Chemotherapy patients often develop anticipatory nausea, a learned response produced by an environmental cue triggering nausea in the absence of the emetic stimulus. This can be modelled in rats by pairing the administration of an emetic treatment with exposure to a distinct context. Rats are a non-emetic species, but they are still capable of experiencing nausea, which is observable through the presence of the gaping response. The rat model of anticipatory nausea mainly utilizes lithium chloride (LiCl) to evoke the gaping response, yet various other putative emetic toxins and agents have remained unexplored. The current study determined if emetine, found in ipecac, and scopolamine methyl nitrate (SMN), a derivative of scopolamine, can evoke the conditioned gaping response. Adult male Long Evans rats (n = 40) were administered emetine (5.0 mg/kg, intraperitoneal [i.p.]), SMN (0.5 or 1.0 mg/kg, i.p.), LiCl (127 mg/kg, i.p.), or sodium chloride (NaCl, 0.9 %, i.p., control) before exposure to a distinct context for 30 min, over four conditioning trials, followed by four extinction (drug-free) trials. During the extinction trials, no treatments were administered, and rats were placed directly into the context. Rat behaviour on all of the trials was videotaped and scored for the frequency of the conditioned gaping response. Findings from this study suggest that, in comparison to LiCl, emetine is an effective conditioning stimulus, whereas SMN is not.

Suspension-cultured cells of a temperate bamboo species (Phyllostachys nigra) accumulate substantial amounts of hydroxycinnamic acid derivatives and lignin under culture conditions that promote xylogenesis. In our previous study, we found a metabolite specifically produced in bamboo cells cultured under lignification-inducing conditions in a medium containing N 6-benzyladenine (BA), but the chemical structure was not elucidated. In this study, we purified and identified this compound as BA N 9-β-D-glucopyranoside (BA-9G). Despite the presence of three nitrogen positions (N-3, N-7, and N-9) that may be glucosylated in the adenine moiety of BA, bamboo cells specifically produced BA-9G (i.e., without other glucoside types) when cells were cultured in the presence of BA. This finding suggests that bamboo cells possess a regio-specific N-glucosyltransferase for catalyzing cytokinin glucoside formation. The biological activity of BA-9G as a cytokinin was compared with that of BA on the basis of adventitious shoot formation on internodal segments of ipecac (Carapichea ipecacuanha) plants grown under in vitro conditions. The activity of BA-9G was more moderate than that of BA, but BA-9G was less cytotoxic than BA at a high concentration, suggesting that BA-9G may be useful as a plant growth regulator. The development of a viable system for the regio-specific bioproduction of BA-9G in bamboo cells may increase the availability of this highly expensive and rare cytokinin derivative.

Ipecac alkaloids are medicinal monoterpenoid-derived tetrahydroisoquinoline alkaloids found in two distantly related plants: Carapichea ipecacuanha (Gentianales) and Alangium salviifolium (Cornales). Here we provide evidence suggesting that both plants initiate ipecac alkaloid biosynthesis through a nonenzymatic Pictet-Spengler reaction and we elucidate the biosynthetic fate of both the 1R and 1S stereoisomers that are produced in this nonstereoselective reaction. Although the biosynthesis of the 1S-derived protoemetine proceeds according to the same chemical logic in both species, each plant uses a distinct monoterpene precursor. Phylogenetic analyses show examples of independent pathway evolution through parallel and convergently evolved enzymes. This work provides insight into how nature can capitalize on highly reactive starting substrates and the manner in which multistep pathways can arise and lays the foundation for metabolic engineering of these important medicinal compounds.

In many plant species, the application of exogenous phytohormones is crucial for initiating de novo shoot regeneration. However, ipecac [Carapichea ipecacuanha (Brot) L. Andersson] has a unique ability to develop adventitious shoots on the epidermis of internodal segments without phytohormone treatment. This characteristic allows us to evaluate the effects of endogenous phytohormones in this species. Here, we showed that the presence of the pith, including vascular bundles in the internodal segment, is required to activate both endogenous cytokinin (CK) biosynthesis and adventitious shoot formation. Adventitious shoots were mainly formed in the apical region of internodal segments, where the CK biosynthesis genes ISOPENTENYL TRANSFERASE 3 (CiIPT3) and LONELY GUY 7 (CiLOG7) were spontaneously upregulated in the early culture stage on phytohormone-free medium. In addition, CiIPT3 and CiLOG7 were respectively expressed in the pith and the epidermis of the internodal segments. The expression of CiLOG7 was localized as several spots on the epidermis. These findings suggest that CK precursors are generated in the pith, transferred to the epidermis, and then converted into active CKs, facilitating adventitious shoot formation on the epidermis. Conversely, auxin levels rapidly decreased during culture and remained low in the region of shoot formation. Auxin is transferred to the basal region of internodal segments, and strongly suppressed the CiLOG7 expression and decreased the CK levels. Thus, we conclude that the ectopic expression of CiLOG7 in the epidermis of internodal segments contributes to de novo shoot regeneration in ipecac.

Ipecac, or syrup of ipecac (SOI), is a medication once used to induce vomiting. Its medical use has virtually vanished, and it is no longer recommended for routine use in toxic ingestion.  The abuse of SOI as a purgative in eating disorders, however, is increasing. 

Foot-and-Mouth Disease (FMD) is a contagious, blistering disease caused by the Foot-and-Mouth Disease virus (FMDV), which affects livestock globally. Currently, no commercial antiviral agent is available for effective disease control. This study investigated the antiviral potential of natural-derived alkaloids against FMDV in BHK-21 cells. Twelve alkaloids were assessed for their antiviral activities at various stages of FMDV infection, including pre-viral entry, post-viral entry, and prophylactic assays, as well as attachment and penetration assays by evaluating cytopathic effect reduction and directed-virucidal effects. The results showed that ipecac alkaloids, cephaeline (CPL) and emetine (EMT), exhibited dual effects with robust antiviral efficacy by reducing cytopathic effect and inhibiting FMDV replication in a dose-dependent manner. Evaluation through immunoperoxidase monolayer assay and RT-PCR indicated effectiveness at post-viral entry stage, with sub-micromolar EC50 values for CPL and EMT at 0.05 and 0.24 µM, respectively, and high selective indices. Prophylactic effects prevented infection with EC50 values of 0.23 and 0.64 µM, respectively. Directed-virucidal effects demonstrated significant reduction of extracellular FMDV, with CPL exhibiting a dose-dependent effect. Furthermore, the replicase (3Dpol) inhibition activity was identified using the FMDV minigenome assay, which revealed strong inhibition with IC50 values of 0.15 µM for CPL and 4.20 µM for EMT, consistent with the decreased negative-stranded RNA production. Molecular docking confirmed the interaction of CPL and EMT with residues in the active site of FMDV 3Dpol. In conclusion, CPL and EMT exhibited promising efficacy through their dual effects and provide an alternative approach for controlling FMD in livestock.

Nausea serves as a protective mechanism in organisms to prevent excessive consumption of toxic substances. Due to the adverse effects of chemical anti-nausea drugs, there is a growing interest in using herbal remedies and natural antioxidants. In this study, we evaluated the neuroprotective effects of quercetin (QU) and N-acetylcysteine (NAC) against oxidative damage induced by nausea. Emesis was induced in chickens using ipecac and copper sulfate (600 and 60 mg/kg, orally, respectively). QU and NAC (with doses of 50, 100, 200 mg/kg), and their combination were administered, along with a standard therapy (metoclopramide; MET 2 mg/kg) for one-time. Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC), glutathione level (GSH), and reactive oxygen species (ROS) as oxidative damage biomarkers were evaluated in the chicken's brain mitochondria. QU and NAC significantly reduced emesis induced by copper sulfate and ipecac compared to the control group (P < 0.001). Significant differences in oxidative damage were observed in the groups received of copper sulfate and ipecac compared with control group. Levels of LPO, ROS, and PC were significantly decreased after the administration of QU and NAC in emesis induced by copper sulfate and ipecac. While, mitochondrial function and GSH levels were increased after the administration of QU and NAC. Combination therapy with QU and NAC yielded the most effective results. This study suggests that QU and NAC possess antiemetic effects through both peripheral and central mechanisms and exhibit neuroprotective effects against oxidative brain damage induced by emesis by increasing plasma antioxidants or scavenging free radicals.

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

Voluntary drug intoxication is mainly due to drug overdose or the interaction of several drugs. Coma and its associated complications such as hypoventilation, aspiration pneumopathy, and heart rhythm disorders are the main hallmarks of drug intoxication. Conventional detoxification treatments, including gastric lavage or vomiting, administration of ipecac or activated charcoal (CH), and the use of antidotes, have proven to be inefficient and are generally associated with severe adverse effects. To overcome these limitations, titanate nanotubes (TiNTs) are proposed as an efficient emerging detoxifying agent because of their tubular shape and high adsorption capacity. In the present study, the detoxifying ability of TiNTs was evaluated on paracetamol (PR)-intoxicated rats. Results indicate that the loading ability of PR into TiNTs (70%) was significantly higher than that recorded for CH (38.6%). In simulated intestinal medium, TiNTs showed a controlled drug release of less than 10% after 72 h of incubation. In PR-intoxicated rats, TiNTs treatment resulted in a 64% decrease of PR after 4 h of poisoning versus 40% for CH. Concomitantly, TiNTs efficiently reduced PR absorption by 90% after 24 h of poisoning, attenuated the elevated levels of biochemical markers (i.e., alanine aminotransferase, aspartate aminotransferase, creatinine, and TNF-α) and mitigated oxidative stress by increasing the activity of superoxide dismutase and reducing the oxidized glutathione/total glutathione ratio, suggesting a histoprotective effect of TiNTs against paracetamol-induced toxicity in rats. In addition to their safety and high stability in the entire gastro-intestinal tract, biodistribution analysis revealed that TiNTs exhibited low intestinal absorption owing to their large cluster size of compact aggregate nanomaterials across the intestinal villi hindering the absorption of paracetamol. Collectively, these data provide a new and promising solution for in vivo detoxification. TiNTs are expected to have great potential for the treatment of voluntary and accidental intoxication in emergency care.

This study evaluated the responses of Carapichea ipecacuanha to sunlight stress-induced changes in the electron transport chain and its extended effects on alkaloid production (emetine and cephalin). The treatments consisted of: (i). 50, 70, and 90% shading (controls) and their respective exposure to full sunlight; besides, full sunlight (55 days of direct sun exposure). Photosynthetic pigments, chlorophyll a fluorescence transient, antioxidant enzymatic system, and quantification of cephalin and emetine were analyzed. Several changes in the Chl a fluorescence induction were observed, such as a decline in the quantum yield of the conversion of photochemical energy and photosynthetic performance and; an increase in emetine production of plants exposed to full sunlight. These results demonstrated that ipecac plants are extremely sensitive to full exposure to solar radiation, especially in periods with high temperatures, such as in summer, however with increment in emetine production.

Circular peptides are attractive lead compounds for drug development; this study investigates the immunomodulatory effects of defined root powder extracts and isolated peptides (called cyclotides) from Carapichea ipecacuanha (Brot.) L. Andersson ('ipecac'). Changes in the viability, proliferation and function of activated human primary T cells were analysed using flow cytometry-based assays. Three distinct peptide-enriched extracts of pulverised ipecac root material were prepared via C18 solid-phase extraction and analysed by reversed-phase HPLC and mass spectrometry. These extracts induced caspase 3/7 dependent apoptosis, thus leading to a suppressed proliferation of activated T cells and a reduction of the number of cells in the G2 phase. Furthermore, the stimulated T cells had a lower activation potential and a reduced degranulation capacity after treatment with ipecac extracts. Six different cyclotides were isolated from C. ipecacuanha and an T cell proliferation inhibiting effect was determined. Furthermore, the degranulation capacity of the T cells was diminished specifically by some cyclotides. In contrast to kalata B1 and its analog T20K, secretion of IL-2 and IFN- γ was not affected by any of the caripe cyclotides. The findings add to our increased understanding of the immunomodulating effects of cyclotides, and may provide a basis for the use of ipecac extracts for immunomodulation in conditions associated with an exessive immune responses.