry analysis, and cytokine antibody array were performed.

Myeloid deletion of Cdc42 significantly alleviated hepatic damages with the reduction of hepatic necrosis and inflammation, and reserved hepatic functions following HIRI in mice. Myeloid Cdc42 deficiency suppressed the infiltration of myeloid macrophages, reduced the secretion of proinflammatory cytokines, restrained M1 polarization, and promoted M2 polarization of myeloid macrophages in livers. In addition, inactivation of Cdc42 promoted M2 polarization via suppressing the phosphorylation of STAT1 and promoting phosphorylation of STAT3 and STAT6 in myeloid macrophages. Furthermore, pretreatment with Cdc42 inhibitor, ML141, also protected mice from hepatic ischemia-reperfusion injury.

Inhibition or deletion of myeloid Cdc42 protects liver from HIRI via restraining the infiltration of myeloid macrophages, suppressing proinflammatory response, and promoting M2 polarization in macrophages.

Liver ischemia/reperfusion (I/R) injury commonly occurs after various liver surgeries. Adelmidrol, an N- palmitoylethanolamide analog, has anti-inflammatory, anti-oxidant, and anti-injury properties. To investigate whether adelmidrol could reduce liver I/R injury, we established a mouse of liver I/R injury and an AML12 cell hypoxia-reoxygenation model to perform experiments using multiple indicators. Serum ALT and AST levels, and H&E staining were used to measure liver damage; MDA content, superoxide dismutase and glutathione activities, and dihydroethidium staining were used to measure oxidative stress; mRNA expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, MCP-1, and Ly6G staining were used to measure inflammatory response; and protein expression of Bax, Bcl-2, C-caspase3, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining were used to measure apoptosis. The experimental results showed that adelmidrol reduced liver I/R injury. In addition, adelmidrol pretreatment elevated AML12 cell activity and reduced I/R-and H/R-induced apoptosis, inflammatory injury, and oxidative stress. ML385, an inhibitor of nuclear factor erythroid2-related factor 2 (Nrf2), reverses liver I/R injury attenuated by adelmidrol. These results suggest that adelmidrol ameliorates liver I/R injury by activating the Nrf2 signaling pathway.

Polydatin, a glucoside of resveratrol, has shown protective effects against various diseases. However, little is known about its effect on hepatic ischemia-reperfusion (I/R) injury. This study aimed to elucidate whether polydatin protects liver against I/R-induced injury and to explore the underlying mechanism.

After gavage feeding polydatin once daily for a week, mice underwent a partial hepatic I/R procedure. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hematoxylin-eosin (H&E) and TdT-mediated dUTP nick-end labeling (TUNEL) staining were used to evaluate liver injury. The severity related to the inflammatory response and reactive oxygen species (ROS) production was also investigated. Furthermore, immunofluorescence and Western blotting were used to detect macrophage polarization and the NF-κB signaling pathway in macrophages.

Compared with the I/R group, polydatin pretreatment significantly attenuated I/R-induced liver damage and apoptosis. The oxidative stress marker (dihydroethidium fluorescence, malondialdehyde, superoxide dismutase and glutathione peroxidase) and I/R related inflammatory cytokines (interleukin-1β, interleukin-10 and tumor necrosis factor-α) were significantly suppressed after polydatin treatment. In addition, the result of immunofluorescence indicated that polydatin reduced the polarization of macrophages toward M1 macrophages both in vivo and in vitro. Western blotting showed that polydatin inhibited the pro-inflammatory function of RAW264.7 via down-regulating the NF-κB signaling pathway.

Polydatin protects the liver from I/R injury by remodeling macrophage polarization via NF-κB signaling.

Ischemia/reperfusion injury (IRI) is generally unavoidable following liver transplantation. Here, we investigated the role of protein phosphatase, Mg2+ /Mn2+ dependent 1G (PPM1G) in hepatic IRI.

Hepatic IRI was mimicked by employing a hypoxia/reperfusion (H/R) model in RAW 264.7 cells and a 70% warm ischemia model in C57BL/6 mice, respectively. In vitro, expression changes of tumor necrosis factor-α and interleukin were detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The protein expressions of PPM1G and the stimulator of interferon genes (STING) pathway components were analyzed by western blot. Interaction between PPM1G and STING was verified by coimmunoprecipitation (CO-IP). Immunofluorescence was applied for detection of p-IRF3. Flow cytometry, qRT-PCR and western blot were utilized to analyze markers of macrophage polarization. In vivo, histological analyses of mice liver were carried out by TUNEL and H&E staining. Changes in serum aminotransferases were also detected.

Following H/R intervention, a steady decline in PPM1G along with an increase in inflammatory cytokines in vitro was observed. Addition of plasmid with PPM1G sequence limited the release of inflammatory cytokines and downregulated phosphorylation of STING. CO-IP validated the interaction between PPM1G and STING. Furthermore, inhibition of PPM1G with lentivirus enhanced phosphorylation of STING and its downstream components; meanwhile, p65, p38, and Jnk were also surged to phosphorylation. Expression of INOS and CD86 was surged, while CD206, Arg-1, and IL-10 were inhibited. In vivo, PPM1G inhibition further promoted liver damage, hepatocyte apoptosis, and transaminases release. Selective inhibition of STING with C-176 partially reversed the activation of STING pathway and inflammatory cytokines in vitro. M1 markers were also suppressed by C-176. In vivo, C-176 rescued liver damage and transaminase release caused by PPM1G inhibition.

PPM1G suppresses hepatic IRI and macrophage M1 phenotype by repressing STING-mediated inflammatory pathways.

Hepatic ischemia and reperfusion (I/R) injury is of common occurrence during liver surgery and transplantation, isosteviol (ISV) is an acid hydrolysate of stevioside, the major component of Stevia rebaudiana. Stevioside and its metabolites have been shown to have varieties of pharmacological activities, However, the effect of ISV on hepatic I/R injury has not determined. The purpose of this paper is to study the effect of ISV on mice with hepatic I/R injury and further investigate its underlying mechanism.

The blood vessels supplying the left/middle lobe of the liver in mice were clamped to cause liver ischemia for 1h, and then removed the clamp to conduct reperfusion for 6 h. ISV or saline was injected intraperitoneally after reperfusion. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 in serum and tissues were evaluated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The infiltration of neutrophils and macrophages into the liver tissue was determined by flow cytometry and myeloperoxidase. Liver hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) and Annexin V probe were used to determine liver injury and hepatocyte apoptosis. western blots (WB) was used to investigate the activation of nuclear factor kappa-B (NF-κB) and c-JunNH2 terminal kinase (JNK), p38 and extracellular regulated protein kinase (ERK), while the expression of apoptosis-related proteins B-cell lymphoma-2 (BCL-2), BCL2-associated X protein (BAX), caspase-3 was detected.

ISV reduced aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to alleviate liver injury. ISV significantly reduced the release of inflammatory cytokines and the accumulation of liver neutrophils and macrophages. Meanwhile, ISV can promote the expression of anti-apoptosis-related protein BCL-2 and inhibit the expression of pro-apoptotic protein BAX and the activation of the protease caspase-3, and reduce the occurrence of hepatocyte apoptosis. Finally, ISV can reduce the phosphorylation level and activation of NF-κB, JNK, p38 and ERK.

ISV inhibits the occurrence of inflammation and hepatocyte apoptosis through mitogen-activated protein kinase (MAPK)/NF-κB signaling pathway to relieve liver injury.

Liver ischemia and reperfusion injury (LIRI) is a major risk for the poor prognosis of patients receiving liver transplantation. The molecular mechanism involved in LIRI is complex and related to various cellular components. We previously reported that adenosine deaminase acting on RNA 1 (ADAR1) alleviated the allogeneic skin graft rejection by regulating macrophage polarization. However, the regulatory effects of ADAR1 on liver macrophages after LIRI remain largely unknown. In this study, we mainly adopted a mouse model of LIRI and cellular experiments with hypoxia and reoxygenation (HR) treatment to explore the regulatory roles of ADAR1 on liver macrophages under LIRI conditions. We found that IRI caused decreased ADAR1 in liver tissues and remarkable changes of liver macrophage polarization and profiles. ADAR1 supplementation alleviated the pathological injury caused by IRI and accelerated the activation of M2 macrophages in the liver of IRI mice. Increased hypoxia duration reduced ADAR1 expression levels in murine RAW264.7 macrophages at the transcriptional level. Further overexpression of ADAR1 significantly increased the expressions of anti-inflammatory cytokines and promoted M2 polarization of macrophages under HR exposure. ADAR1 knockdown exhibited opposite effects on macrophage polarization. Hence, ADAR1 promotes the M2 polarization of liver macrophages that may further alleviate LIRI. The protective effects of ADAR1 against LIRI provide a novel insight into the prevention and treatment of LIRI.

Macrophages present strong immunomodulatory ability and are considered to be core immune cells in the process of hepatic ischaemia‒reperfusion (I/R). The NLRP3 inflammasome is a kind of intracellular multimolecular complex that actively participates in innate immune responses and proinflammatory signalling pathways. Piceatannol (PIC) is a derivative of the natural phenolic compound resveratrol and has antioxidant and anti-inflammatory effects. The purpose of this study was to examine whether pretreatment with PIC can alleviate hepatic I/R injury by targeting NLRP3 inflammasome-induced macrophage pyroptosis.

PIC-pretreated primary hepatic macrophages were subjected to hypoxia/reoxygenation, and liver ischaemia/reperfusion was performed in mice.

PIC pretreatment ameliorated histopathological changes, oxidative stress and inflammation while enhancing antioxidant and anti-inflammasome markers through downregulation of Toll-like receptor 4 (TLR4), p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, caspase-1 (p20), IL-1β, IL-18 and GSDMD-N expression during liver ischaemia‒reperfusion. Moreover, PIC inhibited the translocation of NF-κB p65 after stimulation with hypoxia/reoxygenation in primary hepatic macrophages.

The results indicated that PIC protected the liver against hepatic I/R injury, which was mediated by targeting TLR4-NF-κB-NLRP3-mediated hepatic macrophage pyroptosis.

Eucommia ulmoides (EU) and its diverse extracts have demonstrated antioxidative, anti-inflammatory, and cytoprotective properties against hepatic ischemia-reperfusion injury (HIRI). However, the primary constituents of EU and their putative mechanisms remain elusive. This study aims to explore the potential mechanisms of EU in the prevention and treatment of HIRI by employing network pharmacology and molecular docking methodologies. The main components and corresponding protein targets of EU were searched in the literature and TCMSP, and the compound target network was constructed by Cytoscape 3.9.1. Liver ischemia-reperfusion injury targets were searched in OMIM and GeneCards databases. The intersection points of compound targets and disease targets were obtained, and the overlapping targets were imported into the STRING database to construct the PPI network. We further analyzed the targets for GO and KEGG enrichment. Finally, molecular docking studies were performed on the core targets and active compounds. The component-target network unveiled a total of 26 efficacious bioactive compounds corresponding to 207 target proteins. Notably, the top-ranking compounds based on degree centrality were quercetin, β-sitosterol, and gallic acid. Within the PPI network, the highest degree centrality encompassed RELA, AKT1, TP53. GO and KEGG enrichment analysis elucidated that EU in HIRI primarily engaged in positive regulation of gene expression, positive transcriptional regulation via RNA polymerase II promoter, negative modulation of apoptotic processes, positive regulation of transcription from DNA templates, and drug responsiveness, among other biological processes. Key pathways included cancer pathways, RAGE signaling pathway, lipid metabolism, atherosclerosis, TNF signaling pathway, PI3K-Akt signaling pathway, and apoptotic pathways. Molecular docking analysis revealed robust affinities between quercetin, β-sitosterol, gallic acid, and RELA, AKT1, TP53, respectively. This study reveals EU exhibits substantial potential in mitigating and treating HIRI through multifaceted targeting and involvement in intricate signaling pathways.

Colorectal cancer (CRC) is a growing concern due to its high morbidity and mortality, and the search for effective and less toxic active substances against inflammatory bowel diseases has been a hot topic in the research and development of drugs against CRC. It is reported that monotropein isolated from the roots of Morinda officinalis, can improve Dextran Sodium Sulfate (DSS)-induced ulcerative colitis in mice, but its therapeutic effects and mechanisms for CRC treatment are still to be investigated. In the present study, we first used molecular docking, BLI, CESTA, and DARTS methods to detest whether monotropein targets VDR proteins. In addition, we used tumor cell conditioned co-culture and four models of macrophage polarisation to investigate the regulation of four macrophage polarisations by monotropein using RT-PCR, IF and western blot. Furthermore, we further validated the target of action of monotropein for the treatment of Azoxymethane (AOM)/DSS induced colitis associated cancer (CAC) using knockout animals. Meanwhile, we further explored the mechanism of action of monotropein in regulating polarisation by detecting JAK/STAT1-related genes and proteins. Molecular docking and biofilm interference techniques showed that monotropein bound to the VDR, and additional results from CESTA and DARTS suggested that VDR proteins are targets of monotropein. Furthermore, in tumor cell conditioned co-cultures or LPS + IFN-γ induced RAW264.7 cells, VDR translocation to the nucleus was reduced, JAK1/STAT1 signaling pathway proteins were up-regulated, and macrophages were polarised towards the M1-type after monotropein intervention. Animal models in which normal VDR or myeloid VDR was knocked out confirmed that JAK1 levels in intestinal tissues were increased after monotropein intervention, macrophages were polarised towards the M1 type, and CAC paracarcinomas were ameliorated. Taken together, the present study concluded that monotropein inhibited colitis-associated cancers through macrophage polarisation regulated by VDR/JAK1/STAT1.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.

Poor neurodevelopmental outcomes after pediatric liver transplantation seriously affect the long-term quality of life of recipients, in whom hepatic ischemia reperfusion (HIR) is considered to play a pivotal role. However, the link between HIR and brain injury remains unclear. Because circulating exosomes are considered as the key mediators of information transmission over long distances, we aimed to assess the role of circulating exosomes in HIR-induced hippocampal injury in young rats.

We administered exosomes extracted from the sera of HIR model rats to normal young rats via the tail vein. Western blotting, enzyme-linked immunosorbent assay, histological examination, and real-time quantitative polymerase chain reaction were used to evaluate the role of exosomes in neuronal injury and activation of microglial pyroptosis in the developing hippocampus. Primary microglial cells were cocultured with exosomes to further assess the effect of exosomes on microglia. To further explore the potential mechanism, GW4869 or MCC950 was used to block exosome biogenesis or nod-like receptor family protein 3, respectively.

Serum-derived exosomes played a crucial role in linking HIR with neuronal degeneration in the developing hippocampus. Microglia were found to be the target cells of ischemia-reperfusion derived exosomes (I/R-exosomes). I/R-exosomes were taken up by microglia and promoted the occurrence of microglial pyroptosis in vivo and in vitro. Moreover, the exosome-induced neuronal injury was alleviated by suppressing the occurrence of pyroptosis in the developing hippocampus.

Microglial pyroptosis induced by circulating exosomes plays a vital role in developing hippocampal neuron injury during HIR in young rats.

Hepatic ischemia reperfusion injury (IRI) is a risk factor for early graft nonfunction and graft rejection after liver transplantation (LT). The process of liver IRI involves inflammatory response, oxidative stress, apoptosis and other pathophysiological processes. So far, there is still a lack of effective drugs to ameliorate liver IRI. Trans-anethole (TA) is an aromatic compound. Many medications as well as natural foods contain TA. TA has multiple effects such as anti-inflammation, anti-oxidative stress and anti-apoptosis. However, the mechanism of TA pretreatment in liver IRI is unclear. The mice hepatic IRI model was constructed after gavage pretreatment with TA (10 mg/kg, 20 mg/kg, 40 mg/kg) for 7 consecutive days. Our study confirmed that TA pretreatment significantly improve liver function and reduce serum AST, ALT in hepatic IRI. HE staining showed that TA pretreatment alleviated liver injury. Meanwhile, TA (20 mg/kg) pretreatment attenuated hepatocyte apoptosis in hepatic IRI. In addition, TA (20 mg/kg) pretreatment reduced the inflammatory factors TNF-α, IL-6 and infiltration of CD11b positive cells in liver tissues during hepatic IRI in mice. TA pretreatment also alleviated oxidative stress in mice hepatic IRI. Our study further indicated that TA pretreatment attenuated mice hepatic IRI through inhibiting NLRP3 inflammasome activation via regulation of soluble epoxide hydrolase (sEH). This study provides a novel and effective potential drug with few side effects for easing liver IRI.

Hepatic ischemia-reperfusion injury (HIRI) is a complex pathological phenomenon dominated by the innate immune system and involves a variety of immune cells. This condition frequently occurs during hepatectomy, liver transplantation or hemorrhagic shock. HIRI represents an important factor in the poor prognosis of patients after liver surgery. However, there is still a lack of effective intervention to reduce the incidence of HIRI. In this study, we aimed to describe the overall structure of scientific research on HIRI over the past 20 years and provide valuable information and guidelines for future researchers. Bibliometric analysis was used to comprehensively review developments in HIRI and changes in our understanding of HIRI over the past two decades. We identified a total of 4267 articles on HIRI that were published over the past 20 years of which basic research was predominant. Collaboration network analysis revealed that China, the University of California Los Angeles, and Ronald W Busuttil were the most influential country, institute, and scholar, respectively. Co-occurrence cluster analysis revealed that ischemic preconditioning, liver cirrhosis, hepatic I/R injury, autophagy, acute liver failure, oxygen, donation after circulatory death, Nlrp3, remote organ, and microdialysis were the top 10 clusters. Keyword burst detection indicated that autophagy, inflammation, and early allograft dysfunction represent the current research hotspots. In summary, this is the first bibliometric analysis of HIRI research. Our timely analysis of these hotpots and research trends may provide a framework for future researchers and further promote research on the key mechanisms and therapeutic measures in this field.