• No. 2025KY111 the Zhejiang Provincial Medical and Health Technology Project
• No.92159202 the Major Research Plan of the National Natural Science Foundation of China
• No.2021YFA1100504 the National Key Research and Development Program of China

• Ischemia/reperfusion injury
• Ischemic preconditioning
• MicroRNAs

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Reperfusion Injury/genetics
• Ischemic Preconditioning
• Animals
• Oxidative Stress

• 4020122 Yasuj University of Medical Sciences

• Apoptosis
• Hepatic ischemia reperfusion injury (HIRI)
• Nuclear transfer factor-κB (NF-κB)
• Oxidative stress
• Targeted therapy

• Reperfusion Injury/metabolism
• Reperfusion Injury/drug therapy
• Humans
• NF-kappa B/metabolism
• Signal Transduction/drug effects
• Signal Transduction/physiology
• Animals
• Liver/metabolism
• Liver/pathology
• Liver/drug effects
• Oxidative Stress/drug effects
• Oxidative Stress/physiology
• Molecular Targeted Therapy

• Circular RNAs
• Hepatic ischemia-reperfusion injury
• Long non-coding RNAs
• MicroRNAs
• Non-coding RNAs

• Animals
• Humans
• RNA, Untranslated/genetics
• MicroRNAs/genetics
• Biomarkers
• Reperfusion Injury/genetics
• Liver

• blood-brain barrier
• exosomes
• ischemia/reperfusion
• mir-370-3p
• stroke

• Animals
• Rats
• Apoptosis
• Blood-Brain Barrier/metabolism
• Brain/metabolism
• Brain Ischemia/genetics
• Brain Ischemia/metabolism
• Infarction, Middle Cerebral Artery/genetics
• Ischemic Stroke/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Reperfusion
• Reperfusion Injury/genetics
• Reperfusion Injury/metabolism
• Stroke/genetics
• Stroke/metabolism

• Hepatic ischemia-reperfusion injury
• Research progress
• lncRNA
• miRNA
• ncRNA

• ischaemia-reperfusion
• liver
• liver surgery

• Animals
• Reperfusion Injury/metabolism
• Liver/metabolism
• Liver Transplantation/adverse effects
• Adaptive Immunity
• Shock, Hemorrhagic

Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome.

• CYLD
• NF-κB
• extracellular vesicles
• fibroblasts
• highly metastatic breast cancer cells
• miR-370-3p

Nuclear receptor subfamily 4, group A, member 1 (NR4A1) can aggravate ischaemia‐reperfusion (I/R) injury in the heart, kidney and brain. Thus, the present study aimed to unravel the role of NR4A1 on hepatic I/R injury. For this purpose, the mouse hepatic I/R model and H/R‐exposed mouse hepatocytes model were established to stimulate the hepatic and hepatocellular damage. Then, the levels of ALT and AST as well as TNF‐α and IL‐1β expression were measured in the mouse serum and supernatant of hepatocyte s, respectively. Thereafter, we quantified the levels of NR4A1, CYR61, NF‐kB p65 and TGFβ1 under pathological conditions, and their interactions were analysed using ChIP and dual‐luciferase reporter gene assays. The in vivo and in vitro effects of NR4A1, CYR61, NF‐kB p65 and TGFβ1 on I/R‐induced hepatic and H/R‐induced hepatocellular damage were evaluated using gain‐ and loss‐of‐function approaches. NR4A1 was up‐regulated in the hepatic tissues of I/R‐operated mice and in H/R‐treated hepatocytes. Silencing NR4A1 relieved the I/R‐induced hepatic injury, as supported by suppression of ALT and AST as well as TNF‐α and IL‐1β. Meanwhile, NR4A1 knockdown attenuated the H/R‐induced hepatocellular damage by inhibiting the apoptosis of hepatocyte s. Moreover, we also found that NR4A1 up‐regulated the expression of CYR61 which resulted in the activation of the NF‐κB signalling pathway, thereby enhancing the transcription of TGFβ1, which was validated to be the mechanism underlying the contributory role of NR4A1 in hepatic I/R injury. Taken together, NR4A1 silencing reduced the expression of CYR61/NF‐κB/TGFβ1, thereby relieving the hepatic I/R injury.

• cysteine-rich angiogenic inducer 61
• group A
• hepatic injury
• ischaemia-reperfusion
• member 1
• nuclear receptor subfamily 4
• nuclear-factor kappa B
• transforming growth factor β1

• Ischemia reperfusion injury
• Kidney
• Liver
• Transplantation
• microRNAs

• Acute kidney injury
• Chinese traditional medicine
• HMGB1
• Sepsis
• lnc-MALAT1
• miR-370-3p

• MiR-370
• Nrf2/ARE signal pathway
• SIRT6
• cerebral ischemia reperfusion injury

• Circular RNA
• early allograft dysfunction (EAD)
• liver transplantation

• HMGB1
• NF-κB pathway
• liver ischemia/reperfusion injury
• microRNA-449b-5p

• JAK/STAT and NF-κB pathways
• XIST
• miR-370-3p
• pneumonia

• Acute Disease
• Adult
• Apoptosis/drug effects
• Cells, Cultured
• Female
• Humans
• Inflammation/chemically induced
• Inflammation/drug therapy
• Inflammation/metabolism
• Lipopolysaccharides/antagonists & inhibitors
• Lipopolysaccharides/pharmacology
• Male
• MicroRNAs/analysis
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/metabolism
• NF-kappa B/metabolism
• Pneumonia/diagnosis
• Pneumonia/drug therapy
• Pneumonia/metabolism
• RNA, Long Noncoding/biosynthesis
• RNA, Long Noncoding/genetics
• RNA, Small Interfering/pharmacology
• Signal Transduction/drug effects
• Toll-Like Receptor 4/analysis
• Toll-Like Receptor 4/antagonists & inhibitors
• Toll-Like Receptor 4/metabolism

• 2019HMKY15 HwaMei Hospital, University of Chinese Academy of Sciences

Hepatic ischemia/reperfusion (IR) injury is a critical contraindication of hepatobiliary surgery and results in severe liver damage. It is imperative to identify underlying pathophysiological mechanisms. In the current study, a rat model of liver IR was established to explore the mechanisms of sevoflurane during surgical intervention on IR. The detection of cytokines was performed using ELISA and reverse transcription-quantitative polymerase chain reaction and western blot assays were used to detect mRNA and protein expression levels, respectively. The target protein of microRNA (miR)-9-5p was identified by in vitro luciferase reporter assay. Cell apoptosis was detected by Annexin-V/propidium iodide and TUNEL staining assays. The results demonstrated that sevoflurane exerted protective effect against liver IR. Sevoflurane administration ameliorated a cytokine storm by decreasing serum levels of interleukin (IL)-1 and −6 and tumor necrosis factor (TNF)-α, and improved liver function was determined. IR-induced damage was mediated by an increase in transcription factor p65 expression and activation of the nuclear factor (NF)-κB signaling pathway, which were suppressed by sevoflurane treatment. In situ analysis predicted that NFKB3, encoding for p65, may be targeted by miR-9-5p and the hypothesis was verified by in vitro reporter assays using wild type and mutant sequences of the NFKB3 3′-untranslated region. Furthermore, pretreatment of hepatic tissue with a miR-9-5p mimic inhibited IR-associated injury as suggested by the decrease in the Suzuki score and decreased serum levels of TNF-α, IL-1 and IL-6. The results indicated that sevoflurane protected the liver from IR injury by increasing miR-9-5p expression and miR-9-5p may be a potential treatment target in IR.

• ischemia/reperfusion injury
• microRNA-9-5p
• nuclear factor-κB
• sevoflurane
• volatile anesthetic

A notable liver ischemia/reperfusion (I/R) injury is observed during liver transplantation, shock, trauma and other systemic diseases. The main aim of the present study was to evaluate the fact that HMGB1 acts as an early mediator of inflammation in hepatic injury and the potential of the miR-449b-5p mimic in the restoration of liver disorders. Herein, a miR-449b-5p-loaded spermidine/PLGA nanoparticle system was successfully formulated to improve the systemic delivery and performance of encapsulated miRNA. The major findings of the present study were as follows: (i) the HMGB1 levels were elevated upon the occurrence of I/R in vitro and in vivo; (ii) the inhibition of HMGB1 prevented the spread of inflammation; (iii) miR-449b-5p (PN-miR mimic) increased the cell viability of hepatic cells and decreased cell apoptosis; and (iv) the protective ability of the PN-miR mimic was attributed to the inhibition of the pNF-κB and p-p65 pathways. Compared to the case of the I/R group, the serum AST and ALT levels were significantly reduced in the group treated with miR-449b-5p (PN-miR mimic), indicating the extent of reduction in liver inflammation. The present study highlighted the importance of miR-449b-5p in the treatment of hepatic injury and could serve as a guide to effectively attenuate liver disorders. The application of the proposed nanoparticle system in the systemic delivery of miR-449b-5p further enhances the prospect of this treatment strategy.

The present study highlights the importance of miR-449b-5p in the inhibition of HMGB1 and thereby it's treatment potential in hepatic injury.

Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

• FAM3A
• LncRNA
• PPARγ
• liver ischemia-reperfusion injury
• miRNA