The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

Non-alcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Understanding metabolic pathways involved can provide insights into disease progression. Untargeted metabolomics of livers from mice with early-stage steatosis indicated a decrease in methylated metabolites suggesting altered one carbon metabolism. The levels of glycine, a central component of one carbon metabolism, were lower in steatotic mice, in line with clinical evidence. Isotope tracing studies demonstrated that increased synthesis of serine from glycine is the underlying cause for glycine limitation in fatty livers. Consequently, the low glycine availability in steatotic livers impaired glutathione (GSH) synthesis under oxidative stress induced by acetaminophen (APAP), enhancing hepatic toxicity. Glycine supplementation mitigated acute liver damage and overall toxicity caused by APAP in fatty livers by supporting de novo GSH synthesis. Thus, early metabolic changes in NAFLD that lead to glycine depletion sensitize mice to xenobiotic toxicity even at a reversible stage of NAFLD.

Opioid minimization in the acute postoperative phase is timely in the era of the opioid epidemic. The authors hypothesize that patients with facial trauma receiving multimodal, narcotic-minimizing pain management in the perioperative period will consume fewer morphine milligram equivalents (MMEs) while maintaining adequate pain control compared with a traditional analgesia protocol. An IRB-approved pilot study evaluating isolated facial trauma patients compared 10 consecutive prospective patients of a narcotic-minimizing pain protocol beginning in August 2020 with a retrospective, chart-reviewed cohort of 10 consecutive patients before protocol implementation. The protocol was comprised of multimodal nonopioid pharmacotherapy given preoperatively (acetaminophen, celecoxib, and pregabalin). Postoperatively, patients received intravenous (IV) ketorolac, scheduled acetaminophen, ibuprofen, and gabapentin. Oxycodone was reserved for severe uncontrolled pain. The control group had no standardized protocol, though opioids were ad libitum. Consumed MMEs and verbal Numeric Rating Scale (vNRS) pain scores (0-10) were prospectively tracked and compared with retrospective data. Descriptive and inferential statistics were run. At all recorded postoperative intervals, narcotic-minimizing subjects consumed significantly fewer MMEs than controls [0-8 h, 21.5 versus 63.5 (P = 0.002); 8-16 h, 4.9 versus 20.6 (P = 0.02); 16-24 h, 3.3 versus 13.9 (P = 0.03); total 29.5 versus 98.0 (P = 0.003)]. At all recorded postoperative intervals, narcotic-minimizing subjects reported less pain (vNRS) than controls (0-8 h, 7.7 versus 8.1; 8-16 h, 4.4 versus 8.0; 16-24 h 4.3 versus 6.9); significance was achieved at the 8 to 16-hour time point (P = 0.006). A multimodal, opioid-sparing analgesia protocol significantly reduces opioid use in perioperative facial trauma management without sacrificing satisfactory pain control for patients.

Pain is one of the most common reasons for seeking medical intervention, and self-medication with over-the-counter medications and/or traditional herbal remedies has become increasingly popular. In this review, original articles on understanding possible herb-drug interaction between traditional herbs and four major pain medication: acetaminophen, aspirin, ibuprofen, and naproxen were compiled and analyzed. In terms of analytical methods, high-performance liquid chromatography using an isocratic eluent system coupled to biological sample clean-up is the most common, while a wide variety of detectors have been observed, including a photo diode array, variable wavelength detector, electrochemical detector, and tandem mass spectrometer. Both synergistic and anti-synergistic effects were observed for acetaminophen and aspirin, while only synergistic effects have been found for naproxen. Currently, no interactions have been reported for ibuprofen.

Children are exposed to various environmental organic and inorganic contaminants with effects on health outcomes still largely unknown. Many matrices (e.g., blood, urine, nail, hair) have been used to characterize exposure to organic and inorganic contaminants. The sampling of feces presents several advantages; it is non-invasive and provides a direct evaluation of the gut microbiome exposure to contaminants. The gut microbiome is a key factor in neurological development through the brain-gut axis. Its composition and disturbances can affect the neurodevelopment of children. Characterization of children exposure to contaminants is often performed on vulnerable populations (e.g., from developing countries, low-income neighborhoods, and large urban centers). Data on the exposure of children from middle-class, semi-urban, and mid-size populations to contaminants is scarce despite representing a significant fraction of the population in North America. In this study, 73 organics compounds from different chemical classes and 22 elements were analyzed in 6 years old (n = 84) and 10 years old (n = 119) children's feces from a middle-class, semi-urban, mid-size population cohort from Eastern Canada. Results show that 67 out of 73 targeted organics compounds and all elements were at least detected in one child's feces. Only caffeine (97% & 80%) and acetaminophen (28% & 48%) were detected in more than 25% of the children's feces, whereas all elements besides titanium were detected in more than 50% of the children.

There is an urgent need for scalable Microphysiological Systems (MPS's)1 that can better predict drug efficacy and toxicity at the preclinical screening stage. Here we present Mera, an automated, modular and scalable system for culturing and assaying microtissues with interconnected fluidics, inbuilt environmental control and automated image capture. The system presented has multiple possible fluidics modes. Of these the primary mode is designed so that cells may be matured into a desired microtissue type and in the secondary mode the fluid flow can be re-orientated to create a recirculating circuit composed of inter-connected channels to allow drugging or staining. We present data demonstrating the prototype system Mera using an Acetaminophen/HepG2 liver microtissue toxicity assay with Calcein AM and Ethidium Homodimer (EtHD1) viability assays. We demonstrate the functionality of the automated image capture system. The prototype microtissue culture plate wells are laid out in a 3 × 3 or 4 × 10 grid format with viability and toxicity assays demonstrated in both formats. In this paper we set the groundwork for the Mera system as a viable option for scalable microtissue culture and assay development.

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.

Paracetamol is an optimal non-opioid analgesic and holds considerable advantages over NSAIDs in managing post-operative pain. Literature to date doesn't provide substantial documentation of it's efficacy and safety in major oral and maxillofacial surgeries. The study is designed to compare the effectiveness of intravenous paracetamol with diclofenac sodium for controlling post-operative pain and edema in major oral and maxillofacial surgeries.

1H-14N internuclear distances are readily and accurately measured using the symmetry-based phase-modulated resonance-echo saturation-pulse double-resonance (PM-S-RESPDOR) method in rigid solids. The fraction curve, (S0 - S')/S0, is represented by a single variable of a 1H-14N heteronuclear dipolar coupling, where S0 and S' are the PM-S-RESPDOR signal intensity with and without 14N PM saturation pulse, respectively. Analytical equation of the fraction curve easily provides 1H-14N couplings. This treatment is only applicable when NH proton resonance is well separated from the other proton peaks. With the limited 1H resolution even at fast MAS > 60 kHz, unfortunately, this condition is not necessarily satisfied especially in multi-component systems which often appear in pharmaceutical applications. To overcome this problem, T-HMQC filtering is applied to suppress the 1H signals other than NH proton prior to the PM-S-RESPDOR experiments. The method is well demonstrated on two components acetaminophen-oxalic acid (APAP-OXA) systems. Further analysis of orientation dependence of T-HMQC and PM-S-RESPDOR shows that the analytical equation can be safely applied in the analysis of T-HMQC filtered PM-S-RESPDOR experiments.

The overuse of acetaminophen (APAP) may cause more severe hepatotoxicity in patients with non-alcoholic fatty liver disease (NAFLD). Caveolin-1 (CAV1), is an essential regulator of metabolic function, which can alleviate liver damage by scavenging reactive oxygen species (ROS). Evidence suggests that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated pyroptosis is involved in the development of NAFLD. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linking ROS to NLRP3 inflammasome. However, whether CAV1 alleviates APAP-aggravated hepatotoxicity in NAFLD via the ROS/TXNIP/NLRP3 pathway remains unclear. An in vivo fatty liver model was established by feeding mice a high-fat diet for 56 days. Additionally, using in vitro approach, AML-12 cells were incubated with free fatty acids for 48 h and APAP was added during the last 24 h. We found that the overuse of APAP in NAFLD not only induced oxidative stress, but also increased TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition. In addition to inhibiting ROS generation and lipid deposition, overexpression of CAV1 reduced the elevated levels of TXNIP expression and NLRP3-mediated pyroptosis. However, the effect of CAV1 on TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition was reversed by CAV1 small interfering RNA (siRNA) intervention. Finally, N-acetyl cysteine (NAC) treatment reduced CAV1 siRNA-mediated changes in TXNIP expression and NLRP3-mediated pyroptosis levels. These results demonstrate that the inhibitory effect of CAV1 on NLRP3-mediated pyroptosis may be mediated through the ROS/TXNIP axis. Moreover, the current study provides novel mechanistic insights into the protective effects of CAV1 on APAP-aggravated hepatotoxicity in NAFLD.

This survey of pediatric ophthalmic surgeons on analgesia for postoperative adult strabismus patients indicates that 65% prescribed acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs), and 12% to 16% prescribed opioids. Most surgeons reported reasonable control of pain regardless of analgesia. Acetaminophen and/or NSAIDs may adequately control pain, although certain circumstances may warrant opioid prescriptions. [J Pediatr Ophthalmol Strabismus. 2023;60(1):e5-e7.].

Information on the pattern of acute poisonings in hospitals of Birjand city, Iran, is limited. This study aimed to address this knowledge gap by examining the admissions in a major poisoning center in eastern Iran. This cross-sectional study included patients admitted to the Imam Reza Hospital in Birjand over 12 months. Medical records of the poisoned patients were reviewed, and the study variables were used for data analysis. During the study period, 534 cases of acute poisonings were evaluated. The patient's ages ranged from 12 to 84 years, with a high rate of poisonings between 15 and 35 years. The female predominance in poisoning cases was 52.1%. Most cases of poisonings occurred in spring, and the common route of exposure was oral (93.1%). The incidence of poisoning in married couples, uneducated patients, and residents of urban areas was 56.5%, 90.1%, and 74.6%, respectively. Patients with a previous medical history experienced addiction and psychiatric disorders. Intentional poisoning accounted for 23.4% of acute poisoning cases referred to the hospital in the current study. The main groups of toxicants were pharmaceutical products (48.1%), narcotics (25.8%), chemical products (10.1%), envenomation (7.1%), and alcohol (1.7%). The mean hospital stay was 2.5 ± 3.0 days, and the final treatment outcome was complete recovery, except for one patient intoxicated by warfarin and alprazolam. Our results indicate that the high toxicity cases were related to pharmaceutical product and opioids abuse, especially methadone (8.4%), alprazolam (7.9%), clonazepam (7.5%), and acetaminophen (9.9%) taken orally and more commonly happened at home. Due to the high rate of deliberate poisonings, especially among young adults and students, monitoring drug distribution and exceptional attention to mental health should be seriously considered by national health authorities to prevent suicide attempts.

Analytical techniques must be sensitive, specific, and accurate in order to assess the active pharmaceutical ingredients in pharmaceutical dosage forms. The Quality by Design (QbD) application has proven to be a practical method for magnifying HPLC operations. This article discusses the successfully developed QbD-based stability-indicative LC method for evaluating acetaminophen, caffeine, and aspirin in tablet dosage form. To achieve the necessary chromatographic separation, milli-Q water, methanol, and glacial acetic acid were employed in the following ratios: 63:35:2 (v/v/v) for mobile phase-A and 18:80:2 (v/v/v) for mobile phase-B, respectively. The flow rate, column temperature, and detecting wavelength were 1.0 mL min-1 , 40° C, and 275 nm, respectively, with Inert sustain C18, (150 × 4.6mm), 3 μm analytical column. Linearity between 10.0 and 150.0 μgmL-1 of aspirin and acetaminophen and 2.6 to 39.0 μg mL-1 of caffeine. The accuracy findings were more than 97%, and the correlation coefficient for all three components was found to be greater than 0.999. The validated HPLC methodology yielded reliable and accurate results. Aspirin was shown to be very vulnerable to both acid and alkaline hydrolysis in the forced degradation study. The described method is capable of separating the degradants produced during stress testing and is regarded as stability-indicating. The proposed method can be used for a wider range of other formulations with an appropriate diluent selection and sample preparation procedure optimization.

[This retracts the article DOI: 10.1155/2022/1794258.].

Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both in vitro and in vivo biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5β loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI in vivo. Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.

Wood-rotting fungi and their enzymatic systems represent promising biocatalysts for the removal of pharmaceuticals and personal care products (PPCPs) from wastewater. We designed a fungal wheel reactor (FWR) based on solid-state fermentation (SSF) of Trametes versicolor and a lignocellulosic substrate, which was used as an immobilization carrier for fungal biomass and the sole initial nutrient source for producing fungal oxidative enzymes. Three pharmaceutical and personal care products, acetaminophen, bisphenol A and carbamazepine, were spiked into the synthetic wastewater and the treatment was carried out under non-sterile conditions. Acetaminophen was completely removed from the FWR until laccase was observed. The acetaminophen removal efficiency was retrieved by replacing the fungal wheel with fresh SSF products. Bisphenol A and carbamazepine were removed via enzymatic activity and adsorption. When the fungal wheel was replaced, acetaminophen began to be completely removed, even after laccase depletion. The microbial community analysis indicated that the continuous removal of acetaminophen was mainly due to the high proportion of T. versicolor. The relative abundance of the co-occurring microbial community might be responsible for the divergence in acetaminophen removal between two of fungal wheel-replaced reactors. Overall, FWRs are promising tools for the removal of PPCPs by highly reactive enzymatic mechanisms as well as adsorption on the carrier surface. By replacing SSF and settled microbial communities, FWRs may continuously contribute to bioremediation over a long-term period.

Escherichia coli is one of the main indicators in the quality control of water, pharmaceuticals, and other samples. Compared with the time-consuming and high prices of the classical methods, with their high risks in the case of insensitive, contamination and offline detections, biosensors have long been a fast and accurate approach for identifying different bacteria. The present study reports the development of a newly electrochemical biosensor using a glassy carbon electrode (GCE) modified by multi-walled carbon nanotubes/AuNPs/E. coli polyclonal antibody/Bovine Serum Albumin in 0.1 M phosphate-buffered saline (pH 7) in the presence of acetaminophen, for the detection of E. coli in pharmaceuticals and some real samples. Acetaminophen was added as an indicator for the detection of E. coli by changes in conductivity and current. To identify E. coli, square-wave voltammetry (SWV), differential pulse voltammetry (DPV), and cyclic voltammetry (CV) techniques were used. According to the obtained results of square-wave voltammetry, a limit of 3.02 CFU/ml E. coli detection in 3 min with desirable sensitivity, repeatability, and reproducibility was found with the designed biosensor. This biosensor could be a powerful tool for the detection of indicator bacteria in the food industry, drug safety, quality control, clinical diagnostics, and environmental monitoring.

With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study.

Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0-26.8 mM), diclofenac (475.5->500 µM), perhexiline (9.7->31.5 µM), troglitazone (23.1-90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

Pyrite has been used in photo-Fenton reactions for the degradation of pollutants, but the application of photo-Fenton processes with extra H2O2 in real water/wastewater treatment has still been limited by the economic cost of H2O2 and artificial light sources. Herein, citric acid (CA) and simulated/natural sunlight are used to develop a pyrite-based photo-Fenton system (pyrite-CA-light) in situ generating H2O2 through the enhanced activation of molecular oxygen. The degradation of pharmaceuticals and personal care products (PPCPs), especially acetaminophen (APAP) as the main target pollutant, in the pyrite-CA-light system was investigated. The effects of influencing factors such as various organic acids, APAP concentration, pH, pyrite dosage, CA concentration and co-existing anions (HCO3-, Cl-, NO3-, SO42- and H2PO4-) were examined. At a pyrite dosage of 0.1 g L-1, CA concentration of 0.6 mM and an initial pH of 6.0, the degradation efficiency of APAP (30 μM) was 99.1% within 30 min under the irradiation of xenon lamp (70 W, λ ≥ 350 nm). Almost the same high efficiency of APAP degradation (93.9%) in the system was achieved under natural sunlight irradiation (ca. 650 W m-2). The scavenging experiments revealed that the dominant active species for degrading APAP was hydroxyl radical (HO•). Moreover, a quantitative structural-activity relationship (QSAR) model for pseudo-first-order rate constants (kobs) was established with a high significance (R2 = 0.932, p = 0.001) by using three descriptors: octanol-water partition coefficient (logKow), dissociation constant (pKa) and highest occupied molecular orbital (HOMO). This work provides an innovative strategy of the photo-Fenton process for the degradation of PPCPs using natural minerals and ordinary carboxylic acid under sunlight.

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.

Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.