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.

Investigation of the protective effect of boric acid against hepatotoxic and nephrotoxic injury induced by acrylamide in rats / Investigación del efecto protector del ácido bórico contra lesiones hepatotóxicas y nefrotóxicas inducidas por acrilamida en ratas

SUMMARY: To investigate if the administration of boric acid (BA) would exert any protective effect against possible nephrotoxicity and hepatotoxicity induced by the exposure to acrylamide (ACR) in rats. In our study, we used a total of 28 rats that were divided into four equal groups. Group 1: the control group which was not treated with any procedure. Group 2: the ACR group that was administered ACR 50 mg/kg/day via intraperitoneal (i.p) route for 14 days. Group 3: the BA group that was administered BA 200 mg/kg/ day via gavage via peroral (p.o) route for 14 days. Group 4: the ACR+BA group that was administered BA simultaneously with ACR. Total antioxidant and oxidant (TAS/TOS) capacities were measured in all groups at the end of the experiment. In addition, the specimens obtained were evaluated with histopathological examination. Studies showed that the ACR and ACr+BA groups were not significantly different in terms of hepatic TAS level while the TOS level was higher in the ACR group than the ACR+BA group. The groups did not show any significant difference regarding renal TAS and TOS levels. In the histopathological examination of the hepatic tissue, the histopathological injury score of the ACR group was significantly higher than those of the other groups whereas it was significantly lower in the ACR+BA group than the ACR group. Our study concluded that Boric acid had a protective effect against acrylamide- induced hepatotoxicity, but not against nephrotoxicity.

El objetivo de este estudio fue investigar si la administración de ácido bórico (BA) ejercería algún efecto protector frente a la posible nefrotoxicidad y hepatotoxicidad inducida por la exposición a acrilamida (ACR) en ratas. En nuestro estudio, utilizamos un total de 28 ratas que se dividieron en cuatro grupos iguales. Grupo 1: grupo control que no fue tratado. Grupo 2: grupo ACR al que se le administró ACR 50 mg/kg/día por vía intraperitoneal (i.p) durante 14 días. Grupo 3: grupo BA al que se le administró BA 200 mg/kg/día por sonda por vía peroral (p.o) durante 14 días. Grupo 4: grupo ACR+BA al que se administró BA simultáneamente con ACR. Las capacidades antioxidantes y oxidantes totales (TAS/TOS) se midieron en todos los grupos al final del experimento. Además, los especímenes obtenidos fueron evaluados con examen histopatológico. Los estudios demostraron que los grupos ACR y ACr+BA no fueron significativamente diferentes en términos del nivel hepático de TAS, mientras que el nivel de TOS fue mayor en el grupo ACR que en el grupo ACR+BA. Los grupos no mostraron ninguna diferencia significativa con respecto a los niveles renales de TAS y TOS. En el examen histopatológico del tejido hepático, la puntuación de lesión histopatológica del grupo ACR fue significativamente mayor que la de los otros grupos, mientras que fue significativamente menor en el grupo ACR+BA que en el grupo ACR. Nuestro estudio concluyó que el ácido bórico tiene un efecto protector contra la hepatotoxicidad inducida por acrilamida, pero no contra la nefrotoxicidad.

Protective effect of linoleic acid on liver toxicity induced by methotrexate / Efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato

SUMMARY: We aimed to investigate the protective effect of linoleic acid on liver toxicity induced by methotrexate. The study was carried out in partnership with the Department of Anatomy and Department of Medical Pharmacology of Çukurova University Faculty of Medicine, using the laboratory facilities of the Department of Medical Pharmacology. Human hepatocyte cell line (CRL- 11233) cells obtained from the American Type Culture Collection Organization (ATCC) were used. Expressions of apoptotic pathway markers, apoptosis inducing factor (AIF), BAX, BCL 2, GADD 153, 78-kDa glucose-regulated protein (GRP78), and CASPASE-3 were evaluated. All analyzes were examined in four groups (Group 1; control, Group 2; linoleic acid given, Group 3; methotrexate given and Group 4; linoleic acid and methotrexate given). The mean ± standard error values of the obtained results as nanogram / milliliter (ng / ml) are in Group I, Group II, Group III and Group IV, respectively; AIF values, 0.4150 ± 0.1208, 0.3633 ± 0.2389, 1.792 ± 0.3611 and 1.077 ± 0.1646, BAX values, 0.900 ± 0.1864, 1.002 ± 0.2098, 8.352 ± 1.467 and 4.295 ± 1.522, BCL 2 values, 13.93 ± 1.198, 13.92 ± 1.739, 2.938 ± 1.059 and 9.250 ± 1.492, GADD 153, 0.7333 ± 0.1751, 0.7067 ± 0.2115, 1.650 ± 0.2950 and 1.237 ± 0.1805, GRP78, 0.4767 ± 0.1804, 0.5233 ± 0.1590, 2.183 ± 0.2639 and 1.112 ± 0.2693, CASPASE-3 values , 1.127 ± 0.2033, 0.8317 ± 0.3392, 13.50 ± 1.871 and 8.183 ± 1.030. It was determined that linoleic acid has a protective effect on methotrexate-induced liver toxicity.

Nuestro objetivo fue investigar el efecto protector del ácido linoleico sobre la toxicidad hepática inducida por metotrexato. El estudio se llevó a cabo en colaboración con el Departamento de Anatomía y el Departamento de Farmacología Médica de la Facultad de Medicina de la Universidad de Çukurova, utilizando las instalaciones del laboratorio del Departamento de Farmacología Médica. Se usaron células de la línea celular de hepatocitos humanos (CRL-11233) obtenidas de la American Type Culture Collection Organisation (ATCC). Se evaluaron las expresiones de marcadores de vías apoptóticas, factor inductor de apoptosis (AIF), BAX, BCL 2, GADD 153, proteína regulada por glucosa de 78 kDa (GRP78) y CASPASE-3. Todos los análisis se examinaron en cuatro grupos (Grupo 1; control, Grupo 2; se administró ácido linoleico, Grupo 3; se administró metotrexato y Grupo 4; se administró ácido linoleico y metotrexato). Los valores medios ± error estándar de los resultados obtenidos como nanogramo/mililitro (ng/ml) se encuentran en el Grupo I, Grupo II, Grupo III y Grupo IV, respectivamente; Valores de AIF, 0,4150 ± 0,1208, 0,3633 ± 0,2389, 1,792 ± 0,3611 y 1,077 ± 0,1646, valores de Bax, 0,900 ± 0,1864, 1,002 ± 0,2098, 8,352 ± 1,467 y 4,295 ± 1,522, BCL 2 valores, 13,93 ± 1,199. 2,938 ± 1,059 y 9,250 ± 1,492, GADD 153, 0,7333 ± 0,1751, 0,7067 ± 0,2115, 1,650 ± 0,2950 y 1,237 ± 0,1805, Grp78, 0,4767 ± 0,1804, 0,5233 ± 0,1590, 2,183, ± 1,263. 1,127 ± 0,2033, 0,8317 ± 0,3392, 13,50 ± 1,871 y 8,183 ± 1,030. Se determinó que el ácido linoleico tiene un efecto protector sobre la toxicidad hepática inducida por metotrexato.

Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements / 中国中药杂志

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Hepatotoxicity and mechanism of Rhododendri Mollis Flos based on zebrafish model / 中国中药杂志

This study used the zebrafish model to explore the hepatotoxicity of Rhododendri Mollis Flos(RMF). The mortality was calculated according to the number of the survival of zebrafish larvae 4 days after fertilization under different concentration of RMF, and the dose-toxicity curve was fitted to preliminarily evaluate the toxicity of RMF. The liver phenotypes under the sublethal concentration of RMF in the treatment group and the blank control group were observed by hematoxylin-eosin(HE) staining and acridine orange(AO) staining. Meanwhile, the activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were determined to confirm the hepatotoxicity of RMF. Real-time quantitative polymerase chain reaction(real-time PCR) and Western blot were used to determine the expressions of genes and proteins in zebrafish larvae. Gas chromatography time-of-flight mass spectrometry(GC-TOF-MS) was used to conduct untargeted metabolomics testing to explore the mechanism. The results showed that the toxicity of RMF to zebrafish larvae was dose-dependent, with 1 100 μg·mL~(-1) of the absolute lethal concentration and 448 μg·mL~(-1) of sublethal concentration. The hepatocyte apoptosis and degeneration appeared in the zebrafish larvae under the sublethal concentration of RMF. The content of ALT and AST in zebrafish larvae at the end of the experiment was significantly increased in a dose-dependent manner. Under the sublethal concentration, the expressions of genes and proteins related to apoptosis in zebrafish larvae were significantly increased as compared with the blank control group. The results of untargeted metabolomics showed that the important metabolites related to the he-patotoxicity of RMF were mainly enriched in alanine, aspartic acid, glutamic acid, and other pathways. In conclusion, it is inferred that RMF has certain hepatotoxicity to zebrafish larvae, and its mechanism may be related to apoptosis.

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.

Standardize the diagnosis and treatment of drug-induced liver injury, and strengthen clinical and translational research / 中华肝脏病杂志

As a liver disease with the most complex clinical phenotype, drug-induced liver injury (DILI) poses great challenges in diagnosis and management in clinical practice. Although guidelines based on the latest research advances can provide clinicians with guidance on the identification, diagnosis, and management of DILI, the overall level of evidence in this field is relatively low and high-level evidence is limited. Therefore, we should interpret guidelines with caution and look forward to more clinical and translational research to address the huge unmet clinical needs in DILI.

Drug-induced bile duct injury: progress and challenges / 中华肝脏病杂志

Drug-induced bile duct injury is a specific kind of drug-induced liver injury that has two main pathological types, namely ductopenia, or vanishing bile duct syndrome, and secondary sclerosing cholangitis. However, in recent years, the reports of new drugs that cause bile duct injury have been constantly increasing, and these drugs have different clinicopathological features and a novel pathogenesis. Therefore, this paper summarizes and analyzes the progress and challenges in the etiology, pathogenesis, diagnosis and treatment, and other aspects of drug-induced bile duct injury.

c-Jun N-terminal kinase signaling pathway in acetaminophen-induced liver injury / 中华危重病急救医学

Acetaminophen (APAP) is the most common antipyretic, analgesic and anti-inflammatory drug, but its overdose often leads to acute liver injury, even acute liver failure, and death in some severe cases. At present, there is still a lack of specific treatments. The c-Jun N-terminal kinase (JNK) signal pathway is one of the potential therapeutic targets identified in recent years in overdose APAP-induced acute liver injury. This article reviews the JNK signaling pathway of APAP in liver metabolism, the activation of JNK signaling pathway and the amplification of oxidative stress, other pathways or cellular processes related to JNK signaling pathway, and the possible challenges of drugs targeting JNK, so as to provide direction and feasibility analysis for further research and clinical application of JNK signaling pathway targets in APAP hepatotoxicity, and to provide reference for searching for other targets.

Ferroptosis and drug-induced liver injury / 中华肝脏病杂志

Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.

Significance of histological assessment in drug-induced liver injury / 中华肝脏病杂志

Liver histological assessment is of great clinical significance for the diagnosis, classification, and prognosis prediction of drug-induced liver injury (DILI). Liver histological evaluation can effectively supplement RUCAM. The clinical phenotypes of DILI are complex and diverse, including acute, chronic and severe hepatic injury. DILI has multiple insult-targets, including hepatocytes, cholangiocytes, and vascular endothelial cells and others. The pathological damage patterns are similar to many types of non-DILI liver diseases, therefore making differential diagnosis difficult. New anti-tumor drugs such as immune checkpoints inhibitors and targeted therapy are widely used in clinical antineoplastic practice, thus the growing incidence of related liver injury occurs. Liver histological examination can effectively assess the pathological phenotypes and severity of DILI, so as to guide treatment. In uncommon conditions such as special types of DILI (such as hepatic vascular disease), DILI with other competitive etiology overlapping, chronic DILI, and DILI induced liver failure, liver histological assessment can provide strong support for identifying the cause, rational treatment, and prognosis. Currently, the histological evaluation system for drug-induced liver injury seems to be a lack of consensus, and the diagnosis of DILI is short of highly specific and sensitive serological markers. All in all, liver histological assessment plays a crucial role in the diagnosis and differential diagnosis of DILI.

Comparative analysis of clinical diagnosis and treatment guidelines for drug-induced liver injury at home and abroad / 中华肝脏病杂志

Drug-induced liver injury influencing factors are complex and have diverse clinical manifestations. Simple and reliable diagnostic methods are still deficient, and further classification of toxicological mechanisms is required. There are numerous pertinent discrepancies between domestic and international guidelines aimed at drug-induced liver injury diagnosis and treatment, with partial to no consensus on the content. The American Gastroenterological Association's 2021 Clinical Guidelines, the Asia-Pacific Association for the Study of the Liver's 2021 Consensus Guidelines, the Council for International Organizations of Medical Sciences' 2020 International Consensus, the European Society's Hepatology Committee's 2019 Clinical Practice Guidelines, and the 2015 Chinese Medical Association Guidelines are five influential clinical guidelines on drug-induced liver injury at home and abroad. The epidemiology, risk factors, diagnosis and evaluation, treatment management, and other contents, particularly traditional Chinese medicine, were compared and analyzed using other relevant consensus opinions or guidelines in order to improve understanding and provide a reference for clinical diagnosis and treatment of drug-induced liver injury.

Advances in clinical diagnosis and treatment of drug-induced liver injury in children / 中华肝脏病杂志

Drug-induced liver injury (DILI) is one of the most common adverse drug reactions that may seriously threaten the health of children and is receiving increasing clinical attention day by day. There is still no independent diagnosis and treatment guideline for DILI in children, but its clinical features are not completely similar to those in adults. This article reviews the epidemiology, clinical features, diagnosis, and treatment progress in order to provide a reference for the management of DILI in children.

Genetic susceptibility to drug-induced liver injury / 中华肝脏病杂志

Drug-induced liver injury (DILI) risk prediction, diagnosis establishment, clinical management, and all other aspects are facing great challenges. Although the current understanding of its pathogenesis is still incomplete, research over the past 20 years has shown that genetic susceptibility may play an important role in the occurrence and development of DILI. In recent years, pharmacogenomics studies have further revealed the association between human leukocyte antigen (HLA) genes, some non-HLA genes, and hepatotoxicity from certain drugs. However, due to the lack of well-designed, prospective, large-sample cohort validation and low positive predictive values, there may still be some way to go before the current results can be truly translated into clinical practice for precise prediction and prevention of DILI risk.

Statin-related drug-induced liver injury / 中华肝脏病杂志

Statins are a kind of prescription drug that is widely used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic diseases. A common side effect of statin use is a mild rise in liver aminotransferases, which occurs in less than 3% of patients. Statin-related liver injury is most commonly caused by atorvastatin and simvastatin, but severe liver injury is uncommon. Therefore, understanding and evaluating hepatotoxicity and weighing the benefits and risks is of great significance to better realize the protective effect of statins.

Effects of titanium dioxide nanoparticles on circRNA expression profiles in human hepatocellular carcinoma cells HepG2 / 北京大学学报(医学版)

OBJECTIVE@#To investigate the effect of titanium dioxide nanoparticles (TiO2 NPs) on the expression profile of circular ribonucleic acid (circRNA) in human hepatocytes through in vitro cell experiments, and to attempt to understand the potential mechanism of hepatotoxicity through bioinformatics analysis.@*METHODS@#TiO2 NPs were characterized from the aspects of particle size, shape and agglomeration state. The cell counting kit-8 (CCK8) was used to detect the cytotoxicity of TiO2 NPs against human hepatocellular carcinoma cells (HepG2) after exposure to 0, 1.56, 3.13, 6.25, 12.5, 25, 50, 100, and 200 mg/L TiO2 NPs for 24 h or 48 h. The cells were treated at doses of 0 mg/L TiO2 NPs (control group) and 100 mg/L TiO2 NPs (treatment group), and collected after exposure for 48 h, and then RNA from the extracted cell samples was collected and sequenced. The differential circRNAs between the control and the TiO2 NPs treatment groups were screened, and then the enrichment pathway of the differential circRNA target gene was analyzed by multivariate statistics. According to the sequencing results, significantly altered genes and important genes in the significant enrichment pathways were screened, and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) was performed to verify the results.@*RESULTS@#TiO2 NPs were spherical anatase with a hydrated particle size of (323.50±85.44) nm and a Zeta potential of (-21.00±0.72) mV in a serum-free medium. The results of the CCK8 cytotoxicity assay showed that with the increase of TiO2 NPs concentration, cell viability gradually decreased. A total of 11 478 circRNAs were found by RNA sequencing. Compared with the control groups, TiO2 NPs treatment groups (100 mg/L) had a total of 89 differential circRNAs, of which 59 were up-regulated and 30 were down-regulated. Analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed that the targeted genes of differential circRNAs were mainly enriched in fatty acid degradation, Fanconi anemia pathway, and fatty acid metabolism. The expression levels of circRNA.6730, circRNA.3650 and circRNA.4321 were significantly different between the TiO2 NPs treatment group and the control group, which were consistent with the sequencing results.@*CONCLUSION@#TiO2 NPs can induce changes in circRNA expression profile, and epigenetics may play an important role in the mechanism of hepatotoxicity.

Treatment response of a two-dose regimen of dose-adjusted inotuzumab ozogamicin in relapsed/refractory B-cell acute lymphoblastic leukemia / 中华血液学杂志

Objective: To observe the treatment response of a two-dose regimen of inotuzumab ozogamicin (inotuzumab), a monoclonal antibody targeting CD22, for patients with heavily treated relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), including those failed or relapsed after chimeric antigen receptor (CAR) -T-cell therapy. Methods: Pediatric and adult patients who received two doses of inotuzumab and who were evaluated after inotuzumab treatment were included. Antibody infusions were performed between March 2020 and September 2022. All patients expressed CD22 antigen as detected by flow cytometry (>80% leukemic cells displaying CD22) before treatment. For adults, the maximum dosage per administration was 1 mg (with a total of two administrations). For children, the maximum dosage per administration was 0.85 mg/m(2) (no more than 1 mg/dose; total of two administrations). The total dosage administered to each patient was less than the standard dosage of 1.8 mg/m(2). Results: Twenty-one patients with R/R B-ALL were included, including five children (<18 years old) and sixteen adults. Seventeen patients presented with 5.0% -99.0% leukemic blasts in the bone marrow/peripheral blood or with extramedullary disease, and four patients were minimal residual disease (MRD) -positive. Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Eleven patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). After inotuzumab treatment, 14 of 21 patients (66.7% ) achieved a complete response (CR, one was MRD-positive CR), and all four MRD-positive patients turned MRD-negative. Four of six patients who failed recent CD22 CAR-T-cell therapy achieved a CR after subsequent inotuzumab treatment. Seven patients (33.3% ) demonstrated no response. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. Conclusion: For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.

Identification of Q-markers for Schisandrae Sphenantherae Fructus in treating drug-induced liver injury based on network pharmacology, fingerprint and quantitative analysis / 中国中药杂志

This study aims to establish the ultra-performance liquid chromatography(UPLC) fingerprint and multi-indicator quantitative analysis method for Schisandrae Sphenantherae Fructus(SSF) and to screen out the potential quality markers(Q-markers) of hepatoprotection based on network pharmacology. The similarity analysis was performed using the Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System, which showed that the similarity of the fingerprints of 15 samples from different regions ranged from 0.981 to 0.998. Eighteen common components were identified, from which 3 differential components were selected by cluster analysis and principal component analysis. The "component-target-pathway" network was built to predict the core components related to the hepatoprotective effects. Fourteen core components were screened by network pharmacology. They acted on the targets such as AKT1, CCND1, CYP1A1, CYP3A4, MAPK1, MAPK3, NOS2, NQO1, and PTGS2 to regulate the signaling pathways of lipid metabolism and atherosclerosis, hepatitis B, interleukin-17, and tumor necrosis factor. Considering the chemical measurability, characteristics, and validity, schisantherin A, anwulignan, and schisandrin A were identified as the Q-markers. The content of schisantherin A, anwulignan, and schisandrin A in the test samples were 0.20%-0.57%, 0.13%-0.33%, and 0.42%-0.70%, respectively. Combining the fingerprint, network pharmacology, and content determination, this study predicted that schisantherin A, anwulignan, and schisandrin A were the Q-markers for the hepatoprotective effect of SSF. The results can provide reference for improving the quality evaluation standard and exploring the hepatoprotective mechanism of SSF.

Protective effect and mechanism of Astragalus membranaceus and Angelica sinensis compatibility against triptolide-induced hepatotoxicity by regulating Keap1/Nrf2/PGC-1α / 中国中药杂志

This paper aims to investigate the protective effect and mechanism of Astragalus membranaceus and Angelica sinensis before and after compatibility against triptolide(TP)-induced hepatotoxicity. The experiment was divided into a blank group, model group, Astragalus membranaceus group, Angelica sinensis group, and compatibility groups with Astragalus membranaceus/Angelica sinensis ratio of 1∶1, 2∶1, and 5∶1. TP-induced hepatotoxicity model was established, and corresponding drug intervention was carried out. The levels of alanine transaminase(ALT), aspartate transaminase(AST), and alkaline phosphatase(ALP) in serum were detected. Pathological injuries of livers were detected by hematoxylin-eosin(HE) staining. The levels of malondialdehyde(MDA), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), and reduced glutathione(GSH) in the liver were measured. Wes-tern blot method was used to detect the expression of nuclear factor erythroid 2-related factor 2(Nrf2), Kelch-like ECH-associated protein 1(Keap1), peroxisome proliferator-activated receptor gamma, coactivator-1 alpha(PGC-1α), heme oxygenase-1(HO-1), and NAD(P)H quinone dehydrogenase 1(NQO1) in livers. Immunofluorescence was used to detect the expression of Nrf2 and PGC-1α in livers. The results indicated that Astragalus membranaceus/Angelica sinensis ratio of 2∶1 and 5∶1 could significantly reduce the levels of serum AST, ALT, and ALP, improve the pathological damage of liver tissue, increase the levels of GSH and GSH-Px, and reduce the content of MDA in liver tissue. Astragalus membranaceus/Angelica sinensis ratio of 1∶1 and 2∶1 could significantly improve the level of SOD. Astragalus membranaceus and Angelica sinensis before and after compatibility significantly increased the protein expression of HO-1 and NQO1, improved the protein expression of Nrf2 and PGC-1α, and decreased the protein expression of Keap1 in liver tissue. The above results confirmed that the compatibility of Astragalus membranaceus and Angelica sinensis had antioxidant effects by re-gulating Keap1/Nrf2/PGC-1α, and the Astragalus membranaceus/Angelica sinensis ratio of 2∶1 and 5∶1 had stronger antioxidant effect and significantly reduced TP-induced hepatoto-xicity.

Correlation between drug-induced liver injury in rats caused by Xianling Gubao oral preparation and extraction process / 中国中药杂志

In light of the liver injury risk associated with the oral administration of Xianlin Gubao oral preparation, this study compared the differences in liver injury induced by two different extraction processes in rats and explored the correlation between hepatotoxicity and extraction process from the perspective of the differences in the content of the relevant components. Thirty male Sprague-Dawley(SD) rats were randomly divided into a normal group, tablet extract groups of different doses, and capsule extract groups of different doses, with 6 rats in each group. Each group received continuous oral administration for 4 weeks. The assessment of liver injury caused by different extracts was conducted by examining rat body weight, liver function blood biochemical indicators, liver coefficient, and liver pathological changes. In addition, a high-performance liquid chromatography(HPLC) method was established to simultaneously determine the content of icariin, baohuoside I, and bakuchiol in the extracts to compare the differences in the content of these three components under the two extraction processes. The results showed that both extracts caused liver injury in rats. Compared with the normal group, the tablet extract groups, at the studied dose, led to slow growth in body weight, a significant increase in triglyceride levels(P<0.05), a significant decrease in liver-to-brain ratio(P<0.05), and the appearance of hepatic steatosis. The capsule extract groups, at the studied dose, resulted in slow growth in body weight, a significant increase in aspartate aminotransferase levels(P<0.05), a significant decrease in body weight, liver weight, and liver-to-brain ratio(P<0.05), and the presence of hepatic steatosis and inflammatory cell infiltration. In comparison, the capsule extraction process had a higher risk of liver injury. Furthermore, based on the completion of the liquid chromatography method, the content of icariin and baohuoside Ⅰ in the capsule extract groups was 0.83 and 0.81 times that in the tablet extract groups, respectively, while the bakuchiol content in the capsule extract group was 29.80 times that in the tablet extract groups, suggesting that the higher risk of liver injury associated with the capsule extraction process may be due to its higher bakuchiol content. In summary, the differences in rat liver injury caused by the two extracts are closely related to the extraction process. This should be taken into consideration in the formulation production and clinical application.