As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate of attrition in drug discovery. Recently, there have been continuous attempts in the prediction of DILI. However, it indeed remains a huge challenge to predict DILI successfully. There is an urgent need to develop a quantitative structure–activity relationship (QSAR) model for predicting DILI with satisfactory performance. In this work, we reported a high-quality QSAR model for predicting the DILI risk of xenobiotics by incorporating the use of eight effective classifiers and molecular descriptors provided by Marvin. In model development, a large-scale and diverse dataset consisting of 1254 compounds for DILI was built through a comprehensive literature retrieval. The optimal model was attained by an ensemble method, averaging the probabilities from eight classifiers, with accuracy (ACC) of 0.783, sensitivity (SE) of 0.818, specificity (SP) of 0.748, and area under the receiver operating characteristic curve (AUC) of 0.859. For further validation, three external test sets and a large negative dataset were utilized. Consequently, both the internal and external validation indicated that our model outperformed prior studies significantly. Data provided by the current study will also be a valuable source for modeling/data mining in the future.

Patients with diabetes mellitus (DM) suffer more risks from diabetic encephalopathy such as cognitive dysfunction and depressive-like behaviors. Numerous studies show that ER (endoplasmic reticulum) stress and inflammation play important roles in the development of diabetic encephalopathy. Gastrodin (Gas), one major component of Gastrodia elata, is traditionally used in central nervous system disorders and is believed to possess anti-inflammatory, anti-apoptotic, and other neuroprotective effects. This present study aims to explore the protective effects of Gas on diabetic encephalopathy. Gas was administrated daily (70 and 140 mg/Kg) for 12 weeks. Meanwhile, the fasting blood glucose and body weight of db/db mice were measured every two weeks. After Gas treatment, the Morris water maze (MWM) test and novel object recognition (NOR) test were performed to assess the learning and memory functions of db/db mice, and the forced swim test was performed to evaluate depressive-like behaviors of db/db mice. Additionally, the expression of ER stress and Nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome related proteins were evaluated by using Western blot. Our study suggested that Gas attenuated blood glucose levels and dyslipidemia of db/db mice. It has been shown that Gas could improve learning and memory function and depressive-like behaviors of db/db mice. Moreover, Gas inhibited ER stress and NLRP3 inflammasome activation in the hippocampus. Taken together, this study demonstrates that Gas attenuates the diabetic encephalopathy by inhibiting ER stress and NLRP3 inflammasome activation.

Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the formation of atherosclerotic plaques and the potential mechanisms. In this study, the effects of Rb1 on the development of atherosclerosis were investigated in ApoE-/- deficient mice fed with a western diet. Mice were intragastrically administrated with Rb1 (10 mg/kg) for 8 weeks. This study is that ginsenoside Rb1 exerted an inhibitory effect on early atherosclerosis in ApoE-/- mice via decreasing body weight and food intake daily, upregulating the lipid levels of serum plasma, including those of TC, TG and LDL-C and HDL-C and reducing the atherosclerotic plaque area, suppressing inflammatory cytokines (levels of IL-1β, IL-6 and TNF-α) in the serum of ApoE-/- mice, changing the expression levels of BCL-2, BAX, cleaved caspase-3 and cleaved caspase-9 and weakening apoptosis associated with anti-inflammatory activity. Hence, all these effects against atherosclerosis were tightly associated with regulation of necrosis or apoptosis associated with anti-inflammatory activity. Additionally, the results found that ginsenoside Rb1 increased autophagy flux to inhibit apoptosis via acceleration of autophagy by promoting transformation of LC3 from type I to type II in high-fat diet-induced atherosclerosis in ApoE-/- mice. This finding, along with those of the previous study, provides evidence that Rb1 promotes the process of autophagy to protect against atherosclerosis via regulating BCL-2 family-related apoptosis. These results indicate that Rb1 exhibits therapeutic effects in atherosclerosis by reversing the imbalance between apoptosis and autophagy.

Currently, hundreds of herbal products with potential hepatotoxicity were available in the literature. A comprehensive summary and analysis focused on these potential hepatotoxic herbal products may assist in understanding herb-induced liver injury (HILI). In this work, we collected 335 hepatotoxic medicinal plants, 296 hepatotoxic ingredients, and 584 hepatoprotective ingredients through a systematic literature retrieval. Then we analyzed these data from the perspectives of phylogenetic relationship and structure-toxicity relationship. Phylogenetic analysis indicated that hepatotoxic medicinal plants tended to have a closer taxonomic relationship. By investigating the structures of the hepatotoxic ingredients, we found that alkaloids and terpenoids were the two major groups of hepatotoxicity. We also identified eight major skeletons of hepatotoxicity and reviewed their hepatotoxic mechanisms. Additionally, 15 structural alerts (SAs) for hepatotoxicity were identified based on SARpy software. These SAs will help to estimate the hepatotoxic risk of ingredients from herbs. Finally, a herb-ingredient network was constructed by integrating multiple datasets, which will assist to identify the hepatotoxic ingredients of herb/herb-formula quickly. In summary, a systemic analysis focused on HILI was conducted which will not only assist to identify the toxic molecular basis of hepatotoxic herbs but also contribute to decipher the mechanisms of HILI.

Intracellular calcium overload is an important contributor to myocardial ischemia/reperfusion (MI/R) injury. Total saponins of the traditional Chinese medicinal plant Aralia elata (Miq.) Seem. (AS) are beneficial for treating MI/R injury, and Calenduloside E (CE) is the main active ingredient of AS. This study aimed to investigate the effects of CE on MI/R injury and determine its specific regulatory mechanisms. To verify whether CE mediated cardiac protection in vivo and in vitro, we performed MI/R surgery in SD rats and subjected neonatal rat ventricular myocytes (NRVMs) to hypoxia-reoxygenation (HR). CE’s cardioprotective against MI/R injury was detected by Evans blue/TTC staining, echocardiography, HE staining, myocardial enzyme levels. Impedance and field potential recording, and patch-clamp techniques of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to detect the function of L-type calcium channels (LTCC). The mechanisms underlying between CE and LTCC was studied through western blot, immunofluorescence, and immunohistochemistry. Drug affinity responsive target stability (DARTS) and co-immunoprecipitation (co-IP) used to further clarify the effect of CE on LTCC and BAG3. We found that CE protected against MI/R injury by inhibiting calcium overload. Furthermore, CE improved contraction and field potential signals of hiPSC-CMs and restored sarcomere contraction and calcium transient of adult rat ventricular myocytes (ARVMs). Moreover, patch-clamp data showed that CE suppressed increased L-type calcium current (I_Ca,L) caused by LTCC agonist, proving that CE could regulate calcium homeostasis through LTCC. Importantly, we found that CE promoted the interaction between LTCC and Bcl2-associated athanogene 3 (BAG3) by co-IP and DARTS. Our results demonstrate that CE enhanced LTCC-BAG3 interaction to reduce MI/R induced-calcium overload, exerting a cardioprotective effect.

Myocardial ischemia/reperfusion injury (MI/RI) is an urgent problem with a great impact on health globally. However, its pathological mechanisms have not been fully elucidated. Hydroxysafflor yellow A (HSYA) has a protective effect against MI/RI. This study is aimed at further clarifying the relationship between HSYA cardioprotection and calcium overload as well as the underlying mechanisms. We verified the protective effect of HSYA on neonatal rat primary cardiomyocytes (NPCMs) and human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from hypoxia‐reoxygenation (HR) injury. To explore the cardioprotective mechanism of HSYA, we employed calcium fluorescence, TUNEL assay, JC‐1 staining, and western blotting. Finally, cardio‐ECR and patch‐clamp experiments were used to explain the regulation of L‐type calcium channels (LTCC) in cardioprotection mediated by HSYA. The results showed that HSYA reduced the levels of myocardial enzymes and protected NPCMs from HR injury. HSYA also restored the contractile function of hiPSC‐CMs and field potential signal abnormalities caused by HR and exerted a protective effect on cardiac function. Further, we demonstrated that HSYA protects cardiomyocytes from HR injury by decreasing mitochondrial membrane potential and inhibiting apoptosis and calcium overload. Patch‐clamp results revealed that MI/RI caused a sharp increase in calcium currents, which was inhibited by pretreatment with HSYA. Furthermore, we found that HSYA restored contraction amplitude, beat rate, and field potential duration of hiPSC‐CMs, which were disrupted by the LTCC agonist Bay‐K8644. Patch‐clamp experiments also showed that HSYA inhibits Bay‐K8644‐induced calcium current, with an effect similar to that of the LTCC inhibitor nisoldipine. Therefore, our data suggest that HSYA targets LTCC to inhibit calcium overload and apoptosis of cardiomyocytes, thereby exerting a cardioprotective effect and reducing MI/RI injury.