Search Results (41)

Quinolizidine derivatives are an important class of substances that are used in the pharmaceutical industry. In previous studies, the synthesis of these substances is carried out using lupinine azide (IUPAC: 1-(azidomethyl)octahydro-2H-quinolizine), which is often used to obtain new biologically active compounds. In this regard, its structural characterization is critically important. In this work, the conformational diversity of the molecular structure of this compound has been studied. It is shown that the structure with the axial position of the methyl azide group contains a number of low-energy conformer states with energies higher than the ground state by 0.15–0.60 kcal/mol. Such structural ambiguity should manifest itself in the chemical reactions and biological activity of lupinine azide. The spectroscopic properties of the conformers were studied by modeling chemical shifts for carbon and hydrogen atoms, as well as by simulating IR absorption spectra. An analysis of the most specific spectroscopic features of all of the conformers was carried out. Based on the correlation of the theoretical results and the experimental spectroscopic data, a conclusion was made for the first time regarding the most probable conformational states in the solution. Full article

Oxysophocarpine (OSC), a quinolizidine alkaloid, shows neuroprotective potential, though its mechanisms are unclear. The aim of the present study was to investigate the neuroprotective effects of OSC through the nuclear factor erythroid 2−related factor 2 (Nrf2)/ heme oxygenase−1 (HO–1) signaling pathway using the HT–22 cell line. Assessments of cell viability were conducted utilizing the 3−(4,5−dimethylthiazol−2−yl)−2,5−diphenyltetrazolium bromide (MTT) assay. Assessments of oxidative stress (OS) were conducted through the quantification of reactive oxygen species (ROS). The integrity of the mitochondrial membrane potential (MMP) was scrutinized using fluorescent probe technology. Apoptosis levels were quantified using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The trafficking of Nrf2 within the cell nucleus was examined through immunofluorescence analysis. Furthermore, Western blotting (WB) was applied to evaluate the expression levels of proteins implicated in apoptosis and the Nrf2/HO–1 pathway. To further probe the influence of OSC on the overexpression of antioxidant enzymes, cells were subjected to transfection with HO–1 siRNA. The results showed that OSC inhibited glutamate-induced OS, as evidenced by reduced cell viability and ROS levels. Furthermore, the apoptotic condition induced by glutamate in HT–22 cells was significantly reduced following OSC treatment. More interestingly, the Nrf2/HO–1 signaling pathway was upregulated following OSC treatment. These results suggest that OSC can exert neuroprotective effects by regulating the Nrf2/HO–1 pathway to inhibit neuronal cell apoptosis, potentially aiding in the treatment of neurodegenerative diseases. Full article

The growing interest in vegetable proteins, namely those derived from lupins, has raised concerns over potential safety risks associated with these food products. Lupin serves as the main host for the mycotoxin-producing fungus called Diaporthe toxica. This species, which is associated with animal diseases, has been scarcely characterized. Recently, phomopsin-A (PHO-A), the main mycotoxin produced by D. toxica, was found to be harmful to humans. Therefore, this study aimed at characterizing D. toxica growth and spore formation both in vitro and on lupin samples. In addition, the production of PHO-A and alkaloids was investigated on lupin beans by using three different inoculation methods. Particularly, growth and spore production were evaluated on different media, while PHO-A and alkaloid production were determined by means of µSPE extraction followed by UHPLC-MS/MS and HPLC-MS/MS, respectively. The results have demonstrated differences in growth on different media, with potato and oat-flakes-based media being the best options. Conversely, D. toxica was not able to produce spores on agar media, but only on lupin beans. Moreover, a thorough analysis of PHO-A production revealed an increase over time, reaching values up to 1082.17 ppm after 21 days on artificially rehydrated samples. On the other side, the analysis of alkaloids revealed impressive results, as this species produced great quantities of the quinolizidine alkaloids (QA) that are normally present in lupin seeds such as lupanine, sparteine, multiflorine, and hydroxylupanine. On balance, considering these results, different metabolic pathways were demonstrated in D. toxica, which are not adequately described in the existing literature. These data are of paramount importance to deepen the knowledge about a fungal species that is important to ensure the safety of lupin and lupin-based products. Full article

Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH. Full article

African swine fever (ASF) has become a global pandemic due to inadequate prevention and control measures, posing a significant threat to the swine industry. Despite the approval of a single vaccine in Vietnam, no antiviral drugs against the ASF virus (ASFV) are currently available. Aloperine (ALO), a quinolizidine alkaloid extracted from the seeds and leaves of bitter beans, exhibits various biological functions, including anti-inflammatory, anti-cancer, and antiviral activities. In this study, we found that ALO could inhibit ASFV replication in MA-104, PK-15, 3D4/21, and WSL cells in a dose-dependent manner without cytotoxicity at 100 μM. Furthermore, it was verified that ALO acted on the co- and post-infection stages of ASFV by time-of-addition assay, and inhibited viral internalization rather than directly inactivating the virus. Notably, RT-qPCR analysis indicated that ALO did not exert anti-inflammatory activity during ASFV infection. Additionally, gene ontology (GO) and KEGG pathway enrichment analyses of transcriptomic data revealed that ALO could inhibit ASFV replication via the PRLR/JAK2 signaling pathway. Together, these findings suggest that ALO effectively inhibits ASFV replication in vitro and provides a potential new target for developing anti-ASFV drugs. Full article

Alkaloids play an essential role in protecting plants against herbivores. Humans can also benefit from the pharmacological effects of these compounds. Plants produce an immense variety of structurally different alkaloids, including quinolizidine alkaloids, a group of bi-, tri-, and tetracyclic compounds produced by Lupinus species. Various lupin species produce different alkaloid profiles. To study the composition of quinolizidine alkaloids in lupin seeds, we collected 31 populations of two wild species native to Israel, L. pilosus and L. palaestinus, and analyzed their quinolizidine alkaloid contents. Our goal was to study the alkaloid profiles of these two wild species to better understand the challenges and prospective uses of wild lupins. We compared their profiles with those of other commercial and wild lupin species. To this end, a straightforward method for extracting alkaloids from seeds and determining the quinolizidine alkaloid profile by LC–MS/MS was developed and validated in-house. For the quantification of quinolizidine alkaloids, 15 analytical reference standards were used. We used GC–MS to verify and cross-reference the identity of certain alkaloids for which no analytical standards were available. The results enabled further exploration of quinolizidine alkaloid biosynthesis. We reviewed and re-analyzed the suggested quinolizidine alkaloid biosynthesis pathway, including the relationship between the amino acid precursor l-lysine and the different quinolizidine alkaloids occurring in seeds of lupin species. Revealing alkaloid compositions and highlighting some aspects of their formation pathway are important steps in evaluating the use of wild lupins as a novel legume crop. Full article

Quinolizidine alkaloids (QAs) are toxic secondary metabolites of the Lupinus species, the presence of which limits the expansion of lupin beans consumption, despite their high protein content. Evaluation of the level of alkaloids in edible Lupinus species is crucial from a food safety point of view. However, quantitation of QAs is complicated by the fact that not all important alkaloids used for quantitation are commercially available. In this context, we developed a method for the simultaneous quantitation of eight major lupin alkaloids using quantitative NMR spectroscopy (qNMR). Quantitation and analysis were performed in 15 different seed extracts of 11 Lupinus spp. some of which belonged to the same species, with different geographical origins and time of harvest, as well as in all aerial parts of L. pilosus. The mature seeds of L. pilosus were found to be a uniquely rich source of multiflorine. Additionally, we developed a protocol using adsorption or ionic resins for easy, fast, and efficient debittering of the lupine seeds. The protocol was applied to L. albus, leading to a decrease of the time required for alkaloids removal as well as water consumption and to a method for QA isolation from the debittering wastewater. Full article

Sophoridine (SRP) is a natural quinolizidine alkaloid found in many traditional Chinese herbs, though its effect on adipose tissue is unclear. We improved serum lipid levels by administering SRP by gavage in high-fat diet (HFD)-fed C57BL/6 mice. After 11 weeks, SRP supplementation significantly reduced body weight gain and improved glucose homeostasis, while reducing subcutaneous fat and liver weight. SRP also inhibited cell proliferation and differentiation of 3T3-L1 cells. Proteomics analysis revealed that SRP inhibits adipocyte differentiation by interacting with Src, thereby suppressing vascular endothelial growth factor receptor 2 (VEGFR2) expression and PI3K/AKT phosphorylation. This study provides an empirical basis for the treatment of obesity with small molecules. Full article

The accumulation of oxidative stress is one of the important factors causing cellular senescence. Oxymatrine (OM) is a natural quinolizidine alkaloid compound known for its antioxidant effects. This study aimed to investigate the anti-senescence potential of OM through oxidative stress-induced in vitro and in vivo models. By treating 600 μM of H₂O₂ to the HT22 mouse hippocampal neuronal cell line and by administering 150 mg/kg D-galactose to mice, we generated oxidative stress-induced senescence models. After providing 1, 2, and 4 μg/mL of OM to the HT22 mouse cell line and by administering 50 mg/kg OM to mice, we evaluated the enhancing effects. We evaluated different senescence markers, AMPK activity, and autophagy, along with DCFH-DA detection reaction and behavioral tests. In HT22 cells, OM showed a protective effect. OM, by reducing ROS and increasing p-AMPK expression, could potentially reduce oxidative stress-induced senescence. In the D-Gal-induced senescence mouse model, both the brain and heart tissues recovered AMPK activity, resulting in reduced levels of senescence. In neural tissue, to assess neurological recovery, including anxiety symptoms and exploration, we used a behavioral test. We also found that OM decreased the expression level of receptors for advanced glycation end products (RAGE). In heart tissue, we could observe the restoration of AMPK activity, which also increased the activity of autophagy. The results of our study suggest that OM ameliorates oxidative stress-induced senescence through its antioxidant action by restoring AMPK activity. Full article

In the current era, it is important to consider economic and ecological sustainability issues while optimally meeting the nutrient needs of poultry. The use and research of alternative feedstuffs have gained importance due to these factors. The aim of this study is to reveal the raw lupin seeds’ nutrient ingredients as an alternative feedstuff and the effects of debittering methods. In the present study, two different treatments (germination for 2 days; heat treatment in an autoclave at 130 °C for 20 min) were applied to white and blue lupin seeds, and the differences in nutrient compositions between them and raw seeds were determined. When fatty acid compositions were analyzed, oleic, γ-linolenic, arachidic, behenic, erucic, and lignoceric acid values were found to be the highest in the raw, autoclaved, and germinated forms of white lupin (p < 0.01). The highest values of palmitic, stearic, and linoleic acids were observed in blue lupin (p < 0.01). While the value of total quinolizidine alkaloids (QA) in raw white lupin grains was higher than 1.943 mg/g, it was higher than 1.800 mg/g in autoclaved and germination-treated grains. Similarly, the total QA value of raw blue lupin grains was 0.894 mg/g, 0.609 ± 0.244 mg/g in germination-treated seeds, and 0.705 ± 0.282 mg/g in autoclave-treated seeds. As a result of these findings, it can be said that the methods applied for the removal of bitterness gave promising results. Furthermore, it would be rewarding to use these lupin varieties in in vitro and in vivo experiments to reveal the impacts and mechanisms of debittering methods on poultry. Full article

Cytisine (CYT) is a quinolizidine alkaloid used for nicotine addiction treatment. Recent clinical trial data regarding cytisine confirm its high effectiveness and safety as a smoking cessation treatment. CYT’s popularity is growing due to its increased availability and licensing in more countries worldwide. This increased use by smokers has also resulted in an urgent need for continued drug research, including developing appropriate analytical methods for analyzing the drug in biological samples. In this study, a simple, fast, and reliable method combining hydrophilic interaction liquid chromatography and electrospray ionization quadrupole time of flight mass spectrometry (HILIC/ESI-QTOF-MS) for the determination of CYT in human serum and saliva was developed and validated. This was undertaken after the previous pre-treatment of the sample using solid-phase extraction (SPE). A hydrophilic interaction liquid chromatography (HILIC) column with a silica stationary phase was used for chromatographic analysis. In a linear gradient, the mobile phase consisted of acetonitrile (ACN) and formate buffer at pH 4.0. The proposed method was fully validated and demonstrated its sensitivity, selectivity, precision, and accuracy. The method was successfully applied to determine CYT in serum and, for the first time, in saliva. The findings indicate that saliva could be a promising non-invasive alternative to measure the free concentration of CYT. Full article

Traditionally, Middle Eastern herbal medicines, especially traditional Iranian medicines (TIM), have been used by cancer patients both during and after active cancer treatments. Medicinal plants and herbs which are common in traditional Iranian medicine are considered to be less toxic and less expensive than chemical drugs. Alkaloid anti-cancer compounds are pyrrolidine, tropane, pyridine, piperidine, quinolizidine, pyrrolizidine, isoquinoline, indolizidine, isoxazaole, oxazole, quinoline, quinazoline, purine, indole serin, colchicine, β-phenylethylamine, abornin, benzylamine, narciclasine, and pancratistatin. Anticancer terpenoids compounds from medicinal plants and herbs are alpha-hederin, isoprene, galanal A, galanal B, oleanane, carnosol, and xanthorrhizol. Anticancer phenolic compounds from medicinal plants are kaempferol, flavones, flavonol, curcumin, luteoline, chalcone, apigenin, and cafesterol. All relevant papers in the English language from different research using the keywords traditional Persian medicine, traditional Iranian medicine, natural products, and cancer were collected from PubMed, Google Scholar, and Science Direct. Some of the most important medicinal plants and herbs in the middle east, especially in Iran, with anti-caner activities are Acorus calamus, Aracia seyal, Allium ascalonicum, Allium cepa, Agaricus campestris, Aloe vera, Allium sativum, Apium graveolens, Anethum graveolens, Arum palaestinum, Artemisia absinthium, Beta vulgaris, Astoma seselifolium, Brassica oleraceae, Brassica nigra, Boswellia carterii, Capparis spinosa, Bryonia syriaca, Ceterach officinarum, Cassia senna, Cichorium intybus, Chrysanthemum coronarium, Citrullus colocynthis, Cinnamomum camphora, Crataegus azarolus, Crocus sativus, Cucumis melo, Nigella sativa, Olea europaea, Peganum harmala, Punica granatum, Pistacia lentiscus, Zingiber officinale, Thymus vulgaris, Vitis vinifera, Viscum cruciatum, and Urtica pilulifera. Iranian medicinal plants and herbs should be considered more as a notable and great potential source of novel chemical ingredients with anti-cancer activities. Full article

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC₅₀ = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation. Full article

Teline monspessulana is highly invasive in several countries around the world. This species pressurizes and displaces several native and endemic tree species in south-central Chile such as Nothofagus obliqua, the native species of greatest timber interest. We determined the effects induced by allelochemical stress of T. monspessulana on N. obliqua germination and initial growth. Germination was evaluated under in vitro conditions and in natural substrate obtained from sites inhabited by N. obliqua and from nearby areas invaded by T. monspessulana. Controls irrigated with tap water and treatments with aqueous extracts of aerial organs of the invasive species were used. Morphometric and morphological variables were evaluated, and the composition of alkaloids and phenols from the plant organs used for the aqueous extracts was determined. The substrates were also chemically characterized. Allelochemicals synthesized by T. monspessulana caused germination and growth inhibition and tissue-level alterations, as well as leaf and root damage in N. obliqua seedlings. In the aerial organs of T. monspessulana, the quinolizidine alkaloids aphylline, caulophylline, anagyrine, and sophocarpine were mainly detected. In addition, 21 phenolic compounds were identified, including gallic acid, vanillic acid, chlorogenic acid, p-coumaric acid, and quercetin. The phytotoxic potential of T. monspessulana can compromise the natural multiplication of N. obliqua and its survival from its first phenological stages. This interdisciplinary study model facilitated the clarification of the plant–plant relationship mediated by allelochemicals. The model can be replicated to investigate other interspecific interactions between invasive and native species. Full article

O’nyong-nyong virus (ONNV) is a member of the reemerging arthritogenic alphaviruses that cause chronic debilitating polyarthralgia and/or polyarthritis via their tropism for the musculoskeletal system. Thus, the discovery of dual antiviral and anti-inflammatory drugs is a great challenge in this field. We investigated the effects of the common plant-derived alkaloids berberine (isoquinoline), matrine (quinolizidine), and tabersonine (indole) at a non-toxic concentration (10 μM) on a human fibroblast cell line (HS633T) infected by ONNV (MOI 1). Using qRT-PCR analyses, we measured the RNA levels of the gene coding for the viral proteins and for the host cell immune factors. These alkaloids demonstrated multifocal effects by the inhibition of viral replication, as well as the regulation of the type-I interferon antiviral signaling pathway and the inflammatory mediators and pathways. Berberine and tabersonine proved to be the more valuable compounds. The results supported the proposal that these common alkaloids may be useful scaffolds for drug discovery against arthritogenic alphavirus infection. Full article