Stir-fried Semen Armeniacae Amarum Suppresses Aristolochic Acid I-Induced Nephrotoxicity and DNA Adducts.

OBJECTIVE: To investigate the protective effects of stir-fried Semen Armeniacae Amarum (SAA) against aristolochic acid I (AAI)-induced nephrotoxicity and DNA adducts and elucidate the underlying mechanism involved for ensuring the safe use of Asari Radix et Rhizoma. METHODS: In vitro, HEK293T cells overexpressing Flag-tagged multidrug resistance-associated protein 3 (MRP3) were constructed by Lentiviral transduction, and inhibitory effect of top 10 common pairs of medicinal herbs with Asari Radix et Rhizoma in clinic on MRP3 activity was verified using a self-constructed fluorescence screening system. The mRNA, protein expressions, and enzyme activity levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) were measured in differentiated HepaRG cells. Hepatocyte toxicity after inhibition of AAI metabolite transport was detected using cell counting kit-8 assay. In vivo, C57BL/6 mice were randomly divided into 5 groups according to a random number table, including: control (1% sodium bicarbonate), AAI (10 mg/kg), stir-fried SAA (1.75 g/kg) and AAI + stir-fried SAA (1.75 and 8.75 g/kg) groups, 6 mice in each group. After 7 days of continuous gavage administration, liver and kidney damages were assessed, and the protein expressions and enzyme activity of liver metabolic enzymes NQO1 and CYP1A2 were determined simultaneously. RESULTS: In vivo, combination of 1.75 g/kg SAA and 10 mg/kg AAI suppressed AAI-induced nephrotoxicity and reduced dA-ALI formation by 26.7%, and these detoxification effects in a dose-dependent manner (P<0.01). Mechanistically, SAA inhibited MRP3 transport in vitro, downregulated NQO1 expression in vivo, increased CYP1A2 expression and enzymatic activity in vitro and in vivo, respectively (P<0.05 or P<0.01). Notably, SAA also reduced AAI-induced hepatotoxicity throughout the detoxification process, as indicated by a 41.3% reduction in the number of liver adducts (P<0.01). CONCLUSIONS: Stir-fried SAA is a novel drug candidate for the suppression of AAI-induced liver and kidney damages. The protective mechanism may be closely related to the regulation of transporters and metabolic enzymes.

Prevalence and risk factors of osteoporotic fracture among the elderly population in China: a multicenter cross-sectional study.

PURPOSE: Prevalence of osteoporotic fracture (OPF) is increasing with ageing, resulting in a significant financial burden for healthcare. However, research on the nationwide epidemiological data of OPF in Chinese elderly is still scarce. The aim of this study was to investigate the prevalence and risk factors of OPF in Chinese population aged 60 years or order. METHODS: A cross-sectional survey was conducted in an elderly Chinese population in five centres. Questionnaire investigation and imaging examination were taken in all participants to identify OPF prevalence and risk factors. Diagnosis of OPF was determined based on imaging of vertebral fractures or history of fall-related fractures. We then used multivariate logistic regression model to analyze the associations between the potential risk factors and OPF. RESULTS: The overall prevalence of OPF in population aged 60 years or older was 24.7% (1,071/4,331), showing an increasing trend with age (P < 0.001). The prevalence of OPF was geographically distinct (P < 0.001), but similar between men and women (P > 0.05). Up to 96.8% of OPFs consisted of vertebral fractures, especially involving T11, T12, and L1 segments. Advanced age (≥ 80), vision loss, severe hearing loss, multiple exercise forms, chronic kidney disease, osteoarthritis, and trauma-related vertebral fractures were significantly associated with risk factors, while education level and vitamin D supplementation were associated with protective factors of OPF. CONCLUSION: High prevalence of OPF is a serious threat to bone health among elderly people in China. There is an urgent need for effective strategies to diagnose, prevent, and treat OPF in elderly adults.

A multi-resolution TOF-DOI detector for human brain dedicated PET scanner.

Objective. We propose a single-ended readout, multi-resolution detector design that can achieve high spatial, depth-of-interaction (DOI), and time-of-flight (TOF) resolutions, as well as high sensitivity for human brain-dedicated positron emission tomography (PET) scanners.Approach. The detector comprised two layers of LYSO crystal arrays and a lightguide in between. The top (gamma ray entrance) layer consisted of a 16 × 16 array of 1.53 × 1.53 × 6 mm3LYSO crystals for providing high spatial resolution. The bottom layer consisted of an 8 × 8 array of 3.0 × 3.0 × 15 mm3LYSO crystals that were one-to-one coupled to an 8 × 8 multipixel photon counter (MPPC) array for providing high TOF resolution. The 2 mm thick lightguide introduces inter-crystal light sharing that causes variations of the light distribution patterns for high DOI resolution. The detector was read out by a PETsys TOFPET2 application-specific integrated circuit.Main result. The top and bottom layers were distinguished by a convolutional neural network with 97% accuracy. All crystals in the top and bottom layers were resolved. The inter-crystal scatter (ICS) events in the bottom layer were identified, and the measured average DOI resolution of the bottom layer was 4.1 mm. The coincidence time resolution (CTR) for the top-top, top-bottom, and bottom-bottom coincidences was 476 ps, 405 ps, and 298 ps, respectively. When ICS events were excluded from the bottom layer, the CTR of the bottom-bottom coincidence was 277 ps.Significance. The top layer of the proposed two-layer detector achieved a high spatial resolution and the bottom layer achieved a high TOF resolution. Together with its high DOI resolution and detection efficiency, the proposed detector is well suited for next-generation high-performance brain-dedicated PET scanners.

Investigations of Li-Ion Battery Thermal Management Systems Based on Heat Pipes: A Review.

With increasing concerns about carbon emissions and the resulting climate impacts, Li-ion batteries have become one of the most attractive energy sources, especially in the transportation sector. For Li-ion batteries, an effective thermal management system is essential to ensure high-efficiency operation, avoid capacity degradation, and eliminate safety issues. Thermal management systems based on heat pipes can achieve excellent cooling performance in limited space and thus have been widely used for the temperature control of Li-ion batteries. In this paper, the thermal management systems of Li-ion batteries based on four types of heat pipes, i.e., flat single-channel heat pipes, oscillating heat pipes, flexible heat pipes, and microchannel heat pipes, are comprehensively reviewed based on the studies in the past 20 years. The effects of different influencing factors on the cooling performance and thermal runaway behavior of Li-ion batteries are thoroughly discussed in order to provide an in-depth understanding for researchers and engineers. It is concluded that for all types of thermal management systems based on heat pipes, water spray cooling could achieve better cooling performance than forced air cooling and water bath cooling, while its energy consumption is obviously smaller than forced air cooling. For thermal management systems based on oscillating heat pipes, improved heat transfer characteristics could be achieved by increasing the number of turns, using a relatively larger inner hydraulic diameter and using a length ratio between the evaporator and condenser higher than 1.0. Heat pipes fabricated by flexible materials suffer from permeation of noncondensable gases from ambient and leakage of working fluid. These issues could be partly resolved by adding thermal vias filled with metallic materials and covering the sealing part with indium coating or designing a multilayered structure with metallic materials in it. Moreover, the limitations and future trends of Li-ion battery thermal management systems based on heat pipes are presented. It is pointed out that the thermal runaway behavior and heating performance of battery thermal management systems based on heat pipes should be further elaborated. The analysis of this paper could provide valuable support for future investigations on Li-ion battery thermal management systems based on heat pipes; it could also guide the choice and design of Li-ion battery thermal management systems based on heat pipes in commercial use.

Liuweiwuling Tablet relieves the inflammatory transformation of hepatocellular carcinoma by inhibiting the PI3K/AKT/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. MATERIALS AND METHODS: An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. RESULTS: LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-κB pathway, which affects hepatic inflammation and cancer progression. CONCLUSION: LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC.

Development and performance of SIAT bPET: a high-resolution and high-sensitivity MR-compatible brain PET scanner using dual-ended readout detectors.

PURPOSE: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a powerful tool for brain imaging, but the spatial resolution of the PET scanners currently used for brain imaging can be further improved to enhance the quantitative accuracy of brain PET imaging. The purpose of this study is to develop an MR-compatible brain PET scanner that can simultaneously achieve a uniform high spatial resolution and high sensitivity by using dual-ended readout depth encoding detectors. METHODS: The MR-compatible brain PET scanner, named SIAT bPET, consists of 224 dual-ended readout detectors. Each detector contains a 26 × 26 lutetium yttrium oxyorthosilicate (LYSO) crystal array of 1.4 × 1.4 × 20 mm3 crystal size read out by two 10 × 10 silicon photomultiplier (SiPM) arrays from both ends. The scanner has a detector ring diameter of 376.8 mm and an axial field of view (FOV) of 329 mm. The performance of the scanner including spatial resolution, sensitivity, count rate, scatter fraction, and image quality was measured. Imaging studies of phantoms and the brain of a volunteer were performed. The mutual interferences of the PET insert and the uMR790 3 T MRI scanner were measured, and simultaneous PET/MRI imaging of the brain of a volunteer was performed. RESULTS: A spatial resolution of better than 1.5 mm with an average of 1.2 mm within the whole FOV was obtained. A sensitivity of 11.0% was achieved at the center FOV for an energy window of 350-750 keV. Except for the dedicated RF coil, which caused a ~ 30% reduction of the sensitivity of the PET scanner, the MRI sequences running had a negligible effect on the performance of the PET scanner. The reduction of the SNR and homogeneity of the MRI images was less than 2% as the PET scanner was inserted to the MRI scanner and powered-on. High quality PET and MRI images of a human brain were obtained from simultaneous PET/MRI scans. CONCLUSION: The SIAT bPET scanner achieved a spatial resolution and sensitivity better than all MR-compatible brain PET scanners developed up to date. It can be used either as a standalone brain PET scanner or a PET insert placed inside a commercial whole-body MRI scanner to perform simultaneous PET/MRI imaging.

Aripiprazole-induced liver injury: a spontaneous reporting database study.

Background: There have been individual case reports of aripiprazole in recent years, both domestically and internationally, but no analysis of the characteristics of the occurrence of adverse reactions/events of drug-induced liver injury with aripiprazole using spontaneous reports has been seen. Methods: Using a retrospective study approach, the 452 adverse reaction/event reports of aripiprazole-induced liver injury collected by the China Adverse Drug Reaction Monitoring System from 1 January 2012 to 31 December 2016 were analyzed and evaluated, and exploring it's the clinical characteristics and related risk factors for liver injury occurrence. Results: Among 452 cases of aripiprazole-induced liver injury ADR/ADE reports, there were 121 cases classified as serious, accounting for 26.8% of the total. There were 250 male and 202 female patients, with a male-to-female ratio of 1.24:1. The age of patients ranged from 11 to 77 years old, with an average age of (34.56 ± 12.81) years old, and a high proportion of young adults in the total population. Some patients had used the drug off-label or at a higher than recommended dosage. The onset of liver injury was generally within 15-90 days after continuous use, while some patients are also accompanied by nausea, vomiting, and weight gain. 70% of the combined drug instructions listed that may cause liver injury. Conclusion: In clinical practice, healthcare professionals should pay closely attention to the adverse reactions and risk factors of liver injury caused by aripiprazole. If there are potential risk factors for liver injury, early and regular monitoring of liver function should be carried out to reduce the occurrence of adverse reactions.

Intelligent Fault Diagnosis of Rolling Element Bearings Based on Modified AlexNet.

The reliable and safe operation of industrial systems needs to detect and diagnose bearing faults as early as possible. Intelligent fault diagnostic systems that use deep learning convolutional neural network (CNN) techniques have achieved a great deal of success in recent years. In a traditional CNN, the fully connected layer is located in the final three layers, and such a layer consists of multiple layers that are all connected. However, the fully connected layer of the CNN has the disadvantage of too many training parameters, which makes the model training and testing time longer and incurs overfitting. Additionally, because the working load is constantly changing and noise from the place of operation is unavoidable, the efficiency of intelligent fault diagnosis techniques suffers great reductions. In this research, we propose a novel technique that can effectively solve the problem of traditional CNN and accurately identify the bearing fault. Firstly, the best pre-trained CNN model is identified by considering the classification's success rate for bearing fault diagnosis. Secondly, the selected CNN model is modified to effectively reduce the parameter quantities, overfitting, and calculating time of this model. Finally, the best classifier is identified to make a hybrid model concept to achieve the best performance. It is found that the proposed technique performs well under different load conditions, even in noisy environments, with variable signal-to-noise ratio (SNR) values. Our experimental results confirm that this proposed method is highly reliable and efficient in detecting and classifying bearing faults.

Yin/Yang associated differential responses to Psoralea corylifolia Linn. In rat models: an integrated metabolomics and transcriptomics study.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia Linn. (BGZ) is a commonly used traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency syndrome (Yangsyn) with good curative effect and security. However, BGZ was also reported to induce liver injury in recent years. According to TCM theory, taking BGZ may induce a series of adverse reactions in patients with kidney-yin deficiency syndrome (Yinsyn), which suggests that BGZ-induced liver damage may be related to its unreasonable clinical use. AIM OF THE STUDY: Liver injury caused by TCM is a rare but potentially serious adverse drug reaction, and the identification of predisposed individuals for drug-induced liver injury (DILI) remains challenging. The study aimed to investigate the differential responses to BGZ in Yangsyn and Yinsyn rat models and identify the corresponding characteristic biomarkers. MATERIALS AND METHODS: The corresponding animal models of Yangsyn and Yinsyn were induced by hydrocortisone and thyroxine + reserpine respectively. Body weight, organ index, serum biochemistry, and Hematoxylin and Eosin (HE) staining were used to evaluate the liver toxicity effect of BGZ on rats with Yangsyn and Yinsyn. Transcriptomics and metabonomics were used to screen the representative biomarkers (including metabolites and differentially expressed genes (DEGs)) changed by BGZ in Yangsyn and Yinsyn rats, respectively. RESULTS: The level changes of liver organ index, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), suggested that BGZ has liver-protective and liver-damaging effects on Yangsyn and Yinsyn rats, respectively, and the results also were confirmed by the pathological changes of liver tissue. The results showed that 102 DEGs and 27 metabolites were significantly regulated related to BGZ's protective effect on Yangsyn, which is mainly associated with the glycerophospholipid metabolism, arachidonic acid metabolism, pantothenate, and coenzyme A (CoA) biosynthesis pathways. While 28 DEGs and 31 metabolites, related to the pathway of pantothenate and CoA biosynthesis, were significantly regulated for the BGZ-induced liver injury in Yinsyn. Furthermore, 4 DEGs (aldehyde dehydrogenase 1 family member B1 (Aldh1b1), solute carrier family 25 member 25 (Slc25a25), Pim-3 proto-oncogene, serine/threonine kinase (Pim3), out at first homolog (Oaf)) and 4 metabolites (phosphatidate, phosphatidylcholine, N-Acetylleucine, biliverdin) in the Yangsyn group and 1 DEG [galectin 5 (Lgals5)] and 1 metabolite (5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate) in Yinsyn group were significantly correlated to the ALT and AST levels of BGZ treated and untreated groups (receiver operating characteristic (ROC) ≥ 0.9). CONCLUSIONS: Yinsyn and Yangsyn are the predisposed syndromes for BGZ to exert liver damage and liver protection respectively, which are mainly related to the regulation of amino acid metabolism, lipid metabolism, energy metabolism, and metabolism of cofactors and vitamins. The results further suggest that attention should be paid to the selection of predisposed populations when using drugs related to the regulation of energy metabolism, and the Yinsyn/Yangsyn animal models based on the theory of TCM syndromes may be a feasible method for identifying the susceptible population to receive TCM.

A novel perspective on the preventive treatment of hydrazine compound-induced liver injury: Isoniazid liver injury as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Anethum graveolens L. (dill), which has been used as a medicine, spice and aromatic plant since ancient times, is not only a traditional Chinese medicines but also an important medicinal and functional food in Europe and Central and South Asia. In ethnomedicine, dill reportedly exerts a protective effect on the liver and has been widely used as a traditional medicine for the treatment of jaundice in the liver and spleen and inflammatory gout diseases in Saudi Arabia. Furthermore, studies have found that dill can regulate the NAT2 enzyme, and this plant was thus selected to study its alleviating effect on isoniazid liver injury. AIM OF THE STUDY: The purpose of this study was to explore the effect of dill on alleviating liver injury induced by hydrazine compounds represented by isoniazid through the use of network pharmacology combined with in vivo and in vitro experimental verifications. MATERIALS AND METHODS: First, we screened the key targets of dill in the treatment of liver injury through the use of network pharmacology; we then performed GO and KEGG pathway enrichment analyses using the DAVID database. We also verified the alleviative and anti-inflammatory effects of dill on isoniazid liver injury in rats by animal experiments. We further investigated the modulating effect of dill on the enzymatic activity of NAT2, a common metabolizing enzyme of hydrazine compounds. RESULTS: A total of 111 key targets were screened through network pharmacology. In vivo experiments showed that dill reduced the amount of inflammatory factors produced by isoniazid, such as IL-10, IL-1ß, TNF-α and IL-6, restored the levels of ALT, AST, r-GT, AKP and TBA in vivo, and attenuated isoniazid liver injury. Both in vivo and vitro results indicated that dill could regulate the expression of NAT2 enzymes. CONCLUSIONS: The results tentatively demonstrate that dill can alleviate isoniazid liver injury through multiple components, targets and pathways and exerts a regulatory effect on the NAT2 enzyme, and these findings thus provide new ideas for subsequent studies on hydrazide liver injury--reducing the risk of hydrazide-induced liver injury through anti-inflammation and regulation of NAT2 enzymes.

Edge effect reduction of high-resolution PET detectors using LYSO and GAGG phoswich crystals.

Objective. Small-animal positron emission tomography (PET) is a powerful preclinical imaging tool in animal model studies. The spatial resolution and sensitivity of current PET scanners developed for small-animal imaging need to be improved to increase the quantitative accuracy of preclinical animal studies. This study aimed to improve the identification capability of edge scintillator crystals of a PET detector which will enable to apply a crystal array with the same cross-section area as the active area of a photodetector for improving the detection area and thus reducing or eliminating the inter-detector gaps.Approach. PET detectors using crystal arrays with mixed lutetium yttrium orthosilicate (LYSO) and gadolinium aluminum gallium garnet (GAGG) crystals were developed and evaluated. The crystal arrays consisted of 31 × 31 array of 0.49 × 0.49 × 20 mm3crystals; they were read out by two silicon photomultiplier arrays with pixel sizes of 2 × 2 mm2that were placed at both ends of the crystal arrays. The second or first outermost layer of the LYSO crystals was replaced by GAGG crystals in the two crystal arrays. The two crystal types were identified using a pulse-shape discrimination technique to provide better edge crystal identification.Main results. Using the pulse shape discrimination technique, almost all (except for a few edge) crystals were resolved in the two detectors; high sensitivity was achieved by using the scintillator array and the photodetector with the same areas and achieved high resolution by using crystals with sizes equal to 0.49 × 0.49 × 20 mm3. Energy resolutions of 19.3 ± 1.8% and 18.9 ± 1.5%, depth-of-interaction resolutions of 2.02 ± 0.17 mm and 2.04 ± 0.18 mm, and timing resolutions of 1.6 ± 0.2 ns and 1.5 ± 0.2 ns were achieved by the two detectors, respectively.Significance. In summary, novel three-dimensional high-resolution PET detectors consisting of a mixture of LYSO and GAGG crystals were developed. The detectors significantly improve the detection area with the same photodetectors and thus improve the detection efficiency.

Mutual interferences between SIAT aPET insert and a 3 T uMR 790 MRI scanner.

Objective.Dual-modality small animal PET/MR imaging provides temporally correlated information on two biochemical processes of a living object. An magnetic resonance imaging (MRI)-compatible small animal PET insert named Shenzhen Institutes of Advanced Technology (SIAT) aPET was developed by using dual-ended readout depth encoding detectors to simultaneously achieve a uniform high spatial resolution and high sensitivity at the SIAT. In this work, the mutual interferences between SIAT aPET and the 3 T uMR 790 MRI scanner of United Imaging was quantitatively evaluated.Approach.To minimize the mutual interferences, only the PET detectors and the readout electronics were placed inside the MRI scanner, the major signal processing electronic was placed in the corner of the MRI room and the auxiliary unit was placed in the MRI technical room. A dedicated mouse radio fRequency (RF) coil with a transmitter and receiver was developed for the PET insert. The effects of PET scanner on theB0andB1field of the MRI scanner and the quality of the MRI images were measured. The effects of MRI imaging on the performance of both the PET detectors and scanner were also measured.Main results.The electronic and mechanical components of the PET insert affected the homogeneity of theB0field. The PET insert had no effect on the homogeneity ofB1produced by the dedicated mouse coil but slightly reduced the strength ofB1. The mean and standard deviation of the RF noise map were increased by 2.2% and 11.6%, respectively, while the PET insert was placed in the MRI scanner and powered on. Eddy current was produced while the PET insert was placed in the MRI scanner, and it was further increased while the PET insert was powered on. Despite the above-mentioned interferences from the PET insert, the MR images of a uniform cylindrical water phantom showed that the changes in the signal-to-noise ratio (SNR) and homogeneity as the PET insert was placed in the MRI scanner were acceptable regardless of whether the PET insert was powered off or powered on. The maximum reduction of SNR was less than 11%, and the maximum reduction of homogeneity was less than 2.5% while the PET insert was placed inside the MRI scanner and powered on for five commonly used MRI sequences. MRI using gradient echo (GRE), spin echo (SE) and fast spin echo (FSE) sequences had negligible effects on the flood histograms and energy resolution of the PET detectors, as well as the spatial resolution and sensitivity of the PET scanner.Significance.The mutual interference between the SIAT aPET and the 3 T uMR 790 MRI scanner are acceptable. Simultaneous PET/MRI imaging of small animals can be performed with the two scanners.

Correction: Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study.

Correction for 'Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study' by Le Zhang et al., Food Funct., 2022, 13, 825-833, https://doi.org/10.1039/D1FO03489H.

Landscape of DILI-related adverse drug reaction in China Mainland.

Drug-induced liver injury (DILI) is a type of bizarre adverse drug reaction (ADR) damaging liver (L-ADR) which may lead to substantial hospitalizations and mortality. Due to the general low incidence, detection of L-ADR remains an unsolved public health challenge. Therefore, we used the data of 6.673 million of ADR reports from January 1st, 2012 to December 31st, 2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation. Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system. By cleaning and standardizing the data fields by the dictionary of synonyms and English translation, we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining. The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years. The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men. The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population, despite known underreporting situation in spontaneous ADR reporting system. The percentage of herbal and traditional medicines (H/TM) L-ADR reports in the whole number was 4.5%, while 80.60% of the H/TM reports were new findings. There was great geographical disparity of reported agents, i.e. more cardiovascular and antineoplastic agents were reported in higher socio-demographic index (SDI) regions and more antimicrobials, especially antitubercular agents, were reported in lower SDI regions. In conclusion, this study presented a large-scale, unbiased, unified, and computer-minable L-ADR database for further investigation. Age-, sex- and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.

The relationship between mean platelet volume lymphocyte ratio and collateral circulation in patients with chronic total coronary occlusion.

Objective: To correlate mean platelet volume lymphocyte ratio (MPVLR) and coronary collateral circulation (CCC) in patients with chronic total occlusion (CTO). Materials and methods: A total of 643 patients who were hospitalized at a single large academic medical center from January 2020 to October 2021 and had CTO lesions in at least one major coronary artery confirmed by coronary angiography were retrospectively analyzed. Patients were divided according to the Rentrop criteria into poorly formed CCC (Rentrop grade 0-1, n = 235) and well-formed CCC (Rentrop grade 2-3, n = 408) groups. Mean platelet volume lymphocyte ratio (MPVLR) was calculated from routine laboratory data (MPV divided by lymphocyte count). The clinical data of the two groups were compared, and relationships between MPVLR and CCC formation were analyzed. Results: The MPVLR of patients with poorly formed CCC was significantly higher than that of patients with well-formed CCC (7.82 ± 3.80 vs. 4.84 ± 1.42, P < 0.01). The prevalence of diabetes mellitus and C-reactive protein levels were significantly higher in the poor CCC group than in the good CCC group (P < 0.01), while the proportions of patients with CTO or multivessel lesions in the right coronary artery were significantly lower in the poor CCC group than in the good CCC group (P < 0.01). Multivariate logistic regression analysis identified MPVLR (OR: 2.101, 95% CI: 1.840-2.399, P < 0.01), C-reactive protein level (OR: 1.036, 95% CI: 1.008-1.064, P < 0.05), a history of diabetes mellitus (OR: 2.355, 95% CI: 1.532-3.621, P < 0.01), and right coronary CTO ratio (OR: 0.313, 95% CI: 0.202-0.485, P < 0.01) as independent risk factors for CCC formation. The area under the ROC curve of MPVLR for predicting poorly formed CCC was 0.82 (95% CI: 0.784-0.855, P < 0.01), the best cut-off point was 6.02 and the sensitivity and specificity of MPVLR for predicting poorly formed CCC were 72.3 and 82.4%, respectively. Conclusion: In patients with coronary CTO, MPVLR was negatively correlated with CCC and a high MPVLR level was an independent predictor of poorly formed CCC.

Erratum: lncRNA LCPAT1 Upregulation Promotes Breast Cancer Progression via Enhancing MFAP2 Transcription.

[This corrects the article DOI: 10.1016/j.omtn.2020.07.015.].

Metabolomic profiling for drug-induced liver injury with autoantibodies.

BACKGROUNDS: Drug induced liver injury (DILI) is sometimes similar to autoimmune hepatitis (AIH) in serology and histology. Clinicians empirically screened DILI with significant autoimmune characteristics to implement clinical intervention. We tried to characterize DILI with autoantibodies by metabolomics. METHODS: Untargeted metabolomics coupled with pattern recognition approaches were performed on sera samples including AIH (n = 59), DILI with autoantibodies (DILIAb+, n = 68), and DILI without autoantibodies (DILIAb-, n = 75). The differential metabolites and fingerprint metabolites between AIH and DILIAb- were screened by orthogonal partial least squares-discriminant analysis and hierarchical clustering respectively. RESULTS: Of the 388 annotated differential metabolites between AIH and DILIAb-, 74 fingerprint metabolites were screened. The eigenmetabolite compressed from the fingerprint possessed high discrimination efficacy (AUC:0.891; 95 %CI, 0.838-0.944). In the fingerprint-based PCA model, AIH and DILIAb- were separated into three regions: the "pure region" of AIH (Region 1), the "pure region" of DILIAb- (Region 3), the mixture region of AIH and DILIAb- (Region 2). After incorporated into the PCA model, DILIAb+ samples were distributed into the three regions, indicating that DILIAb+ samples had different etiological tendencies. Moreover, the fingerprint-based radar model verified the results of PCA model characterizing DILIAb+. Notably, the antibody titers of DILIAb+ in the three regions did not differ significantly, while the response rates for glucocorticoids were obviously different. The metabolic difference among DILIAb+ in different regions mainly lies in energy metabolism. CONCLUSIONS: In terms of metabolic signature, DILIAb+ may not be a community of same pathogenesis, including AIH-inclined parts. Which deserves further study.

Hepatic Organoid-Based High-Content Imaging Boosts Evaluation of Stereoisomerism-Dependent Hepatotoxicity of Stilbenes in Herbal Medicines.

The complexity of chemical components of herbal medicines often causes great barriers to toxicity research. In our previous study, we have found the critical divergent hepatotoxic potential of a pair of stilbene isomers in a famous traditional Chinese herb, Polygonum multiflorum (Heshouwu in Chinese). However, the high-throughput in vitro evaluation for such stereoisomerism-dependent hepatotoxicity is a critical challenge. In this study, we used a hepatic organoids-based in vitro hepatotoxic evaluation system in conjunction with using high content imaging to differentiate in vivo organ hepatotoxicity of the 2,3,5,4'-tetrahydroxy-trans-stilbene-2-O-ß-glucoside (trans-SG) and its cis-isomer (cis-SG). By using such an organoid platform, we successfully differentiated the two stereoisomers' hepatotoxic potentials, which were in accordance with their differences in rodents and humans. The lesion mechanism of the toxic isomer (cis-SG) was further found as the mitochondrial injury by high-content imaging, and its hepatotoxicity could be dose-dependently inhibited by the mitochondrial protective agent. These results demonstrated the utility of the organoids-based high-content imaging approach in evaluating and predicting organ toxicity of natural products in a low-cost and high-throughput way. It also suggested the rationale to use long-term cultured organoids as an alternative toxicology platform to identify early and cautiously the hepatotoxic new drug candidates in the preclinical phase.

Metabolomic Analysis Uncovers Lipid and Amino Acid Metabolism Disturbance During the Development of Ascites in Alcoholic Liver Disease.

Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.