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.

Ricin and Ricinus communis in pharmacology and toxicology-from ancient use and "Papyrus Ebers" to modern perspectives and "poisonous plant of the year 2018".

While probably originating from Africa, the plant Ricinus communis is found nowadays around the world, grown for industrial use as a source of castor oil production, wildly sprouting in many regions, or used as ornamental plant. As regards its pharmacological utility, a variety of medical purposes of selected parts of the plant, e.g., as a laxative, an anti-infective, or an anti-inflammatory drug, have been described already in the sixteenth century BC in the famous Papyrus Ebers (treasured in the Library of the University of Leipzig). Quite in contrast, on the toxicological side, the native plant has become the "poisonous plant 2018" in Germany. As of today, a number of isolated components of the plant/seeds have been characterized, including, e.g., castor oil, ricin, Ricinus communis agglutinin, ricinin, nudiflorin, and several allergenic compounds. This review mainly focuses on the most toxic protein, ricin D, classified as a type 2 ribosome-inactivating protein (RIP2). Ricin is one of the most potent and lethal substances known. It has been considered as an important bioweapon (categorized as a Category B agent (second-highest priority)) and an attractive agent for bioterroristic activities. On the other hand, ricin presents great potential, e.g., as an anti-cancer agent or in cell-based research, and is even explored in the context of nanoparticle formulations in tumor therapy. This review provides a comprehensive overview of the pharmacology and toxicology-related body of knowledge on ricin. Toxicokinetic/toxicodynamic aspects of ricin poisoning and possibilities for analytical detection and therapeutic use are summarized as well.

Picrotoxane Sesquiterpene Glycosides and a Coumarin Derivative from Coriaria nepalensis and Their Neurotrophic Activity.

Two picrotoxane sesquiterpene lactone glycosides, nepalactones A (1) and B (2), and one new coumarin, nepalarin (3), were isolated from the root barks of the poisonous plant Coriarianepalensis. Their structures were elucidated via HRESIMS and 1D and 2D NMR spectroscopic analyses, and further verified via transformation methods. In addition, compounds 1-3 and five semisynthetic congeners (1a-e) were assayed for the activity to induce neurite outgrowth in rat pheochromocytoma (PC12) cells. As a result, nepalactone A derivative 1c and nepalarin (3) significantly enhanced nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells.

Therapeutic values, chemical constituents and toxicity of Taiwanese Dysosma pleiantha--a review.

Dysosma pleiantha (Hance) Woodson also called as Bajiaolian belongs to the family Berberidaceae, is widely used in Taiwan as traditional Chinese herbal medicine for more than thousands of years. It is usually recommended by various traditional Chinese medical doctors and herbal pharmacies for general remedies including postpartum recovery, treatment of weakness, neck mass, acne, hepatoma, lumbago, snakebite, tumor growth and dysmenorrhea. In the textbooks of traditional Chinese medicine, there is limited information about the toxicity of Bajiaolian. Podophyllotoxin, a lignan is the main toxic ingredient of Bajiaolian rhizome. Therefore, Bajiaolian is documented as the fifth highest cause of poisoning among the herbal medicine in Taiwan. Since the therapeutic and toxic doses are very close, Bajiaolian poisoning cases are frequently reported in Taiwan. Moreover, Dysosma poisoning cases are difficult to diagnosis because physicians are unfamiliar with this medicine's multiple clinical presentations in different stages of intoxication. Therefore, the objective of this review is to represent the collective information available in literatures regarding D. pleiantha, a cytotoxic lignan containing medicinal plant. Specifically, the literatures have been reviewed for articles pertaining to chemical constituents, properties, therapeutical benefits, toxicity, poisoning symptoms, toxic as well as therapeutic dose and medical management.

Residue potential of norsesquiterpene glycosides in tissues of cattle fed Austral bracken (Pteridium esculentum).

Austral bracken, Pteridium esculentum , occurs widely in Australian grazing lands and contains both the known carcinogen ptaquiloside and its hydroxy analogue, ptesculentoside, with untested carcinogenic potential. Calves were fed a diet containing 19% P. esculentum that delivered 1.8 mg of ptaquiloside and 4.0 mg of ptesculentoside per kilogram of body weight (bw) per day to explore the carcass residue potential of these compounds. Concentrations of ptaquiloside and ptesculentoside in the liver, kidney, skeletal muscle, heart, and blood of these calves were determined as their respective elimination products, pterosin B and pterosin G, by HPLC-UV analysis. Plasma concentrations of up to 0.97 µg/mL ptaquiloside and 1.30 µg/mL ptesculentoside were found, but were shown to deplete to <10% of these values within 24 h of bracken consumption. Both glycosides were also detected in all tissues assayed, with ptesculentoside appearing to be more residual than ptaquiloside. Up to 0.42 and 0.32 µg/g ptesculentoside was present in skeletal muscle and liver, respectively, 15 days after bracken consumption ended. This detection of residual glycosides in tissues of cattle feeding on Austral bracken raises health concerns for consumers and warrants further investigation.

Pyrrolizidine alkaloid-containing toxic plants (Senecio, Crotalaria, Cynoglossum, Amsinckia, Heliotropium, and Echium spp.).

Pyrrolizidine alkaloid (PA)-containing plants are found throughout the world and are probably the most common plant cause of poisoning of livestock, wildlife, and humans. PAs are potent liver toxins that under some conditions can be carcinogenic. This article briefly introduces high-risk North American PA-containing plants, summarizing their toxicity and subsequent pathology. Current diagnostic techniques, treatments, and strategies to avoid losses to PA poisoning are also reviewed.

Coping with toxic plant compounds--the insect's perspective on iridoid glycosides and cardenolides.

Specializing on host plants with toxic secondary compounds enforces specific adaptation in insect herbivores. In this review, we focus on two compound classes, iridoid glycosides and cardenolides, which can be found in the food plants of a large number of insect species that display various degrees of adaptation to them. These secondary compounds have very different modes of action: Iridoid glycosides are usually activated in the gut of the herbivores by ß-glucosidases that may either stem from the food plant or be present in the gut as standard digestive enzymes. Upon cleaving, the unstable aglycone is released that unspecifically acts by crosslinking proteins and inhibiting enzymes. Cardenolides, on the other hand, are highly specific inhibitors of an essential ion carrier, the sodium pump. In insects exposed to both kinds of toxins, carriers either enabling the safe storage of the compounds away from the activating enzymes or excluding the toxins from sensitive tissues, play an important role that deserves further analysis. To avoid toxicity of iridoid glycosides, repression of activating enzymes emerges as a possible alternative strategy. Cardenolides, on the other hand, may lose their toxicity if their target site is modified and this strategy has evolved multiple times independently in cardenolide-adapted insects.

Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.

BACKGROUND & AIMS: One major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of pyrrolizidine alkaloid (PA)-containing products. Over 8000 PA-induced HSOS cases have been reported worldwide and at least 51 among them were suspected to be attributed to exposure to the Chinese medicine 'Tusanqi'. PA-induced hepatotoxicity involves cytochrome P450-mediated metabolic activation of PAs to electrophilic pyrrolic metabolites which react with macromolecules, such as proteins. However, no studies have found such protein adduction in HSOS patients. We report one HSOS case confirmed by liver biopsy, where the patient claimed taking 'Tusanqi' as self-medication. METHODS: The herb was analyzed by HPLC-MS, and its induced hepatotoxicity in rats was assessed by monitoring the alteration of serum ALT level and liver morphology. Blood pyrrole-protein adducts were determined by UPLC-MS. RESULTS: The herb the patient consumed was identified as Gynura segetum, an erroneous substitute of non-PA-containing Sedum aizoon, called 'Tusanqi'. Hepatotoxic PAs senecionine and seneciphylline were detected in G. segetum. In the PA-exposed patient, serum pyrrole-protein adducts were detected by a newly developed analytical approach. The animal study showed a good correlation of liver injury with the ingestion of G. segetum. CONCLUSIONS: For the first time, serum pyrrole-protein adducts were unequivocally detected in a PA-induced HSOS patient, and such adducts show a potential to be developed as a biomarker for the assessment of PA-induced HSOS. Similar to the well-known case of aristolochic acid-poisoning, the observed HSOS was confirmed to arise from the consumption of PA-containing G. segetum, an erroneous substitute of non-PA-containing S. aizoon.

Glycocluster design for improved avidity and selectivity in blocking human lectin/plant toxin binding to glycoproteins and cells.

Blocking lectin/toxin binding to human cells by suitable inhibitors can therapeutically protect them from harmful effects. Clustered design of ligand presentation holds the promise of affinity increase relative to the free sugar and inherent selectivity among lectin targets. Using first a solid-phase assay with a glycoprotein presenting N-glycans as lectin-reactive probe, we assessed the inhibitory potency of bi- to tetravalent clusters on a plant toxin and three human adhesion/growth-regulatory lectins. Enhanced avidity relative to the free sugar was detected together with lectin-type selectivity. These effects were confirmed on the level of cells in vitro, also for two leguminous lectins. The lack of toxicity in cell proliferation assays excluded concerns to further work on these compounds. The given cluster design and the strategic combination of the two assay systems of increasing biorelevance will thus be helpful to take the next steps in drug development, e.g. tailoring the sugar headgroup.

Attempted suicide, by mail order: Abrus precatorius.

OBJECTIVE: Abrus precatorius is cultivated in many subtropical areas. The seeds exist in a variety of colors such as black, orange, and most commonly, glossy red. A black band is found at the end of the seed. The plant contains multiple pods which typically contain three to five Abrus seeds. The seeds contain abrin, which inhibits ribosomal function, halting protein synthesis and leading to cellular death. A unique aspect of this case is the use of the internet to order a potentially lethal poison as well as transmission of a picture to identify the seed. CASE REPORT: A 20-year-old man presented to the emergency department complaining of vomiting and watery diarrhea for 6-8 h prior to arrival. He denied any medication use, recent illness, travel, or changes in his diet. Initial vital signs were normal. The patient was diagnosed with viral gastroenteritis. During his evaluation, the patient admitted to feeling suicidal. While awaiting psychiatry evaluation, the patient's father arrived with a box of small hard red seeds, which he believed that his son ingested in a suicide attempt. The seeds could not be identified by the staff. A picture of the seeds was transmitted by e-mail to the New York City Poison Control Center, allowing their identification as A. precatorius. The patient was reinterviewed and admitted to chewing and swallowing 10 seeds. Given the potential toxicity of abrin, the patient was admitted to the intensive care unit. He continued to have frequent episodes of emesis as well as diarrhea. He gradually improved over 2 days. He admitted to ordering a box of Abrus seeds online from Asia after reading on the Internet about their use in suicide. He was eventually discharged for outpatient follow-up with no permanent sequelae. CONCLUSION: Abrin has an estimated human fatal dose of 0.1-1 µg/kg. Most cases of Abrus seed ingestions are unintentional and occur in children. Ingesting the intact seeds typically results in no clinical findings, as they pass through the gastrointestinal tract due to their hard shell. Abrin released during chewing is poorly absorbed systemically from the gastrointestinal tract. This causes the vomiting and diarrhea with resultant hypovolemia and electrolyte disturbances, which can be severe and life threatening, particularly in areas with less advanced health care systems. Management is primarily supportive.

Genotoxicity of pyrrolizidine alkaloids.

Pyrrolizidine alkaloids (PAs) are common constituents of many plant species around the world. PA-containing plants are probably the most common poisonous plants affecting livestock and wildlife. They can inflict harm to humans through contaminated food sources, herbal medicines and dietary supplements. Half of the identified PAs are genotoxic and many of them are tumorigenic. The mutagenicity of PAs has been extensively studied in different biological systems. Upon metabolic activation, PAs produce DNA adducts, DNA cross-linking, DNA breaks, sister chromatid exchange, micronuclei, chromosomal aberrations, gene mutations and chromosome mutations in vivo and in vitro. PAs induced mutations in the cII gene of rat liver and in the p53 and K-ras genes of mouse liver tumors. It has been suggested that all PAs produce a set of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine-derived DNA adducts and similar types of gene mutations. The signature types of mutations are G : C --> T : A transversion and tandem base substitutions. Overall, PAs are mutagenic in vivo and in vitro and their mutagenicity appears to be responsible for the carcinogenesis of PAs.

Toxin-based therapeutic approaches.

Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin.

Role of melatonin against oxidative tissue damage induced by Cleistanthus collinus in rat brain.

BACKGROUND & OBJECTIVES: The leaves of Cleistanthus collinus, an extremely poisonous plant are consumed for suicidal purposes in various parts of India. The mortality rate is high and there is no antidote. In this study, we attempted to delineate oxidative stress as a possible mechanism of action of C. collinus toxicity in rats and the role of melatonin against injury to brain and heart caused by C. collinus. METHODS: Adult Wistar rats (130 -200 g, n = 6 per group) of either sex were used. C. collinus at 8 mg/kg body weight (LD(50)) was administered orally followed by melatonin 15 mg/kg body weight ip or cysteine 500 mg/kg body weight ip (standard) after 2 h. Malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase and catalase levels in brain, heart and blood were estimated and histopathological examinations (brain and heart) were done. For the survival study, rats were treated with increasing doses of melatonin (5, 10 and 15 mg/kg body weight ip) following a lethal dose of C. collinus (10.5 g/kg body weight orally). RESULTS: The results showed a significant (P<0.05) increase in blood and brain MDA levels and decrease in tissue GSH in the LD(50) group. This was accompanied by marked gliosis, spongiform necrosis and lymphocytic inflammatory infiltrates in brain and marked congestion, inflammation and muscle necrosis in heart. Melatonin significantly (P<0.05) reduced lipid peroxidation and reversed the histopathological changes induced by C. collinus in the brain but not in the heart. INTERPRETATION & CONCLUSION: Our results suggest that oxidative mechanisms play an important role in C. collinus induced tissue damage and melatonin, by balancing oxidant-antioxidant status ameliorates oxidative organ injury in brain due to C. collinus toxicity.

Cigarette smoke extract induces activation of beta-catenin/TCF signaling through inhibiting GSK3beta in human alveolar epithelial cell line.

Cigarette smoke is known to have various injurious and cytotoxic effects on alveolar epithelial cells. However, the mechanism about the effects caused by cigarette smoke on alveolar epithelial cells remains unclear. In the present study, we first validated that cigarette smoke extract (CSE) impaired the viability of alveolar epithelial cells (A549 cells) and resulted in some morphological changes. Next, we found that glycogen synthase kinase 3beta (GSK3beta) was highly expressed in A549 cells, and CSE significantly inhibited GSK3beta by reducing GSK3beta expression and increasing inactive phosphorylated GSK3beta. It was also observed that CSE promoted beta-catenin accumulation and nuclear translocation, and further activated beta-catenin/TCF signaling. Finally, we demonstrated that GSK3beta over-expression promoted the degradation of beta-catenin and abolished beta-catenin/TCF transcriptional activity that was induced by CSE in alveolar epithelial cells. These results suggest that CSE induces the activation of beta-catenin/TCF signaling through inhibiting GSK3beta, implying a possible mechanism responsible for the injurious and cytotoxic effects on alveolar epithelial cell caused by cigarette smoke.

Reductions in the tobacco specific nitrosamine (TSNA) content of tobaccos taken from commercial Canadian cigarettes and corresponding reductions in TSNA deliveries in mainstream smoke from such cigarettes.

Tobacco specific nitrosamines (TSNAs) are suspected to cause smoking-related neoplastic diseases. The change from direct-fired to indirect-fired barns (aka kilns) for curing bright (aka Virginia, flue-cured) tobaccos was made to reduce the TSNA concentrations. The effectiveness of such processes in reducing the deliveries of TSNAs to the users of the products should be monitored. However, it is difficult to assess the effects of this reduction on the TSNA levels in mainstream smoke when cigarette blends contain burley tobaccos and other blend components that can increase smoke TSNA concentrations. Canadian cigarettes made prior to and in the few years just after the conversion to indirect-fired curing should not be subject to such interferences. Thus, the TSNA content of tobaccos and mainstream smoke from six brands of Canadian cigarettes produced in 2003, 2004, and 2005 were determined. Reductions in NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], the most important TSNA in flue-cured tobaccos, levels in the tobacco blends ranged from 60% to 85%. The corresponding reductions in mainstream smoke TSNA levels ranged from 59% to 72% (ISO smoking conditions) and 58-76% (Health Canada Intensive smoking conditions). These results show that other factors (microorganisms, nitrite levels) may be negating the TSNA reductions achieved by indirect-fired curing.

A comparative study of the mutagenicity of various types of tobacco products.

Toxicological data are an important aspect of tobacco product characterization. In this study, TPM (Total Particulate Matter) (three replicates) was collected from cigarettes [five brands, ISO conditions: puff volume, 35 mL; duration, 2s; interval, 60s (35/2/60)], cigars (two brands, 45/2/30), cigarillos (two brands, 35/2/60), bidis (two brands, 45/2/30), and pipe tobacco (two brands, 50/2/12). TPM was extracted from the Cambridge filter pad using dimethyl sulfoxide (DMSO). Smokeless tobacco (ST) (six brands) was extracted with DMSO using an ultrasonic homogenizer. Both types of extracts were filtered and stored at -80 degrees C. All extracts were analyzed for humectants, water and nicotine. Mutagenic activity was assessed per OECD guideline 471 using Salmonella typhimurium TA98+S9 and TA100+S9. TA98+S9 response (specific activity expressed as revertants/mg nicotine) was greatest for the cigarette fabricated with dark, air-cured tobaccos. Average product responses with TA98+S9 based on nicotine and relative to cigarettes (excluding dark tobacco) were cigars, 242%; cigarillos, 238%; bidis, 91%; and pipe tobacco, 44%. ST response was not significant for TA98+S9. Corresponding values for TA100+S9 were cigars, 189%; cigarillos, 155%; pipe tobacco, 130%; bidis, 114% and ST, 34%. ST TA100+S9 response ranged from a low of 501 to a high of 8547 revertants/mg nicotine, depending on ST composition.

Effects of 3-methoxy-2(5H)-furanone-containing extracts from Narthecium ossifragum (L.) Huds. on renal tubular cells in vitro.

Narthecium ossifragum, a perennial herb of the lily family, causes toxic renal tubular necrosis in several ruminant species. 3-Methoxy-2(5H)-furanone (3M2F) has been identified as a nephrotoxin present in N. ossifragum extracts. We studied effects of three different 3M2F-containing fractions isolated from N. ossifragum and synthetic 3M2F on the porcine kidney cell line LLC-PK1. In some of the experiments, we included the glioma cell lines U251 and BT4Cn to compare the effects of the toxin on LLC-PK1 cells to the effect on these cell lines. The synthetic 3M2F was shown to be only mildly toxic, and the most purified fraction from N. ossifragum showed the highest degree of toxicity in our studies. When monolayer cultures were exposed to increasing amounts of 3M2F-containing extract, a dose-dependent increase in cell death was observed. Similarly, reduced neutral red uptake and 3H-thymidine uptake (DNA synthesis) was observed. There was increased apoptotic activity in the LLC-PK1 cells with increasing concentration of 3M2F-containing extract. Multicellular three-dimensional spheroids from LLC-PK1 cells stopped fluid transport, showed degenerative changes and collapsed totally 6 h after extract exposure. Our findings indicate junctional damage, reduced cellular endocytosis and DNA-synthesis as well as induction of apoptosis as possible mechanisms for the acute tubular necrosis observed in ruminant species.

The role of alkaloids in Ipomoea carnea toxicosis: a study in rats.

Ipomoea carnea promotes in livestock a toxicosis histologically characterized by vacuolated cells in different organs. The toxic principles of I. carnea are the alkaloids swainsonine and calystegines B1, B2, B3 and Cl. However, it has not been determined whether the effects observed in rats treated with this plant are only due to swainsonine or if the calystegines have some additive toxic effect. Thus, the aim of the present study was to evaluate in rats the toxic effects of the L carnea aqueous fraction (AF) and of its different alkaloids when administered individually at the same concentration as in this fraction, for 14 days. No anorexic effect and/or alteration in body weight was observed in any group. The histopathologic study showed that while calystegines did not produce any toxic effects, swainsonine and I carnea AF promoted vacuolation in different organs, being more severe in the animals from the I. carnea AF group and extensible to other organs evaluated. No alterations were detected in the central nervous system of rats of any group assayed. The results obtained here suggest that calystegines may act as coadjuvants of swainsonine in I carnea toxicosis; however, little can be proposed about the neurotoxic effect of I. carnea since rats did not prove to be a good model for the reproduction of neuronal storage disease.

Recent developments in the field of arrow and dart poisons.

Arrow and dart poisons, considered as conventional natural sources for future drug discovery, have already provided numerous biologically active molecules used as drugs in therapeutic applications or in pharmacological research. Plants containing alkaloids or cardiotonic glycosides have generally been the main ingredients responsible for the efficacy of these poisons, although some animals, such as frogs, have also been employed. This paper, without being exhaustive, reports the greater strides made during the past 15 years in the understanding of the chemical nature and biological properties of arrow and dart poison constituents. Examples both of promising biological properties shown by these molecules and of crucial discoveries achieved by their use as pharmacological tools are given. Further studies of these toxic principles are likely to enable scientists to find new valuable lead compounds, useful in many fields of research, like oncology, inflammation and infectious diseases.