Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity

Jatrorrhizine, an isoquinoline alkaloid, is a bioactive metabolite in common medicinal plants, such as Berberis vernae Schneid., Tinospora sagittata (Oliv.) Gagnep. and Coptis chinensis Franch. These plants have been used for centuries in traditional medicine for their wide-ranging pharmacological properties. This review emphasizes the latest and comprehensive information on the sources, pharmacology, pharmacokinetics and toxicity of jatrorrhizine. Studies on this alkaloid were collected from scientific internet databases, including the Web of Science, PubMed, ScienceDirect, Google Scholar, Elsevier, Springer, Wiley Online Library and Europe PMC and CNKI, using a combination of keywords involving “jatrorrhizine”, “sources”, “pharmacology,” “pharmacokinetics,” and “toxicology”. Jatrorrhizine exhibits anti-diabetic, antimicrobial, antiprotozoal, anticancer, anti-obesity and hypolipidemic properties, along with central nervous system activities and other beneficial activity. Studies of jatrorrhizine have laid the foundation for its application to the treatment of various diseases, but some issues still exist. Further investigations might emphasize 1) specific curative mechanisms of jatrorrhizine and clinical utility, 2) application prospect in the treatment of metabolic disorders, 3) comprehensive investigations of the toxicity mechanisms and 4) interactions of jatrorrhizine with other pharmaceuticals and development of derivatives.

Delineating Toxicity Mechanisms Associated with MRI Contrast Enhancement through a Multidimensional Toxicogenomic Profiling of Gadolinium

Although gadolinium is widely used for magnetic resonance imaging in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent (GBCA) administration have been raised and published...

Toxicity assessment of gelsenicine and the search for effective antidotes

Background Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth ( G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. Objective This study aimed to analyse the toxicity characteristics of gelsenicine. Methods Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. Results In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. Conclusions Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine -related poisoning and its toxicity mechanisms.

Lipotoxicity Downstream of α-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies?

Neuronal loss in Parkinson’s disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher’s disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.

Toxicodynamic aspects and new tools for assessing acetaminophen toxicity: a review

Acetaminophen (Tylenol®) or APAP is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication, suicide, and liver toxicity. Due to its toxicity mechanisms are not yet fully elucidated and this literature review aims to objectively bring some of the most recent and relevant scientific discoveries that can help in the understanding of the subject. After being ingested, paracetamol is absorbed and begins to be digested in the stomach, then being metabolized by the liver through phase I and phase II (glucuronyltransferases and sulfotransferases). When present in excess in the body, APAP forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing damages, which are largely responsible for injuries, especially in the liver. As a conclusion of this study, it can be inferred that the lesions caused by acetaminophen, in addition to protein adducts, also extend to mitochondria and proteins. New markers, in addition to enzymes already known from the CYP families, also include proteins and cytokines, in addition to molecular methods, messenger RNA and micro RNA have been used to study hepatotoxicity by APAP. This makes it easier to deeply understand the mechanisms of toxicity induced by acetaminophen and then to advance in studies with new therapies.

iTRAQ-Based Quantitative Proteomic Analysis Reveals Toxicity Mechanisms in Chlamys farreri Exposed to Okadaic Acid

Okadaic acid (OA), produced by dinoflagellates during harmful algal blooms, is a principal diarrhetic shellfish poisoning toxin. This toxin poses a potential threat to bivalves with economic values. To better understand the toxicity mechanism of OA to bivalves, in this study, oxidative stress biomarkers (superoxide dismutase, SOD; catalase, CAT; glutathione S-transferase, GST; malondialdehyde, MDA) and the expression of detoxification genes (heat shock protein 70, HSP70; heat shock protein 90, HSP90; cytochrome P450, CYP450) were assessed in the gills of scallops Chlamys farreri after 24 h, 48 h and 96 h exposure to OA. In addition, the digestive glands of scallops exposed to OA for 96 h were dissected for an iTRAQ based quantitative proteomic analysis. The results of OA exposure experiments showed that OA induces oxidative stress and significant enhancement of the expression of detoxification genes in scallops. The proteomics analysis revealed that 159 proteins altered remarkably in OA-treated scallops, and these proteins were involved in phagosomes, regulation of actin cytoskeleton, adherens junction, tight junction, and focal adhesion. Amino acid biosynthesis, carbon metabolism, pentose phosphate pathway, fructose and mannose metabolism in the digestive glands were also significantly impacted. Our data shed new insights on the molecular responses and toxicity mechanisms of C. farreri to OA.

Gelsemium elegans Benth: Chemical Components, Pharmacological Effects, and Toxicity Mechanisms

Gelsemium elegans Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family Loganiaceae and genus Gelsemium that has broad application prospects in medicine. This article reviews its chemical components, pharmacological effects, toxicity mechanisms, and research progress in clinical applications in recent years. Indole alkaloids are the main active components of GEB and have a variety of pharmacological and biological functions. They have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the therapeutic dose being close to the toxic dose. Application of small-dose indole alkaloids fails to work effectively, while high-dose usage is prone to poisoning, aggravating the patient’s conditions. Special caution is needed, especially to observe the changes in the disease condition of the patients in clinical practice. In-depth research on the chemical components and mechanisms of GEB is essential to the development of promising lead compounds and lays the foundation for extensive clinical application and safe usage of GEB in the future.