[Interpretation of the Chinese guideline for diagnosis and management of drug-induced liver injury (2023 version)].

Drug can cause almost all known types of acute, subacute, and chronic liver injuries. Drug-induced liver injury (DILI) is an important cause of unexplained liver injury in clinical practice. Correct diagnosis of DILI is challenging due to lack of specific diagnostic biomarkers, especially in patients with pre-existing liver disease and multiple concomitant drugs. A comprehensive understanding of the risk factors, clinical features, and prognosis of liver injury caused by different drugs will help physicians to recognize, diagnose, and manage it timely. Although the guideline was developed based on evidence-based medicine provided by the latest studies, there is limited high-quality evidence in the field of DILI. Therefore, this guideline should be interpreted with caution, and physicians should adopt an optimal diagnostic and therapeutic strategy for individual patients within the framework of the guideline.

[Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].

Metabolic dysfunction-associated fatty liver disease (MASLD) is a major public health problem that seriously affects human health. At present, some good progress has been made in the research and development of new drugs for MASLD, but there is still great space for exploration. This paper summarizes and analyzes the reasons in the current clinical status and challenges for the research and development of new drugs for MASLD.

[Standardize the diagnosis and treatment of drug-induced liver injury, and strengthen clinical and translational research].

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.

[Strategies for immunotherapy-related hepatotoxicity in liver cancer].

The successful market availability of immune checkpoint inhibitors (ICIs) has brought revolutionary changes to the treatment of hepatocellular carcinoma (HCC). With the widespread application of ICIs in HCC patients, the impact or even termination of antitumor therapy due to ICIs hepatotoxicity is a clinical problem that must be faced. However, it is currently unclear whether there are differences in the occurrence and risk factors of ICI hepatotoxicity between HCC patients and other tumors. At the same time, the chronic liver disease that often accompanies HCC patients also poses great challenges to their diagnosis and management. Therefore, clinical physicians need to understand the coping strategies for ICIs hepatotoxicity so as to improve the benefit of immunotherapy for patients.

[Genetic susceptibility to drug-induced liver injury].

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].

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.

[Follow-up study of patients with chronic obstructive pulmonary disease complicated with pulmonary hypertension].

Objective: To investigate the relationship between clinical characteristics of patients with chronic obstructive pulmonary disease (COPD) with pulmonary hypertension (PH) and COPD exacerbation over a three-year observation period. Methods: A total of 366 cases of stable COPD patients were enrolled from the Department of Respiratory Medicine of the First Affiliated Hospital of Henan University of Science and Technology. The patients underwent pulmonary function tests(PFT), COPD assessment test (CAT), Saint George's respiratory questionnaire (SGRQ), transthoracic echocardiogrophy(TTE), chest CT and biochemical detection. The likelihood of PH was evaluated based on the peak tricuspid regurgitation velocity (TRV) measured by echocardiography at rest and other indicators, which were represented by low, medium, and high probability, respectively. Highly probability was defined as PH. The mean values of the groups were compared using a two-tailed unpaired t test for normally distributed variables. Qualitative data were assessed using a χ2 test. Pearson correlation analysis was performed, and risk factors were analyzed using logistic regression analysis and stepwise regression analysis. P<0.05 was considered to indicate statistical significance. Results: The prevalence of patients with high likelihood of PH was 18.3% (n=67) in a series of 366 patients with COPD. The median estimated systolic pulmonary artery pressure in patients with PH was (51.7±6.7) mmHg(1mmHg=0.133 kPa). There were differences between patients with high likelihood of PH and those with low to moderate likelihood of PH for the following factors: age (76.0 vs. 64.0), body mass index (BMI) [(21.4±6.0) kg/m2 vs. (22.6±7.2)kg/m2], brain natriureticpeptide (BNP) [(50.8±9.1) pg/ml vs. (36.4±8.1) pg/ml], toral number of acute exacerbation in three-year [(6.1±0.1) times vs. (2.8±0.4) times], CAT (17.0 vs. 10.0), SGRQ (48.9 vs. 32.1), carbon monoxide diffusion percentage of predicted value (DLCO%) [(51.9±21.9)% vs. (67.0±22.1)%]; all the differences being statistically significant(mean P<0.05).There was a negative correlation between DLCO% and SPAP (r=-0.28, P<0.01).In patients with high likelihood of PH, the percentage of low attenuation area (LAA%) and interstitial abnormalities in chest CT were higher than those in patients with low to moderate likelihood of PH (56.1% vs. 34.3% and 30.8% vs. 15.6%, mean P<0.05).LAA% ≥ 30% and pulmonary interstitial abnormalities were independent risk factors for pH [beta value were 1.479, 1.065, OR value was (3.640-5.720), 95%CI (1.462-8.571), mean P<0.01]. The ratio of main pulmonary diameter to aortic artery diameter was significantly correlated with estimated systolic pulmonary artery pressure(r=-0.35, P<0.01).Age ≥75 years, FEV1%predicted value<50% and the presence of PH increased the likelihood of exacerbations of COPD over three years[beta value (0.459-1.211), OR value (3.643-5.722), 95%CI (1.463-8.904), mean P<0.01]. Conclusions: COPD patients with high likelihood of PH assessed by echocardiography were older, had a lower BMI, and presented with a worse health status compared to those with low to moderate likelihood of PH. The presence of PH assessed by echocardiography was related to future COPD exacerbations in COPD patients, and emphysema was closely related to PH assessed by echocardiography.

MiR-638 regulates gastric cardia adenocarcinoma cell proliferation, apoptosis, migration and invasion by targeting MACC1.

Gastric cardia adenocarcinoma (GCA) is one of the most common types of cancer and the incidence is increasing globally. MicroRNAs (miRNAs) have been reported to play critical roles in the progression of GCA. However, the exact role of miR-638 in GCA and its underlying mechanism remain largely unknown. The expression levels of miR-638 and metastasis-associated in colon cancer 1 (MACC1) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration and invasion were detected by Cell Counting Kit-8 (CCK-8) assay, flow cytometry and transwell assay, respectively. Western blot analysis was performed to determine the protein levels of cleaved-caspase 3 (C-caspase 3) and MACC1. The possible binding sites of miR-638 and MACC1 were predicted by TargetScan online software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. A xenograft model was established to investigate the roles of MACC1 in GCA in vivo. The expression of miR-638 was evidently reduced and MACC1 expression was obviously enhanced in GCA tissues and cells. Overexpression of miR-638 or knockdown of MACC1 inhibited cell proliferation, migration and invasion but increased apoptosis in GCA cells. Moreover, MACC1 was a direct target of miR-638 and its upregulation attenuated the inhibitory effect of miR-638 overexpression on the progression of GCA. In addition, overexpression of miR-638 significantly decreased tumor growth by downregulating MACCI in vivo. In conclusion, miR-638 overexpression suppressed cell proliferation, migration and invasion but induced cell apoptosis by targeting MACC1 in GCA cells, providing a potential therapeutic strategy for the treatment of GCA.

[Hepatotoxicity associated with tumor immune checkpoint inhibitors].

Although tumor immune checkpoint inhibitors therapy brings survival benefits to cancer patients, it also faces many challenges, such as the occurrence of immune-mediated hepatotoxicity. Therefore, an in-depth understanding of the conditions, possible mechanisms, and risk factors that cause liver injury during the treatment of tumor immune checkpoint inhibitors will facilitate better clinical management.

Effect of air pollution on hospital admissions for systemic lupus erythematosus in Bengbu, China: a time series study.

Recently, exposure to air pollutants has been associated with the development and progression of systemic lupus erythematosus (SLE). The current study aims to evaluate the effects of air pollutants on SLE hospital admissions in Bengbu, China. We performed distributed lag non-linear model combined with quasi-Poisson generalized linear regression to assess the impacts of air pollutants on SLE admissions from 2015 to 2017. Subgroup analyses by admission status (first admission or readmission) were also evaluated. A total of 546 hospital admissions during 2015-2017 were included. For single-day lag structures, the risk effects occurred from lag 2 to lag 9 for the 75th percentile particulate matter (PM)2.5, lag 3 to lag 9 for the 80th percentile PM2.5. For cumulative lag structures, the risk effects occurred from lag 0-5 to lag 0-14 for both 75th PM2.5 and 80th PM2.5, and no significant effect was observed for 90th PM2.5. In addition, the adverse effects on SLE first admissions occurred from lag 0 to lag 1 for NO2, lag 1 to lag 2 for SO2. The maximum effect of PM2.5 on SLE was 4.27 (95% confidence interval: 1.34-13.59) at lag 0-13 day, the minimum effect value was 1.12 (95% confidence interval: 1.03-1.23) at lag 9 day. These findings demonstrate that high PM2.5, NO2 and SO2 are associated with SLE hospital admissions. In addition, this study further revealed that exposure to high concentration of PM2.5 increased the risk of SLE relapse, while high levels of NO2 and SO2 increased the risk of SLE first admissions.

[Effects of overexpression of human tissue inhibitor of metalloproteinase-1 on the inflammatory response in rats with myocardial infarction and related mechanisms].

Objective: To observe the effects of recombinant adenovirus with human tissue inhibitor of metalloproteinase-1(Ad-hTIMP-1) on the inflammatory response in rats with myocardial infarction (MI) and explore the related mechanisms. Methods: The male Wistar rats were randomly divided into sham-operated group, saline group, Ad-Track group and Ad-hTIMP-1 group according to the random number table (n=8 each group). MI was induced by ligation of the left anterior descending coronary artery and MI rats were injected with saline, Ad-Track and Ad-hTIMP-1, respectively. Sham-operated rats received similar surgical procedure without ligation of the left anterior descending coronary artery. After 4 weeks, the cardiac function was measured by echocardiography, then rats were sacrificed and hearts were removed for morphological and biological analysis. The morphology of myocardial tissue in each group was detected by HE staining and Masson staining. The mRNA expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and C-reactive protein(CRP) were detected by real-time PCR. Immune histochemical staining was performed to observe the protein expression levels of IL-6 and CRP. Results: (1) Left ventricular end systolic dimension derived from echocardiography was increased in saline group ((5.10±0.72) mm) and Ad-Track group ((4.88±0.64) mm) compared to sham-operated group ((4.25±0.46) mm), which was reduced in Ad-hTIMP-1 group ((4.13±0.35) mm, all P<0.05). The left ventricular ejection fraction was (72.46±5.74)%, (64.27±8.52)%, (64.65±3.90)%, and (71.55±6.95)%, the fractional shortening was (36.90±4.97)%, (29.03±3.40)%, (30.95±2.51)%, and (36.31±5.68)% in sham-operated group, saline group, Ad-Track group and Ad-hTIMP-1 group, respectively. The left ventricular ejection fraction and fractional shortening in saline group and Ad-Track group were lower than those in sham-operated group and Ad-hTIMP-1 group (all P<0.05). (2) Necrosis of myocardial cells was not found and a small amount of immune cell infiltration and interstitial fibrosis were observed on HE and Masson stained myocardial sections of Ad-hTIMP-1 group. (3) Real-time PCR showed that mRNA expressions of TNF-α, IL-6, IL-10 and CRP were lower in Ad-hTIMP-1 group than in saline group. mRNA expressions of TNF-α, IL-10 and CRP were lower in Ad-hTIMP-1 group than in Ad-Track group (all P<0.05). (4) Immune histochemical staining showed that protein expressions of IL-6 and CRP were higher in saline group and Ad-Track group than those in Ad-hTIMP-1 group (all P<0.05). Conclusion: Recombinant adenovirus Ad-hTIMP-1 can improve cardiac function in rats with myocardial infarction via inhibiting the inflammatory response and downregulating the expression of TNF-α, IL-6 and CRP.

Common genetic risk factors of venous thromboembolism in Western and Asian populations.

Venous thromboembolism (VTE) is a multifactorial disorder involving both acquired and genetic risk factors. The common genetic factors in Western populations have been studied and reported for several decades, while studies on Asian populations are relatively scarce. Evidence suggests that the prevalence and genetic risk factors of VTE vary significantly among ethnic populations. In this review, we summarize the common genetic risk factors of VTE in both Western and Asian populations. In addition to the development of DNA sequencing technology, genome-wide association studies have many advantages and are becoming more important in identifying new genetic risk factors and susceptible loci. They can therefore help in the prediction and prevention of VTE.

[Promoting translational research on drug-induced liver injury].

Drug-induced liver injury (DILI) is one of the most important drug-induced diseases and an important reason for failure to obtain approval, an increase in warnings, and withdrawal from market. DILI has a complex clinical phenotype and can cause almost all types of acute, subacute, and chronic liver injury, and it may cause liver failure and even death in patients with severe conditions. The diversity of drugs involved and heterogeneity of populations are the main reasons for unpredictability of most DILI cases in clinical practice. Therefore, the prediction, diagnosis, and treatment of DILI become challenging issues in the field of liver disease, and it is of great significance to strengthen clinical translational research in this aspect, so as to transform more achievements into actual diagnostic and treatment methods.

[Research advances in drug-induced autoimmune hepatitis].

Drug induced autoimmune hepatitis (DIAIH) refers to the liver injury mediated by drug-induced autoimmune reaction. Since it has similar clinical features as idiopathic autoimmune hepatitis, it is often difficult to make differential diagnosis in clinical practice. A deep understanding of the development, pathogenesis, related drugs, risk factors, and clinical and histological features of DIAIH helps with the correct diagnosis and treatment of DIAIH.

Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial.

Tenofovir disoproxil fumarate (TDF) has demonstrated long-term efficacy and a high barrier to resistance in multiple chronic hepatitis B (CHB) populations outside of China. This study aimed to evaluate the efficacy and safety of TDF compared with adefovir dipivoxil (ADV) in Chinese patients with CHB during 48 weeks of treatment (ClinicalTrial.gov number, NCT01300234). A Phase 3, multicentred, randomized, double-blind, controlled trial compared the efficacy and safety of TDF with ADV in Chinese patients with CHB. The primary endpoint was the proportion of patients with HBV DNA <400 copies/mL in each treatment group at Week 48, using an unpooled Z-test for superiority. Secondary endpoints included viral suppression, serologic response, histological improvement, normalization of alanine aminotransferase (ALT) levels and the emergence of resistance mutations. A total of 509 patients, 202 hepatitis B e antigen (HBeAg)-positive and 307 HBeAg-negative, with HBV DNA ≥10(5) copies/mL received either TDF 300 mg od or ADV 10 mg od. At Week 48, TDF demonstrated superior viral suppression compared with ADV in both HBeAg-positive (76.7% vs 18.2%, P < 0.0001) and HBeAg-negative (96.8% vs 71.2%, P < 0.0001) patients. The majority of patients in both treatment arms achieved ALT normalization (>85%). No resistance to TDF was observed. The frequency of adverse events was comparable between treatment arms (TDF 3.9% vs ADV 4.8%). In this double-blind, randomized, clinical trial, TDF demonstrated superiority over ADV with respect to viral suppression in Chinese patients with CHB at 48 weeks of treatment and without the development of resistance.

Time course effect of hypoxia on bone marrow-derived endothelial progenitor cells and their effects on left ventricular function after transplanted into acute myocardial ischemia rat.

OBJECTIVE: Ischemic heart disease is the most common cause of cardiovascular morbidity and mortality in the industrialized world, and the incidence has been increasing in developing countries. Stem cell transplantation has emerged as a potent new therapeutic strategy for acute/chronic ischemic heart disease and has been explored extensively. The present study aimed to investigate whether hypoxic preconditioning of endothelial progenitor cells (EPCs) before transplantation could ameliorate their survival and engraftment in ischemic tissue and the potential mechanisms. MATERIALS AND METHODS: EPCs extracted were subjected to increasing hypoxia for 24-72 h, survival and function of the preconditioned EPCs were assayed in both in vitro and in vivo. RESULTS: Hypoxia for 24 h caused significant enhancements in formation of tube like structure and motility of BM-EPCs (p < 0.05), as well as mRNA expressions of CXCR4, PI3K, AKT, and NF-κB, while these effects were reversed by prolonged hypoxia (48 and 72 h, p < 0.05). Hypoxia of BM-EPCs for 24 h did not result in increased apoptosis resistance, and cell apoptosis was even enhanced by prolonged hypoxia. In vivo transplantation experiments demonstrated the beneficial effect of hypoxic EPCs on left ventricular (LV) functions after acute myocardial ischemia (AMI). CONCLUSIONS: Shorter-term hypoxia showed better survival, differentiation and function of BM-EPCs in vivo, further study was still needed to optimize the hypoxic pattern of BM-EPCs so as to better protect heart from myocardial ischemic injury. The present study showed evidence suggested that hypoxic preconditioning did exert further beneficial effects of BM-EPCs on preservation of LV function after AMI. Short-term exposure to hypoxia for about 24 h provided better condition for survival and function of BM-EPCs.

Aerosolization of P2Y(2)-receptor agonists enhances mucociliary clearance in sheep.

The purpose of this study was to determine whether aerosolized INS316 (UTP) stimulates lung mucociliary clearance (MCC) in sheep and, if so, to compare its effects with INS365, a novel P2Y(2)-receptor agonist. In the first series of studies, we used a previously described roentgenographic technique to measure tracheal mucus velocity (TMV), an index of MCC, before and for 4 h after aerosolization of INS316 (10(-1) M and 10(-2) M) and INS365 (10(-1) M and 10(-2) M), or normal saline in a randomized crossover fashion (n = 6). In a second series of studies, we compared the ability of these agents to enhance total lung clearance. For these tests, the clearance of inhaled technetium-labeled human serum albumin was measured serially over a 2-h period after aerosolization of 10(-1) M concentration of each agent (n = 7). Aerosolization of both P2Y(2)-receptor agonists induced significant dose-related increases in TMV (P < 0.05) compared with saline. The greatest increase in TMV was observed between 15 and 30 min after drug treatment. The highest dose (10(-1) M) of INS316 produced a greater overall stimulation of TMV than did INS365 (10(-1) M). Both compounds, compared with saline, induced a significant increase in MCC (P < 0.05) within 20 min of treatment. This enhancement in MCC began to plateau at 60 min. Although the response to INS316 started earlier, there was no significant difference between the clearance curves for the two compounds. We conclude that inhaled P2Y(2)-receptor agonists can increase lung MCC in sheep and that for P2Y(2)-receptor stimulation TMV accurately reflects changes in whole lung MCC.