Efficacy of partial and complete resuscitative endovascular balloon occlusion of the aorta in the hemorrhagic shock model of liver injury / 世界急诊医学杂志（英文）

@#BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) can temporarily control traumatic bleeding. However, its prolonged use potentially leads to ischemia-reperfusion injury (IRI). Partial REBOA (pREBOA) can alleviate ischemic burden; however, its security and effectiveness prior to operative hemorrhage control remains unknown. Hence, we aimed to estimate the efficacy of pREBOA in a swine model of liver injury using an experimental sliding-chamber ballistic gun. METHODS: Twenty Landrace pigs were randomized into control (no aortic occlusion) (n=5), intervention with complete REBOA (cREBOA) (n=5), continuous pREBOA (C-pREBOA) (n=5), and sequential pREBOA (S-pREBOA) (n=5) groups. In the cREBOA and C-pREBOA groups, the balloon was inflated for 60 min. The hemodynamic and laboratory values were compared at various observation time points. Tissue samples immediately after animal euthanasia from the myocardium, liver, kidneys, and duodenum were collected for histological assessment using hematoxylin and eosin staining. RESULTS: Compared with the control group, the survival rate of the REBOA groups was prominently improved (all P<0.05). The total volume of blood loss was markedly lower in the cREBOA group (493.14±127.31 mL) compared with other groups (P<0.01). The pH was significantly lower at 180 min in the cREBOA and S-pREBOA groups (P<0.05). At 120 min, the S-pREBOA group showed higher alanine aminotransferase (P<0.05) but lower blood urea nitrogen compared with the cREBOA group (P<0.05). CONCLUSION: In this trauma model with liver injury, a 60-minute pREBOA resulted in improved survival rate and was effective in maintaining reliable aortic pressure, despite persistent hemorrhage. Extended tolerance time for aortic occlusion in Zone I for non-compressible torso hemorrhage was feasible with both continuous partial and sequential partial measures, and the significant improvement in the severity of acidosis and distal organ injury was observed in the sequential pREBOA.

Liver Injury Caused by Psoraleae Fructus： A Review / 中国实验方剂学杂志

Psoraleae Fructus （PF） is a non-toxic Chinese herbal medicine， while the liver injury caused by PF has aroused wide concern in recent years. At present， animal experiments and in vitro studies have been carried out to explore the mechanism， targets， and toxic components of PF in inducing liver injury， which， however， have differences compared with the actual conditions in clinical practice， and there are still some potential hepatotoxic components and targets of PF that have not been discovered. With the continuous progress in systems biology， establishing the drug-induced liver injury model and the liver injury prediction model based on network toxicology can reduce the cost of animal experiments， improve the toxicity prediction efficiency， and provide new tools for predicting toxic components and targets. To systematically explain the characteristics of liver injury in the application of PF and explore the potential hepatotoxic components and targets of PF， we reviewed the related articles published by China National Knowledge Infrastructure （CNKI）， Wanfang Data， VIP， and PubMed from 1962 to 2021 and analyzed the characteristics and influencing factors of liver injury caused by PF in the patients. Furthermore， we summarized the chemical components of PF and the components entering blood. By reviewing the mechanism， targets， and components of PF in inducing liver injury that were discovered by in vivo and in vitro experiments， we summarized the known compounds in PF that may cause liver injury. Finally， the current methods for building the prediction model of PF-induced liver injury were summarized， and the predicted toxic components and targets were introduced. The possible factors of PF in causing liver injury were explained from three aspects： clinical characteristics， preclinical studies， and computer-assisted network prediction， which provide a reference for predicting the risk of PF-induced liver injury.

Captopril inhibits thioacetamide-induced chronic liver injury associated with the suppression of inflammation / hypoxia- inducible factor 1-alpha / profibrogenic axis-mediated hepatotoxicity in rats / Captopril inhibe la lesión hepática crónica inducida por tioacetamida asociada con la supresión de la inflamación/factor 1-alfa inducible por hipoxia/hepatotoxicidad mediada por el eje profibrogénico en rata

SUMMARY: Liver transplantation is the only available method to treat liver failure induced by chronic liver injury. We sought to determine whether the angiotensin-converting enzyme inhibitor, captopril, can inhibit the development of chronic liver injury induced by the hepatotoxic agent thioacetamide (TAA) in association with the suppression of inflammation (hsCRP, TNF-α, and IL-6) / hypoxia- inducible factor 1-alpha (HIF-1α) / profibrosis (TIMP-1, MMP-9, and α-SMA) axis that mediates liver injury. Therefore, the model group of rats was injected for eight weeks with 200 mg/kg TAA starting at week two. The protective group was pretreated with 150 mg/ kg captopril daily for two weeks prior to TAA injections and continued receiving both capropril and TAA agents until being humanely scrificed at week 10. We observed a substantial damage to liver tissue in the model group as demonstrated by a significant (p<0.0001) increase in blood and hepatic tissue levels of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-a (TNF-α), interleukin- 6 (L-6), HIF-1α, tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), alpha-smooth muscle actin (α-SMA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All these parameters were significantly (p<0.0244) protected by captopril. Also, a significant (p<0.0001) positive correlation was observed between a-SMA (profibrosis) and the serum and tissue levels of hsCRP, TNF-α, HIF-1α, TIMP-1, MMP-9, and ALT. Thus, these findings suggest that the induction of chronic liver injury by the hepatotoxic compound, TAA is associated with the upregulation of inflammation/HIF-1α/profibrosis, with captopril exhibiting beneficial hepatic pleotropic effects.

El trasplante de hígado es el único método disponible para tratar la insuficiencia hepática inducida por una lesión hepática crónica. Buscamos determinar si el inhibidor de la enzima convertidora de angiotensina, captopril, puede inhibir el desarrollo de lesión hepática crónica inducida por el agente hepatotóxico tioacetamida (TAA) en asociación con la supresión de la inflamación (hsCRP, TNF-α e IL-6) / factor inducible por hipoxia 1-alfa (HIF-1α) / profibrosis (TIMP-1, MMP-9 y α- SMA) eje que media la lesión hepática. Por lo tanto, al grupo modelo de ratas se le inyectó durante ocho semanas 200 mg/kg de TAA a partir de la semana dos. El grupo protector fue pretratado con 150 mg/kg de captopril al día durante dos semanas antes de las inyecciones de TAA y continuó recibiendo capropril y agentes TAA hasta que fue sacrificado en la semana 10. Observamos un daño sustancial en el tejido hepático en el grupo modelo, como lo demuestra un aumento significativo (p<0,0001) de los niveles en sangre y tejido hepático de proteína C reactiva de alta sensibilidad (hsCRP), factor de necrosis tumoral-α (TNF-a), interleucina-6 (L-6), HIF-1α, inhibidor tisular de metaloproteinasas-1 (TIMP-1), metaloproteinasa de matriz-9 (MMP-9), actina de músculo liso alfa (α-SMA), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Todos estos parámetros estaban significativamente (p<0,0244) protegidos por captopril. Además, se observó una correlación positiva significativa (p<0,0001) entre α-SMA (profibrosis) y los niveles séricos y tisulares de hsCRP, TNF-α, HIF-1α, TIMP- 1, MMP-9 y ALT. Por lo tanto, estos hallazgos sugieren que la inducción de daño hepático crónico por el compuesto hepatotóxico, TAA, está asociada con la regulación al alza de la inflamación/HIF-1α/profibrosis, con captopril exhibiendo efectos pleotrópicos hepáticos beneficiosos.

Clinician's dilemma: Naproxen-induced liver injury

Naproxen is a widely used nonsteroidal anti-inflammatory drug (NSAID) in pediatric population, used for mild-to-moderate pains, arthritis, and other immune-mediated disorders. It rarely causes clinically apparent liver injury in the adult population taking high doses of the drug over a prolonged period and is reported even rarer in pediatric population. We present a case of drug-induced liver injury (DILI) in a 13-year-old girl taking naproxen in therapeutic doses for juvenile rheumatoid arthritis. There was a complete recovery of liver function following discontinuation of naproxen therapy.

Uso del esquema Scottish and Newcastle Anti-Emetic Pretreatment (SNAP) en la recuperación de una intoxicación por sobredosis masiva de acetaminofén (paracetamol) con injuria hepática aguda - Reporte de caso

Acetaminophen is a drug widely used in the world and easily accessible due to its antipyretic, analgesics characteristics, among others (1); however, exposure to toxic doses causes organic damage and even death. We present the case of an 18-year-old female patient who ingested 40 grams of acetaminophen and developed severe liver dysfunction, being treated with N-acetylcysteine (NAC) antidotal therapy according to the simplified scheme: Scottish and Newcastle Anti-emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presenting improvement in the clinical course and decrease in liver profiles, coagulation disorder, INR and resolution of the condition.

El acetaminofén es un fármaco ampliamente usado en el mundo y de fácil acceso por sus características antipiréticas, analgésicas, entre otras (1); sin embargo la exposición a dosis tóxicas produce daños a nivel orgánico e incluso la muerte. Presentamos el caso de una paciente mujer de 18 años que ingirió 40 gramos de acetaminofén y desarrolló injuria hepática severa, siendo tratada con terapia antidotal de N-acetilcisteína (NAC) según el esquema simplificado: Scottish and Newcastle Anti-Emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presentando mejoría del curso clínico y disminución de los perfiles hepáticos, trastorno de coagulación, INR y resolución del cuadro.

Lesión hepática inducida por consumo de Valeriana officinalis y Passiflora incarnata, reporte de caso / Hepatic injury induced by the consumption of Valeriana officinalis and Passiflora incarnata, a case report

Los medicamentos homeopáticos y fitoterapéuticos que contienen productos herbarios son cada vez más utilizados, sin embargo, se desconoce el potencial de efectos adversos por parte de los usuarios y personal sanitario. Se reporta el caso de una mujer de 34 años quien consulta por dolor abdominal y náuseas, con alteraciones al ingreso de función hepática con patrón hepatocelular, se descartaron múltiples etiologías y se consideró que pudiera ser lesión hepática medicamentosa secundaria al consumo de medicamentos desde hacía una semana para dismenorrea, y a fitoterapéuticos que consumía de forma crónica, los cuales se suspendieron. A los doce días de su egreso, reingresó por sintomatología similar; se documentó nuevamente perfil hepático con patrón hepatocelular. Al reinterrogatorio, la paciente comentó la ingesta crónica de Valeriana officinalis y Passiflora incarnata, que retomó al egreso hospitalario, por lo que luego de descartar diagnósticos diferenciales, se consideró que el cuadro era inducido por el consumo de dichos medicamentos. Durante la hospitalización se suspendió su consumo, con normalización del perfil hepático. Es importante que los consumidores estén informados sobre los riesgos potenciales de los productos herbarios, sus efectos por consumos prolongados y las implicaciones de la autoformulación.

Homeopathic and phytotherapeutic medicines containing herbal products are increasingly used, however the potential for adverse effects on users and healthcare personnel is unknown. We report the case of a 34-year-old woman who consulted for abdominal pain and nausea, accompanied by hepatocellular pattern on liver function tests. Multiple etiologies were ruled out and it was considered that it could be a drug-induced liver injury secondary to the consumption of medications she had been taking a week prior for dysmenorrhea, and phytotherapeutics that she had been taking for seve-ral years, which were all discontinued. Twelve days after her discharge, she was readmitted due to similar symptoms; a liver profile with a hepatocellular pattern was again documented. Upon further questioning, the patient mentioned a chronic intake of Valeriana officinalis and Passiflora incarnata, which she resumed upon discharge. After ruling out the differential diagnoses, it was concluded that the symptoms of the patient were induced by the consumption of these herbal products. During hos-pitalization, their consumption was suspended, with normalization of the liver profile. It is important that consumers are informed about the potential risks of herbal products, their effects from long-term use, and the implications of self-medication.

Manifestaciones hepatobiliares asociadas a la enfermedad inflamatoria intestinal / Hepatobiliary manifestations associated with inflammatory bowel disease

La enfermedad inflamatoria intestinal (EII) engloba dos entidades, la enfermedad de Crohn (EC) y la colitis ulcerativa (CU), las cuales son enfermedades inmunomediadas, crónicas y recurrentes que, aunque afectan al intestino, pueden ir acompañadas de manifestaciones extraintestinales de tipo hepatobiliar en el 5 % de los casos. Entre ellas, las más frecuentes son la enfermedad por hígado graso no alcohólico (EHGNA), la colelitiasis, la colangitis esclerosante primaria (CEP), la colangitis relacionada con IgG4, la hepatitis autoinmune (HAI), el síndrome de superposición HAI/CEP, así como la lesión hepática inducida por fármacos (DILI); y otras menos frecuentes como la colangitis biliar primaria (CBP), la trombosis de la vena porta, los abscesos hepáticos, la hepatitis granulomatosa, las hepatitis B y C, la reactivación de la hepatitis B por terapia inmunosupresora, y la amiloidosis. Estas manifestaciones hepatobiliares cursan con una fisiopatología similar o inclusive la misma de la EII, en la que participan el sistema inmune innato y adaptativo, alteración de la microbiota (disbiosis), permeabilidad intestinal, factores de riesgo genéticos (comunes para EII y manifestaciones hepatobiliares) y desencadenantes ambientales. La primera manifestación de un trastorno hepatobiliar es la alteración del perfil de función hepática, por lo que el abordaje diagnóstico se debe dirigir a evaluar y monitorizar las enzimas hepáticas y su asociación a algún patrón diferencial de alteración hepatocelular o colestásico, con el fin de tomar decisiones oportunas con respecto a la suspensión, indicación o modificación de algún medicamento, o cualquier otro abordaje que impida o retrase la evolución de la enfermedad hepatobiliar, y al mismo tiempo garantice el control de la EII, mejorando potencialmente el pronóstico de estos pacientes.

Inflammatory bowel disease (IBD) encompasses two entities, Crohn's disease (CD) and ulcerative colitis (UC), which are chronic, recurrent, immune-mediated inflammatory diseases that, although affect the gut, may be accompanied by extraintestinal hepatobiliary manifestations in 5% of the cases. Among them, the most frequent are non-alcoholic fatty liver disease (NAFLD), cholelithiasis, primary sclerosing cholangitis (PSC), IgG4-related cholangitis, autoimmune hepatitis (AIH), AIH/PSC overlap syndrome, as well as drug-induced liver injury (DILI); and other less frequent such as primary biliary cholangitis (PBC), portal vein thrombosis, liver abscesses, granulomatous hepatitis, hepatitis B and C, reactivation of hepatitis B due to different drugs, and amyloidosis. These hepatobiliary manifestations present with a pathophysiology similar or even the same as that of IBD, where several factors participate, including the innate and adaptive immune system, an interaction with the components of the microbiota, leaky gut, genetic risk factors (common for both IBD and hepatobiliary manifestations) and environmental triggers. The first manifestation of a hepatobiliary disorder is the alteration of the liver profile; therefore, the diagnostic approach should be aimed at evaluating and monitoring liver enzymes and their association with some differential pattern of hepatocellular or cholestatic changes, in order to make appropriate decisions regarding the suspension or modification of any medication, or any other approach that prevents or delays the evolution of hepatobiliary disease, and at the same time guarantees control of IBD, improving the prognosis of these patients.

Lyciumbarbarum polysaccharides ameliorate canine acute liver injury by reducing oxidative stress, protecting mitochondrial function, and regulating metabolic pathways / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.

Construction and Application of Liver Injury Risk Prediction Model of Chinese Medicinals based on Indirect Toxicity / 中医杂志

ObjectiveTo explore and establish the liver injury risk prediction model of indirect toxicity of Chinese medicinals under the condition of compound formulas， and provide new ideas and methods for the study of evaluation of liver injury of Chinese medicinals based on indirect toxicity. MethodsTaking Buguzhi （Fructus Psoraleae） pre-parations as model drug， the combined Chinese medicinals with Buguzhi （Fructus Psoraleae） of high frequency are screened out， and their components and action targets were obtained through TCMSP， TCMIP and PharmMapper databases. The association strength value and risk value of Chinese medicinals that acted on the nuclear factor κB （NF-κB） pathway were analyzed. For those having greater values than the median association strength value and risk value were regarded as indirect Chinese medicinals of liver injury risk. In this way， a prediction model of liver injury risk of Chinese medicinals was constructed based on immune activation-related indirect liver injury process （taking NF-κB pathway as an example）. And verification of the prediction model was performed using Heshouwu （Radix Polygoni Multiflori） preparations. ResultsThe prediction model of liver injury risk based on important immunoactivated pathway （taking NF-κB pathway as an example） found that Yinyanghuo （Herba Epimedii） （association strength value = 0.18， risk value = 0.25） was a Chinese medicinal with potential risk of indirect liver injury within Buguzhi （Fructus Psoraleae） prepartions， which may increase the risk of liver injury by positively regulating Bruton's tyrosine kinase （Btk） and protein kinase C theta （PKCθ） on NF-κB pathway. Further verification of prediction model by Heshouwu （Radix Polygoni Multiflori） preparations showed that Buguzhi （Fructus Psoraleae） （association strength value = 0.25， risk value = 0.33） and Tusizi （Semen Cuscutae） （Semen Cuscutae， association strength value = 0.34， risk value = 0.33） may increase the liver injury risk of Heshouzu. ConclusionThe liver injury risk prediction model of indirect toxicity of Chinese medicinals has been constructed in this study， providing metho-dological reference for the identification of Chinese medicinals of indirect liver injury risk under the condition of compound formulas.

Effect and mechanism of ionizing radiation on ferroptosis in mouse hepatocytes / 中华放射肿瘤学杂志

Objective:To investigate the effect and mechanism of ionizing radiation on ferroptosis in mouse hepatocytes.Methods:Twenty-four C57BL/6J mice were divided into two groups by random number table method: healthy control group (control group, n=6) and irradiation group (whole liver was irradiated with a single dose of 30 Gy X-ray, n=18). Mice were sacrificed at 6, 24 and 72 h (6 mice per time point) after irradiation to obtain liver tissue and plasma samples. The contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma were measured by automatic biochemical analyzer. The prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured by automatic biochemical analyzer. Pathological changes of liver tissues were observed by hematoxylin-eosin (HE) staining. The iron deposition in liver tissues was detected by Prussian blue staining. The expression levels of 4-Hydroxynonenal (4HNE) and hepcidin in the liver were determined by immunohistochemical staining, and quantitative analysis was performed. Plasma malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC) and glutathione (GSH) content were determined by microplate reader analysis according to the kit instructions. The expression levels of transferrin receptor 1 (TfR1), p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the liver were measured by Western blot. Results:Compared with the control group, the plasma contents of ALT ( t=5.15, 5.47, both P<0.001) , AST at 6 and 24 h after irradiation were increased ( t=8.42, 2.50, both P<0.001), the plasma PT was prolonged ( t=3.12, P=0.011) and the APTT was shortened ( t=3.26, P=0.009) at 72 h after radiation in the irradiation group. Histopathological results showed that evident liver edema was observed at 6, 24 and 72 h after irradiation ( t=9.58, 10.09, 18.70, all P<0.001). Different degrees of iron deposition were observed ( t=8.57, 15.31, 32.11, all P<0.001). The infiltration of hepcidin positive cells was significantly increased after irradiation ( t=5.36, 13.17, 17.11, all P<0.001). The number of 4HNE positive cells was significantly increased ( t=18.86, 22.67, 9.12, all P<0.001). At the same time, ionizing radiation induced a significant increase in plasma MDA content ( t=4.36, 7.47, 8.22, all P<0.001), and a decrease in SOD ( t=4.52, 5.80, 7.60, all P<0.001), T-AOC ( t=13.24, 20.49, 24.96, all P<0.001) and GSH ( t=2.78, 6.07, 11.25, P=0.020, <0.001, <0.001), respectively. The expression level of TfR1 protein was significantly up-regulated ( t=3.46, 5.40, P=0.026, 0.006), whereas that of GPX4 protein was significantly down-regulated ( t=11.88, 30.63, both P<0.001) at 24 and 72 h after irradiation. At 6, 24 and 72 h after irradiation, the expression level of p53 protein was significantly up-regulated and maintained at a high level ( t=7.84, 4.25, 8.22, P=0.001, 0.013, 0.001), while that of SLC7A11 protein was significantly down-regulated ( t=9.29, 19.96, 9.09, all P<0.001). Conclusion:Ionizing radiation induces the ferroptosis in hepatocytes, and its mechanism may be related to the activation of p53-SLC7A11-GPX4 pathway.

Retrospective investigation on the normal range of serum alanine aminotransferase levels in healthy adults in Ningbo area / 中华传染病杂志

Objective:To reevaluate the upper limit of normal (ULN) of serum alanine aminotransferase (ALT) by retrospectively analyzing the ALT levels in healthy people in Ningbo area.Methods:A total of 56 140 people who underwent health examination and detection of liver biochemical indexes in the Affiliated Hospital of Medical School of Ningbo University and Yinzhou Huamao Hospital of Ningbo from 2018 to 2020 were enrolled. After excluding relevant factors that may lead to liver injury, 11 411 people were included to compare the difference of serum ALT levels among different genders and age groups (20 to 29 years, 30 to 39 years, 40 to 49 years and 50 to 59 years) to determine the ALT ULN in different gender groups. Statistical methods were performed using two independent samples t test and analysis of variance. Results:The serum ALT of males was (19.20±7.90) U/L, which was higher than that of females ((13.75±6.17) U/L), with statistical significance ( t=41.16, P<0.001). The serum ALT ULN in males and in females were 35 U/L and 26 U/L, respectively. The serum ALT levels of 20 to 29, 30 to 39, 40 to 49 and 50 to 59 years old groups were (15.48±7.61) U/L, (16.21±7.40) U/L, (17.36±7.52) U/L and (18.77±7.57) U/L, respectively.The difference was statistically significant ( F=71.51, P<0.001). Serum ALT level in 50 to 59 years old group was higher than that in 20 to 29 years old group, and the difference was statistically significant ( t=13.11, P<0.01). In males, the ALT ULN of 20 to 29 years old was the lowest of 34.43 U/L, and highest of 35.29 U/L in 40 to 49 years old. In females, the ALT ULN in the 20 to 29 years old group was the lowest of 23.01 U/L, and the ALT ULN in the 50 to 59 years old group was the highest of 30.79 U/L. ALT ULN increased with age in females. The serum ALT of males was higher than that of females in all age groups ( t=29.55, 26.91, 13.43 and 4.62, respectively, all P<0.05). Conclusions:The serum ALT level is significantly correlated to gender and age. The serum ALT ULNs of healthy adult are 35 U/L in males and 26 U/L in females in Ningbo area.

Clinical characteristics of liver function injury in patients with coronavirus disease 2019 / 中华传染病杂志

Objective:To investigate the incidence of liver injury in patients with coronavirus disease 2019 (COVID-19), and to explore its impact on the condition and prognosis of patients.Methods:The medical records of 67 patients with COVID-19 who presented with pneumonia hospitalized at Tongji Hospital, Huazhong University of Science and Technology from February 11 to March 28, 2020 were collected. The results of liver biochemistry and coagulation function test at admission were analyzed. Data were compared by chi-square test, analysis of variance or Kruskal-Wallis H test. Results:Among 67 patients, total bilirubin increased in seven (10.4%) patients, which was slightly abnormal, albumin decreased in 36(53.7%) cases, and was below 30 g/L in 15(22.4%) cases, alanine transaminase (ALT) and aspartate transaminase (AST) were elevated in 19(28.4%) and 12(17.9%) cases, respectively. A total of 22(32.8%) cases had elevated ALT and (or) AST. The incidences with elevated ALT and (or) AST in moderate and severe patients were 33.3%(10/30) and 26.9%(7/26), respectively. Five of 11 critical patients had elevated ALT and (or) AST. There was no significant difference among the three groups ( χ2=1.21, P=0.546). Abnormal alkaline phosphatase and (or) γ-glutamyl transpeptidase were observed in 11(16.4%) cases. The prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) occurred in 10(14.9%) and 17(25.4%) patients, respectively, while most of them were slightly abnormal. Only one patient presented with prolongation of PT and APTT meeting the standard of liver failure. A total of 61.2%(41/67) and 65.7%(44/67) of cases showed increase of fibrinogen and D-dimer, respectively, and 28.4%(19/67) and 19.4%(13/67), respectively increased to an obvious extent. The albumin levels in moderate, severe and critical patients were (37.85±6.19) g/L, (32.96±4.33) g/L and (33.02±3.63) g/L, respectively, which were significantly different ( F=7.36, P=0.001). There were significant differences in PT, APTT, fibrinogen and D-dimer among the three groups ( F=3.22, 3.31, 4.06 and H=17.63, respectively, all P<0.05). Conclusions:COVID-19 only leads to mild liver injury and has only mild impact on liver function. The decrease of albumin level and the increase of fibrinogen and D-dimer may be early predicting indexes for the disease severity.

Clinical analysis of 202 patients with drug-induced liver injury / 中国基层医药

Objective:To investigate the clinical characteristics of drug-induced liver injury and provide a theoretical basis for the prevention and treatment of drug-induced liver injury.Methods:The clinical data of 202 patients with complete information on drug-induced liver injury who received treatment in First Hospital of Shanxi Medical University from November 2018 to November 2021 were collected. The information including gender, age, type and name of drugs taken or exposed, clinical characteristics, autoantibodies, and liver function was statistically analyzed.Results:Among the 202 patients with drug-induced liver injury, 77 patients (38.1%) were male and 125 patients (61.9%) were female. Age distribution was mainly at > 40-60 years. There were 141 cases (69.8%) of hepatocellular type, 27 cases (13.4%) of cholestatic type, and 34 cases (16.8%) of mixed type. There were statistically significant differences in alanine aminotransferase, aspartate aminotransferase, γ-glutamine transferase, alkaline phosphatase, prothrombin time, international standardized ratio, and prothrombin activity between different clinical types ( H = 91.43, 58.65, 9.25, 32.69, 9.56, 8.19, 9.40, all P < 0.05). Among the 202 patients with drug-induced liver injury, severe liver injury occurred in the largest proportion of cases (40.6%). There was no significant difference in the disease severity between different clinical types ( P = 0.789). The top three types of drugs causing liver injury were traditional Chinese medicine [52.0% (105/202)], antineoplastic drugs [6.4% (13/202)], and antipsychotics [5.9% (12/202)]. The detection rate of autoantibodies in 202 patients with drug-induced liver injury was 29.7% (60/202). Conclusion:Drug-induced liver injury lacks specificity in clinical manifestations. A wide variety of drugs can cause liver injury. Clinicians should strengthen liver function monitoring in key populations. The proportion of patients with mixed-type liver failure is high, which should be taken seriously. When patients with drug-induced liver injury are positive for liver disease-related antibodies, clinicians should be vigilant about the possibility of drug-induced liver injury.

The expression of miR-122 in the liver of rats infected with Clonorchis sinensis and its correlation with inflammatory cytokines / 中华地方病学杂志

Objective:To observe the expression changes of microRNA(miR)-122 in liver tissue of rats infected with Clonorchis sinensis and its correlation with expression level of inflammatory cytokines. Methods:Totally 24 SPF grade Wistar male rats were selected and randomly divided into a control group (100 μl physiological saline gavage), a 4-week infection group (100 Clonorchis sinensis metacercariae gavage), and an 8-week infection group (100 Clonorchis sinensis metacercariae gavage) based on body weight (100-120 g) using a random number table method, with 8 rats in each group. Starting from the third week of infection, rat feces were collected and directly smeared with physiological saline for identification of Wistar rat animal models infected with Clonorchis sinensis. After 4 and 8 weeks of infection, the rats in the 4- and 8-week infection groups were euthanized, while 4 rats in the control group were euthanized, respectively. The heart blood and left lobe liver tissue and serum samples were collected from each group of rats. Using hematoxylin-eosin (HE) staining to observe liver pathological damage under the light microscope, real-time fluorescence quantitative PCR to detect the expression level of miR-122 in liver tissue, and Luminex 200 liquid suspension chip to detect the expression levels of serum inflammatory cytokines [tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6 (IL-6)]. The correlation between miR-122 and inflammatory cytokines was analyzed using Pearson correlation. Results:Under the light microscope, the morphology of hepatocytes in control group was normal, and no inflammatory cell infiltration was observed. There was inflammatory cells such as lymphocyte, eosinophil and other inflammatory cell infiltration around the portal area in the 4-week infection group. The hepatocytes of the 8-week infected rats were arranged in a disordered manner, with varying degrees of swelling, loose and lightly stained cytoplasm, and some hepatocytes showed watery degeneration; additionally, bile duct dilation and thickening of the bile duct wall were observed in the liver tissue. There were statistically significant differences of liver miR-122 (1.00 ± 0.32, 2.57 ± 0.60, 3.63 ± 1.63), serum TNF-α [(0.14 ± 0.06), (0.43 ± 0.09), (0.61 ± 0.10) ng/ml], and IL-6 expression levels [(0.03 ± 0.01), (1.06 ± 0.24), (1.48 ± 0.33) ng/ml] in control group, 4- and 8-week infection groups ( F = 13.36, 69.99, 82.23, P < 0.001). There was no statistically significant difference in expression level of IL-1β between different groups ( F = 2.15, P = 0.141). The Pearson correlation analysis showed that the expression level of miR-122 was positively correlated with the expression levels of inflammatory cytokines TNF-α and IL-6 ( r = 0.67, 0.80, P < 0.001). Conclusion:Clonorchis sinensis infection can increase the expression of miR-122 in the host liver tissue, and the miR-122 is closely related to the expression levels of inflammatory cytokines TNF-α and IL-6.

Short-term medication of dapagliflozin exacerbates CCl4 induced acute liver injury / 西安交通大学学报(医学版)

【Objective】 To investigate the role and mechanism of dapagliflozin (Dapa), a sodium glucose co-transporter 2 inhibitor, in acute liver injury. 【Methods】 Eight-week-old C57BL6/J mice were given a single intraperitoneal injection of CCl4 to induce acute liver injury. The mice were preventively given 5 mg/kg Dapa by gavage 24 h and 2 h before CCl4 injection, while those in the control group were given an equal volume of solvent gavage. After 24 h, the mice were anesthetized and sacrificed. H&E staining, plasma biochemistry, RT-qPCR, and Western blotting were used to detect the severity of liver injury and the expressions of macrophage-related genes. 【Results】 In the CCl4 group, hepatic infiltration of inflammatory cells increased, and liver and renal functions significantly deteriorated, which was further aggravated by Dapa. CCl4 could promote the expressions of M1 macrophages and fibrosis-related genes in the liver, but reduce those of M2 and antioxidant-related genes, and the latter was further inhibited by Dapa. In addition, the protein expression of arginase 1 decreased and that of SGLT2 increased after Dapa intervention, while NF-κB pathway did not change significantly, suggesting that Dapa might directly affect the energy metabolism homeostasis in the liver and aggravate acute liver injury induced by CCl4. 【Conclusion】 Dapa can exacerbate hepatic and renal damage in acute stage of liver injury, inhibit macrophages M2 polarization, and aggravate oxidative stress and inflammatory injury induced by CCl4.

The S1P1 regulator IMMH002 and its therapeutic effect and mechanism on autoimmune hepatitis / 药学学报

This study assessed and explored the pharmacological effects and mechanisms of action of IMMH002 {2-amino-2-(2-(4ʹ-(2-ethyloxazol-4-yl)-[1,1ʹ-biphenyl]-4-yl)ethyl)propane-1,3-dio}, a selective sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, in a concanavalin A (ConA)-induced autoimmune hepatitis (AIH) mouse model. The experimental protocol strictly adhered to the guidelines of the Ethics Committee for Animal Research of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No.: 00004046). Male ICR mice were pre-treated with the drug for four days, followed by induction of AIH through tail vein injection of ConA protein. Liver function, hepatic tissue pathology, peripheral blood parameters, as well as immunoglobulin G (IgG), inflammatory cytokines, T cell distribution, and inflammatory pathways were evaluated in mice. Results demonstrated that IMMH002 significantly reduced liver function indicators such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated hepatic tissue inflammation and necrotic damage, decreased serum IgG levels, and lowered the expression of inflammatory mediators including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). Additionally, it facilitated T lymphocyte homing, downregulated the phosphorylation of nuclear factor kappa-B (NF-κB), IκB kinase β (IKKβ) and nuclear factor inhibitor protein-α (IκBα) proteins in hepatic tissue and cellular inflammation models. Collectively, IMMH002 effectively ameliorated ConA-induced autoimmune hepatitis in mice, exhibiting extensive anti-inflammatory and anti-necrotic effects, thereby laying a theoretical foundation for AIH clinical treatment.

Hepatoprotective activity of Zha Xun and its different solvent-eluting components / 药学学报

A pharmacophore-based study was conducted to investigate the therapeutic activity of the traditional Tibetan medicine Zha Xun (ZX) in liver diseases. In the present study, the protective effect of ZX on the acute liver injury induced by concanavalin A (ConA) and 0.15% carbon tetrachloride (0.15% CCl4) in ICR mice was evaluated, and the results showed that ZX significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the ConA-induced acute immune liver injury model and the CCl4-induced acute oxidative liver injury model (P < 0.05). Subsequently, the protective effects of aqueous, 95% ethanol, 60% ethanol and 30% ethanol eluting fractions of ZX, and fulvic acid, the main water-soluble constituent of ZX, were evaluated against acute oxidative liver injury induced by 0.15% CCl4 in mice. The results showed that different solvent-eluting fractions of ZX showed certain hepatoprotective activities, among which the aqueous extract of ZX and 30% ethanol extract of ZX significantly reduced the serum levels of ALT, AST, and lactate dehydrogenase (LDH) in mice (P < 0.05), and the serum levels of LDH in mice were significantly reduced by fulvic acid (P < 0.05), which showed significant hepatoprotective activity. The protective activities and preliminary mechanisms of the total extract of ZX, the aqueous extract of ZX, the 30% ethanol extract of ZX, and fulvic acid against hepatocellular injury in vitro were further evaluated by using the H2O2-induced hepatocellular injury model. The results showed that the components could significantly inhibit H2O2-induced hepatocellular injury, reduce the levels of ALT, alkaline phosphatase (ALP), and LDH, improve the survival rate of hepatocellular cells, and reduce the content of intracellular reactive oxygen species (ROS) in cell culture. At the same time, it can inhibit hepatocyte apoptosis by increasing the expression ratio of Bcl-2/BAX protein and decreasing the expression ratio of cleaved caspase-3/pro caspase-3 protein. The present study showed that ZX has clear hepatoprotective activity in vitro and in vivo, and the different solvent elution fractions of ZX showed certain hepatoprotective activity, among which the aqueous extract of ZX, 30% ethanol extract of ZX had better hepatoprotective activity, and the activity of 60% ethanol extract of ZX was stronger than that of 95% ethanol extract of ZX. The activity of ZX and its water-soluble elution site exerted hepatoprotective effects by inhibiting hepatocyte apoptosis and oxidative stress. The animals used in this experiment and related disposal meet the requirements of animal welfare, and have been reviewed and approved by the Laboratory Animal Management and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences (approval number: 00004018).

Value of the serum levels of Clusterin and sphingosine 1-phosphate in assessing the prognosis of sepsis patients with acute liver injury / 临床肝胆病杂志

ObjectiveTo investigate the value of the serum levels of Clusterin and sphingosine 1-phosphate （S1P） in assessing the prognosis of sepsis patients with acute liver injury. MethodsA total of 127 sepsis patients with acute liver injury who were admitted to Lianyungang Hospital， Xuzhou Medical University， from March 2019 to May 2022 were enrolled， and according to their prognosis after 28 days of treatment， they were divided into death group with 35 patients and survival group with 92 patients. The independent-samples t test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between groups. A pearson correlation analysis was used to investigate the correlation. The prognostic value of serum Clusterin and S1P was analyzed by receiver operating characteristic curve. ResultsThere were significant differences between the two groups in the degree of liver injury， Acute Physiology and Chronic Health Evaluation Ⅱ （APACHEⅡ） score， Sequential Organ Failure Assessment （SOFA） score， the presence or absence of acute kidney injury， prothrombin time （PT）， international normalized ratio （INR）， Child-Pugh class， and C-reactive protein （all P<0.05）. The death group had significantly lower serum levels of Clusterin and S1P than the survival group （t=11.094 and 10.390， both P<0.05）. The patients with severe liver injury had significantly lower serum levels of Clusterin and S1P than those with mild or moderate liver injury （t=9.825 and 11.418， both P<0.05）. The multivariate regression analysis showed that the degree of liver injury （odds ratio ［OR］=1.260， 95% confidence interval ［CI］： 1.081 — 1.468， P<0.05）， APACHEII score （OR=1.031， 95%CI： 1.019 — 1.044， P<0.05）， SOFA score （OR=1.066， 95%CI： 1.039 — 1.094， P<0.05）， Clusterin （OR=0.899， 95%CI： 0.859 — 0.940， P<0.05）， and S1P （OR=0.824， 95%CI： 0.749 — 0.908， P<0.05） were independent risk factors for the prognosis of patients with sepsis. The ROC curve analysis showed that serum Clusterin and S1P used alone or in combination had an area under the ROC curve of 0.864， 0.861， and 0.949， respectively. Serum Clusterin and S1P were significantly negatively correlated with alanine aminotransferase， total bilirubin， PT， and INR in sepsis patients with acute liver injury （all P<0.05）. ConclusionThe sepsis patients with acute liver injury who died had significant reductions in serum Clusterin and S1P compared with those who survived， and the levels of Clusterin and S1P are closely associated with the degree of liver injury. The combination of Clusterin and S1P has a good value in predicting the prognosis of sepsis patients with acute liver injury and is expected to become a potential marker for predicting the prognosis of sepsis patients with acute liver injury.

Protective mechanism of Yinchenzhufu decoction against cholestatic liver injury induced by lithic acid based on network pharmacology / 药学学报

Yinchenzhufu decoction (YCZFD) is a classic formula for treating Yin Huang syndrome, which can improve liver injury caused by cholestasis. However, the mechanism of action of YCZFD still remains unclear. This article used network pharmacology, molecular docking, animal experiments, and molecular biology methods to explore the mechanism of YCZFD in treating liver injury caused by cholestasis. A mouse model of acute cholestasis induced by lithocholic acid was used to investigate the effects of YCZFD on liver injury. The experimental procedures described in this paper were reviewed and approved by the Ethical Committee at the Shanghai University of Traditional Chinese Medicine (approval NO. PZSHUTCM190823002). The results showed that YCZFD could reduce the levels of blood biochemical indicators and improve hepatocyte damage of cholestatic mice. Then, multiple databases were used to predict the corresponding targets of YCZFD active components on cholestatic liver injury. An intersection target protein-protein interaction (PPI) networks based on String database and Cytoscape software was used to demonstrate the possible core targets of YCZFD against cholestatic liver injury. The results indicated that core targets of YCZFD include tumor necrosis factor, interleukin-1β, non-receptor tyrosine kinase Src, interleukin-6, etc. GO (gene ontology) and KEGG (kyoto encyclopedia of genes and genomes) enrichment analysis indicated that YCZFD may regulate the tumor necrosis factor signaling pathway, nuclear factor-κB signaling pathway, bile secretion, and other related factors to ameliorate the cholestatic liver injury. AutoDockTools software was used to perform molecular docking verification on the core targets and components of YCZFD. To verify the results of network pharmacology, UPLC-MS/MS method was used to determine the effect of YCZFD on levels of bile acid profiles in mouse liver tissues. It was found that treatment with YCZFD significantly reduced the content of free bile acids, taurine bound bile acids, and total bile acids in the liver tissues of cholestatic mice. Then, results from real time PCR and Western blot also found that YCZFD can upregulate the expression of hepatic nuclear receptor farnesoid X receptor, metabolizing enzyme (UDP glucuronidase transferase 1a1), and efflux transporters (bile salt export pump, multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, etc) in cholestasis mice, promote bile acid metabolism and excretion, and improve bile acid homeostasis. Moreover, YCZFD can also inhibit pyroptosis and inflammation by regulating NOD-like receptors 3 pathway, thereby inhibiting cholestatic liver injury.

Polysaccharide of Balanophora involucrata Hook. f. attenuates cell ferroptosis in rats with experimental liver injury through SLC7A11/GPX4 pathway / 药学学报

Polysaccharide of Balanophora involucrata Hook. f. (BPS), the major component of Balanophora involucrata Hook. f., was confirmed the protective effect on liver injury in our previous study. This research aimed to investigate the protective mechanism of BPS on experimental liver injury by attenuating cell ferroptosis through modulating solute carrier family 7 member 11/glutathione peroxidase 4 (SLC7A11/GPX4) pathway. The animal experiment was approved by the Experimental Animal Ethical Committee of Hubei Minzu University and all rats had received human care in compliance with the institutional animal care guidelines. Rats were given intraperitoneal injection of (D-galactosamine, D-GalN) solution (800 mg·kg-1) one time to establish the acute liver injury model. The results showed aspartate amino transferase (AST), alanine aminotransferase (ALT) and 4-hydroxynonenal (4-HNE) levels in serum were decreased, and the contents of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA) and lipid peroxide (LPO) in liver tissues also decreased and glutathione (GSH) level increased after BPS administration with 200 mg·kg-1. Besides, BPS reduced iron deposition and increased the expression of SLC7A11 and GPX4 proteins in liver tissue. In conclusion, BPS ameliorated experimental liver injury by alleviating cell ferroptosis through SLC7A11/GPX4 pathway. The present study pointed to the possibility of utilizing BPS for protection against liver injury in clinic.