Molecular mechanisms of hepatotoxicity induced by compounds occurring in Evodiae Fructus.

Evodiae Fructus (EF) is a common herbal medicine with thousands of years of medicinal history in China, which has been demonstrated with many promising pharmacological effects on cancer, cardiovascular diseases and Alzheimer's disease. However, there have been increasing reports of hepatotoxicity associated with EF consumption. Unfortunately, in a long term, many implicit constituents of EF as well as their toxic mechanisms remain poorly understood. Recently, metabolic activation of hepatotoxic compounds of EF to generate reactive metabolites (RMs) has been implicated. Herein, we capture metabolic reactions relevant to hepatotoxicity of these compounds. Initially, catalyzed by the hepatic cytochrome P450 enzymes (CYP450s), the hepatotoxic compounds of EF are oxidized to generate RMs. Subsequently, the highly electrophilic RMs could react with nucleophilic groups contained in biomolecules, such as hepatic proteins, enzymes, and nucleic acids to form conjugates and/or adducts, leading to a sequence of toxicological consequences. In addition, currently proposed biological pathogenesis, including oxidative stress, mitochondrial damage and dysfunction, endoplasmic reticulum (ER) stress, hepatic metabolism disorder, and cell apoptosis are represented. In short, this review updates the knowledge on the pathways of metabolic activation of seven hepatotoxic compounds of EF and provides considerable insights into the relevance of proposed molecular hepatotoxicity mechanisms from a biochemical standpoint, for the purpose of providing a theoretical guideline for the rational application of EF in clinics.

Nephrotoxicity induced by natural compounds from herbal medicines - a challenge for clinical application.

Herbal medicines (HMs) have long been considered safe and effective without serious toxic and side effects. With the continuous use of HMs, more and more attention has been paid to adverse reactions and toxic events, especially the nephrotoxicity caused by natural compounds in HMs. The composition of HMs is complex and various, especially the mechanism of toxic components has been a difficult and hot topic. This review comprehensively summarizes the kidney toxicity characterization and mechanism of nephrotoxic natural compounds (organic acids, alkaloids, glycosides, terpenoids, phenylpropanoids, flavonoids, anthraquinones, cytotoxic proteins, and minerals) from different sources. Recommendations for the prevention and treatment of HMs-induced kidney injury were provided. In vitro and in vivo models for evaluating nephrotoxicity and the latest biomarkers are also included in this investigation. More broadly, this review may provide theoretical basis for safety evaluation and further comprehensive development and utilization of HMs in the future.

Combination of RNA-seq and proteomics reveals the mechanism of DL0410 treatment in APP/PS1 transgenic mouse model of Alzheimer's disease.

There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was firstly employed to uncover the mechanism of action of DL0410 in APP/PS1 transgenic mice. The results of behavioral tests showed that oral administration of DL0410 for 8 weeks improved memory and cognition of APP/PS1 mice. DL0410 significantly reduced ß-amyloid deposition and resulted in significant upregulation of synaptophysin, PSD95 and NMDAR/ CaMKⅡ signaling pathway in the hippocampus and cortex, indicating that DL0410 improved synaptic plasticity in APP/PS1 mice, which agrees with the results of RNA-seq and proteomics. Furthermore, the enrichment results of differentially expressed genes identified by RNA-seq and proteomics demonstrate the potential protective effects of DL0410 against oxidative stress and mitochondrial dysfunction. As expected, DL0410 dose-dependently ameliorated oxidative damage and markedly increased the expression of PGC-1α, TFAM, SOD1 and SOD2. Mitochondrial high-resolution respirometry results revealed that mitochondrial respiratory function was significantly improved in APP/PS1 mice administered with DL0410. In addition, DL0410 treatment reduced oxidative damage, strengthened antioxidant system and improved mitochondrial function in Aß-induced HT22 cells. Altogether, our findings suggest the potential of DL0410 as a novel candidate for AD treatment.