The p21+ perinecrotic hepatocytes produce the chemokine CXCL14 after a severe acetaminophen overdose promoting hepatocyte injury and delaying regeneration.

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.

Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.

Intravenous Acetaminophen Overdose in an Infant With Toxicokinetic Data.

CASE REPORT: A 12-month-old (former 24 week gestational age), 8.7 kg male was hospitalized after an uneventful colostomy reversal. In the postoperative unit, the patient unintentionally received 1000 mg IV (114.9 mg/kg) acetaminophen instead of the intended 100 mg IV. Serial acetaminophen concentrations were drawn. The patient received IV Nacetylcysteine and ultimately had no adverse outcomes. DISCUSSION: This case report adds to the existing literature regarding toxicokinetics of IV APAP in infants. Our patient had a calculated ke of 0.263 h-1, correlating with a half-life of 2.63 hours. Based on current available data, the half-life of IV APAP in infants varies (2.6 to 4.9 hours). The reason for this variation is unknown and further research is needed in this area.

Toxicology in the emergency department: what's new?

Intentional and accidental drug overdose, recreational drug use and exposure to toxic substances are common reasons for people presenting to emergency departments. Although the mortality rate associated with these presentations is low in the UK, they can lead to significant morbidity and prolonged hospital admissions. This review discusses new developments in the management of paracetamol overdose. Several new protocols for the infusion of acetylcysteine, the antidote for paracetamol overdose, have been proposed in the past decade and evaluated in clinical studies. The 12-hour Scottish and Newcastle Acetylcysteine Protocol regimen and 20-hour Australian two-infusion bag protocol have been widely adopted into clinical practice and endorsed in national guidelines because of their shorter duration, reduction in adverse effects and efficacy in treating overdose. This article includes a care pathway that can facilitate the implementation of the Scottish and Newcastle Acetylcysteine Protocol. This article also discusses the emergency management of ingested button batteries, describes the emerging threat of novel psychoactive substances, and provides an update on new UK antidote guidelines. Further up-to-date guidance on management of clinical toxicology is available to healthcare professionals on the internet database TOXBASE.

Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options.

Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.

Ameliorative effect of Spatoglossum asperum and its solvent fractions against acetaminophen-induced liver dysfunction in rats.

Acetaminophen (APAP) is a widely consumed drug for pain management and treatment of pyrexia. However, beyond its recommended dose, it becomes harmful for health and may induce acute liver dysfunction. Current work is designed to ameliorate the APAP induced liver toxicity which was induced in rats by giving intra-peritoneal injection of APAP (800mg/kg) dissolved in 40% polyethylene glycol at day 1 and day 14. APAP dosed/intoxicated rats orally administered either with ethanol extract of Spatoglossum asperum (200mg/kg) and its fractions including n-hexane, chloroform and methanol soluble in a dose of 150mg/kg each daily for 14 days in their respective groups. APAP dosed rats showed remarkable elevation in hepatic biomarkers viz., alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenases, total bilirubin, pro-inflammatory cytokines interleukine-6 and apoptotic protein (caspase-3). In addition, hepatic oxidative stress (lipid per oxidation and indirect nitric oxide) and antioxidant biomarkers (glutathione peroxidase, catalase and reduced glutathione) were also altered. Whereas APAP dosed rats treated with ethanol extract of S. asperum and its fractions showed amelioration in concentration of hepatic enzymes, pro-inflammatory cytokines, apoptotic protein and reduction in hepatic oxidative stress by decreasing the lipid peroxidation, indirect nitric oxide and uplifting the activities of antioxidant enzymes and protein.

Comprehensive in vivo and in silico approaches to explore the hepatoprotective activity of poncirin against paracetamol toxicity.

In the present study, poncirin was evaluated against paracetamol-induced liver injury using in vivo and computational approaches. Paracetamol was administered intraperitoneally (i.p,) to establish liver injury in mice and, subsequently, to investigate the hepatoprotective effect of poncirin (administered intraperitoneally) on liver injury. The effect of poncirin was evaluated against the liver injury markers and inflammatory cytokines. Similarly, in the present study, the antioxidants and oxidative stress parameters were also assessed following paracetamol-induced liver injury. The histological studies following liver injury were also assessed using H and E staining, Masson's trichrome staining, and periodic acid-Schiff staining. Similarly, the computational approach was used to assess the pharmacokinetic parameters of poncirin and its interaction with various protein targets. Poncirin markedly improved the antioxidant enzymes while attenuated the oxidative stress markers and inflammatory cytokines. Poncirin also markedly improved hematological parameters. Furthermore, poncirin treatment significantly improved the histological parameters using H and E staining, Masson's trichrome, and PAS staining compared to the control. Poncirin treatment also improved the liver function tests and liver synthetic activity compared to paracetamol treated group. The immunohistochemistry analysis revealed significant decrease in the inflammatory signaling protein such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB), Jun N-terminal kinase (JNK), and cyclooxygenase-2 (COX-2) expression level compared to the paracetamol treated group. Computational analysis (molecular docking and molecular dynamic simulation) showed significant binding affinity of poncirin with the NF-κB, JNK, COX-2, IL-1ß, IL-6, and TNF-α via multiple hydrophilic and hydrophobic binds. Similarly, the SwissADME software revealed that poncirin follows various drug-likeness rules and exhibited better pharmacokinetic parameters. Poncirin improved the sign and symptoms associated with liver injury using both in vivo and computational approaches.

Role of caspase-8 and/or -9 as biomarkers that can distinguish the potential to cause toxic- and immune related-adverse event, for the progress of acetaminophen-induced liver injury.

AIMS: Acetaminophen (APAP) overdose can cause acute liver failure. Although it is well known that APAP-induced liver injury (AILI) is caused by toxic mechanism, recently it is also reported to be immune related. However, the detail of the mechanism has been unclear. Therefore, elucidation of the pathophysiology is required. MAIN METHODS: In AILI model rats (800 mg/kg), the levels of AST, ALT and Caspase (C)-3/-8/-9 levels were measured. In in vitro study using human hepatocyte cells (FLC-4) and THP-1 cells, APAP (0.03-1.0 mM) were added to FLC-4 and the cell viability, C-9, cytochrome c, mitochondria membrane potential, and glutathione levels of FLC-4 and inflammasome activation of THP-1 were evaluated. KEY FINDINGS: In AILI model rats, the levels of AST and ALT were increased only at 12-24 h. C-3/-9 levels rose at 6-9 h, whereas C-8 level rose hours later, moreover, 24 h after; C-3/-8/-9 levels re-rose. In FLC-4 cells, cytochrome c was released from the mitochondria which is promoted by oxidative stress due to drug metabolism and C-9 was activated. Thus, AILI was caused mitochondrial damage by NAPQI as early reaction (first stage). In the next stage, inflammasomes of human antigen presenting cells, which released inflammatory cytokines were activated by damage-associated molecular patterns (DAMPs) released from damaged hepatocyte by APAP. SIGNIFICANCE: It is confirmed that AILI includes immune related mechanism. Thereby, in case of N-acetylcysteine refractory, additional administration of steroid hormones should be effective and recommended as a novel strategy for AILI with immune related adverse event (irAE).

PIWI-interacting RNA-23210 protects against acetaminophen-induced liver injury by targeting HNF1A and HNF4A.

Acetaminophen (APAP) overdose is one of the leading causes of acute liver failure in the US and other developed countries, the molecular mechanisms of APAP-induced hepatotoxicity remain speculative. PIWI-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, have been identified as epigenetic regulators of transposon silencing, mRNA deadenylation, and elimination. However, the functional role of piRNAs in APAP-induced liver injury remains unclear. In the current study, the piRNA profiles were constructed in HepaRG cells after APAP exposure, and the roles of piR-23210 in regulating nuclear receptors (NRs) expression, metabolizing enzymes expression, and consequently APAP-induced liver injury were systematically investigated. As a result, 57 upregulated piRNAs were identified after APAP exposure, indicating the stress-response characteristic of piRNA molecules. Subsequent in vitro and in vivo experiments proved that piR-23210 is a novel self-protective molecule that targets HNF1A and HNF4A transcripts by interacting with RNA binding protein Nucleolin (NCL), suppresses downstream CYPs (CYP2E1, CYP3A4, and CYP1A2) expression, and protects against APAP-induced liver injury. In conclusion, our findings provided new mechanistic clues revealing potential protective role of a piRNA against the hepatoxicity of APAP.

Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome.

BACKGROUND AND AIMS: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. APPROACH AND RESULTS: A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients. CONCLUSIONS: Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.

Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation.

Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury. In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions. In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.

Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.

Intrauterine and Lactational Exposure to Paracetamol: Cardiometabolic Evaluation in Adult Female and Male Offspring.

ABSTRACT: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.

Roles of Suaeda vermiculata Aqueous-Ethanolic Extract, Its Subsequent Fractions, and the Isolated Compounds in Hepatoprotection against Paracetamol-Induced Toxicity as Compared to Silymarin.

Suaeda vermiculata, a halophyte consumed by livestock, is also used by Bedouins to manage liver disorders. The aqueous-ethanolic extract of S. vermiculata, its subsequent fractions, and pure compounds, i.e., pheophytin-A (1), isorhamnetin-3-O-rutinoside (2), and quercetin (3), were evaluated for their hepatoprotective efficacy. The male mice were daily fed with either silymarin, plant aq.-ethanolic extract, fractions, pure isolated compounds, or carboxyl methylcellulose (CMC) for 7 days (n = 6/group, p.o.). On the day 7th of the administrations, all, except the intact animal groups, were induced with hepatotoxicity using paracetamol (PCM, 300 mg/kg). The anesthetized animals were euthanized after 24 h; blood and liver tissues were collected and analysed. The serum aspartate transaminase (AST) and alanine transaminase (ALT) levels decreased significantly for all the S. vermiculata aq.-ethanolic extract, fraction, and compound-treated groups when equated with the PCM group (p < 0.0001). The antioxidant, superoxide dismutase (SOD), increased significantly (p < 0.05) for the silymarin-, n-hexane-, and quercetin-fed groups. Similarly, the catalase (CAT) enzyme level significantly increased for all the groups, except for the compound 2-treated group as compared to the CMC group. Also, the glutathione reductase (GR) levels were significantly increased for the n-butanol treated group than for the PCM group. The oxidative stress biomarkers, lipid peroxide (LP) and nitric oxide (NO), the inflammatory markers, IL-6 and TNF-α, and the kidney's functional biomarker parameters remained unchanged and did not differ significantly for the treated groups in comparison to the PCM-induced toxicity bearing animals. All the treated groups demonstrated significant decreases in cholesterol levels as compared to the PCM group, indicating hepatoprotective and antioxidant effects. The quercetin-treated group demonstrated significant improvement in triglyceride level. The S. vermiculata aq.-ethanolic extract, fractions, and the isolated compounds demonstrated their hepatoprotective and antioxidant effects, confirming the claimed traditional use of the herb as a liver protectant.

Therapeutic role of Typha elephantina leaves aqueous extract in paracetamol intoxicated rabbits.

Present study is aimed to investigate the hepatoprotective and hematopoietic effect of Typha elephantina leaves aqueous (T.E.AQ), extract in paracetamol (PCM) intoxicated rabbits. Experimental animals were divided into various groups. The blood was taken on day 7th (W1=Week 1), day 14th (W2 = week 2) and day 21st (W3 = week 3) of treatments and was analyzed for all hematological and serum biochemical markers. PCM administration caused marked increase in the levels of serum biochemical and hematological parameters. The leaves of T.E.AQ extract at dose rate 300mg/kg body weight significantly (P<0.05) reduced the elevated levels of serum biochemical and hematological indices towards normal values on third week (day 21st) of treatment while treatment in the first two weeks revealed non-significant effects even at all doses of extract. The levels of glutathione (GSH) and radical scavenging activity (RSA) were reduced and thiobarbituric acid reactive substances (TBARS) levels was high in the PCM feed animals. Administration of (T.E.AQ) extract at high dose (300mg/kg) significantly regulated and normalized these antioxidant values. The antioxidant capacity of (TE.AQ) extract, showed increase inhibition against various extract concentrations on the basis of percent scavenging of (DPPH) free radical. The histological sections of liver further supported the hepatoprotective activity of extract.

The effects of mitochondrial transplantation in acetaminophen-induced liver toxicity in rats.

AIMS: Acetaminophen (APAP) toxicity is one of the leading causes of acute liver injury-related death and liver failure worldwide. In many studies, mitochondrial dysfunction has been identified as an important cause of damage in APAP toxicity. Therefore, our study aimed to investigate the possible effects of mitochondrial transplantation on liver damage due to APAP toxicity. MAIN METHODS: APAP toxicity model was implemented by administering a toxic dose of APAP. To demonstrate the efficiency of mitochondria transplantation, it was compared with N-acetylcysteine (NAC) application, which is now clinically accepted. Mitochondrial transplantation was carried out by delivering mitochondria to the liver via the portal circulation, which was injected into the spleen. In our study, the rats were randomly divided into 6 groups as Sham, APAP, Control 1, APAP+mito, Control 2, and APAP+NAC. In the end of the experiment, histological and biochemical analysis were performed and the biodistribution of the transplanted mitochondria to target cells were also shown. KEY FINDINGS: Successful mitochondrial transplantation was confirmed and mitochondrial transplantation improved the liver histological structure to a similar level with healthy rats. Moreover, plasma ALT levels, apoptotic cells, and total oxidant levels were decreased. It was also observed that NAC treatment increased GSH levels to the highest level among the groups. However, mitochondrial transplantation was more effective than NAC application in terms of histological and functional improvement. SIGNIFICANCE: It has been evaluated that mitochondrial transplantation can be used as an important alternative or adjunctive treatment method in liver damage caused by toxic dose APAP intake.

Establishing a 3D In Vitro Hepatic Model Mimicking Physiologically Relevant to In Vivo State.

Three-dimensional (3D) bioprinting is a promising technology to establish a 3D in vitro hepatic model that holds great potential in toxicological evaluation. However, in current hepatic models, the central area suffers from hypoxic conditions, resulting in slow and weak metabolism of drugs and toxins. It remains challenging to predict accurate drug effects in current bioprinted hepatic models. Here, we constructed a hexagonal bioprinted hepatic construct and incorporated a spinning condition with continuous media stimuli. Under spinning conditions, HepG2 cells in the bioprinted hepatic construct exhibited enhanced proliferation capacity and functionality compared to those under static conditions. Additionally, the number of spheroids that play a role in boosting drug-induced signals and responses increased in the bioprinted hepatic constructs cultured under spinning conditions. Moreover, HepG2 cells under spinning conditions exhibited intensive TGFß-induced epithelial-to-mesenchymal transition (EMT) and increased susceptibility to acetaminophen (APAP)-induced hepatotoxicity as well as hepatotoxicity prevention by administration of N-acetylcysteine (NAC). Taken together, the results of our study demonstrate that the spinning condition employed during the generation of bioprinted hepatic constructs enables the recapitulation of liver injury and repair phenomena in particular. This simple but effective culture strategy facilitates bioprinted hepatic constructs to improve in vitro modeling for drug effect evaluation.

[Research progress on hepatotoxicity of acetaminophen].

Acetaminophen (APAP) is a widely used antipyretic and analgesic drug that is safe and effective in the therapeutic doses, but overdose may cause hepatotoxicity and even acute liver failure (ALF). Finding reliable biomarkers for APAP toxicity is not only a hot spot of current research, but also a problem that needs to be solved urgently. Clinicians should consider the existence of APAP hepatotoxicity when using APAP treatment, and explain that APAP may have a certain degree of dose dependence. This paper reviews the most promising biomarkers currently being evaluated, and expounds their application in the field of APAP hepatotoxicity, as well as the mechanism of mitochondrial damage and mitochondrial autophagy, thereby contributing to the diagnosis, prognosis, mechanism and research progress of therapeutic targets of APAP hepatotoxicity.

Can granulocyte colony stimulating factor (G-CSF) ameliorate acetaminophen-induced hepatotoxicity?

Acetaminophen (APAP) is often used as an antipyretic and analgesic agent. Overdose hepatotoxicity, which often results in liver cell failure and liver transplantation, is a severe complication of APAP usage. To save the liver and save lives from acute liver damage caused by APAP, the search for new strategies for liver defense is important. Wistar rats have been used for the induction of APAP hepatotoxicity. Elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were evaluated for liver toxicity. In addition, the levels of hepatic tissue oxidative markers such as malondialdehyde (MDA), nitric oxide (NO) increased while glutathione (GSH) was depleted and catalase (CAT) activity was curtailed. The biochemical findings were consistent with the changes in histology that suggested liver damage and inflammation. Treated rats with N-acetylcysteine (N-AC) and granulocyte colony stimulating factor (G-CSF) showed a decrease in serum levels of ALT, AST and LDH, while the level of ALP in the G-CSF group was still high. After administration of APAP, treatment with N-AC or G-CSF substantially reduced the level of MDA and NO while maintaining the GSH content and CAT activity. Treatment with N-AC and G-CSF after administration of APAP has also attenuated inflammation and hepatocytes necrosis. The results of this study showed that G-CSF could be viewed as an alternative hepatoprotective agent against APAP-induced acute liver injury compared to N-AC.