Clinicopathological features of Bu Gu Zhi-induced liver injury, a long-term follow-up cohort study

Background & Aims Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI. Methods Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed. Results Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 mu mol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation. Conclusions BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end-stage liver disease or died

A High Serum Level of Taurocholic Acid is Correlated with the Severity and Resolution of Drug-induced Liver Injury

Background & Aims Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 ( ABCB11) gene and expression of its product, ABCB11 (also called BSEP). Methods We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n=100; healthy controls) and patients with chronic hepatitis B (n=105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP were analyzed by immunohistochemistry in liver biopsy specimens. Results Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71–0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids. Conclusions In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids

DiDang Tang Inhibits Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Oxygen Glucose Deprivation and Intracerebral Hemorrhage Through Blockade of the GRP78-IRE1/PERK Pathways

DiDang Tang (DDT), a Chinese traditional medicine formula, contains 4 Chinese traditional medicine substances, has been widely used to treat intracerebral hemorrhage (ICH) patients. However, the molecular mechanisms of DDT for protecting neurons from oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress and apoptosis after ICH still remains elusive. In this study, high-performance liquid chromatography fingerprint analysis was performed to learn the features of the chemical compositions of DDT. OGD-induced ER stress, Ca2+ overload, and mitochondrial apoptosis were investigated in nerve growth factor -induced PC12, primary neuronal cells, and ICH rats to evaluate the protective effect of DDT. We found that DDT treatment protected neurons against OGD-induced damage and apoptosis by increasing cell viability and reducing the release of lactate dehydrogenase. DDT decreased OGD-induced Ca2+ overload and ER stress through the blockade of the glucose-regulated protein 78 (GRP78)- inositol-requiring protein 1α (IRE1)/ protein kinase RNA-like ER kinase (PERK) pathways and also inhibited apoptosis by decreasing mitochondrial damage. Moreover, we observed similar findings when we studied DDT for inhibition of ER stress in a rat model of ICH. In addition, our experiments further confirmed the neuroprotective potential of DDT against tunicamycin (TM)-induced neural damage. Our in vitro and in vivo results indicated that the neuroprotective effect of DDT against ER stress damage and apoptosis occurred mainly by blocking the GPR78-IRE1/PERK pathways. Taken together, it provides reliable experimental evidence and explains the molecular mechanism of DDT for the treatment of patients with ICH

Effects of Low-Level Autonomic Stimulation on Prevention of Atrial Fibrillation Induced by Acute Electrical Remodeling

Background. Rapid atrial pacing (RAP) can induce electrical and autonomic remodeling and facilitate atrial fibrillation (AF). Recent reports showed that low-level vagosympathetic nerve stimulation (LLVNS) can suppress AF, as an antiarrhythmic effect. We hypothesized that LLVNS can reverse substrate heterogeneity induced by RAP. Methods and Results. Mongrel dogs were divided into (LLVNS+RAP) and RAP groups. Electrode catheters were sutured to multiple atrial sites, and LLVNS was applied to cervical vagosympathetic trunks with voltage 50% below the threshold slowing sinus rate by ⩽30 msec. RAP induced a significant decrease in effective refractory period (ERP) and increase in the window of vulnerability at all sites, characterized by descending and elevated gradient differences towards the ganglionic plexi (GP) sites, respectively. The ERP dispersion was obviously enlarged by RAP and more significant when the ERP of GP-related sites was considered. Recovery time from AF was also prolonged significantly as a result of RAP. LLVNS could reverse all these changes induced by RAP and recover the heterogeneous substrate to baseline. Conclusions. LLVNS can reverse the electrical and autonomic remodeling and abolish the GP-central gradient differences induced by RAP, and thus it can recover the homogeneous substrate, which may be the underlying mechanism of its antiarrhythmic effect

Bidirectional acoustic negative refraction based on a pair of metasurfaces with both local and global PT-symmetries

Abstract Negative refraction plays an important role in acoustic wave manipulation and imaging. However, conventional systems based on acoustic metamaterials suffer from the limits induced by loss-related and resolution issues. In this work, a parity-time (PT)-symmetric system is introduced to realize loss-free bidirectional acoustic negative refraction. The system is composed of a pair of locally PT-symmetric multi-layer metasurfaces sandwiching a region of free space, which also forms a global PT symmetry. The property of bidirectional negative refraction, which is rare for general PT-symmetric structures, is related to the coexistence of amplification and absorption in the locally PT-symmetric metasurfaces at their PT-broken phases. Such metasurfaces can freely switch their states between coherent perfect absorber (CPA) and amplifier depending on the direction of incidence. Our results provide a physical mechanism for realizing bidirectional functions in acoustic PT-symmetric systems