Somniferum Research Articles

Studies on Sensory and Phytochemical Characteristics of Poppy (Papaver somniferum L.) Varieties for Their Oil Utilisation.

Poppy is a significant pharmaceutical crop, but the seeds and the cold-pressed oil have a big potential as healthy foods. Breeding has mainly focused on agronomical characteristics and alkaloid content. Here, we compared the sensory values, fatty acid and headspace volatile composition of poppy oils and flours produced from different varieties. Two industrial and four culinary varieties were cultivated in our field in 2021-2022. The sensory test differentiated well among varieties. Typical poppy odour and flavour were stronger both in the oils and the flours of the blue-seed varieties compared to the white-seed ones. For most varieties, the harvest year caused no relevant differences. Linoleic, oleic, and palmitic acids were the main components both in oils and flours. Larger differences were detected in the volatiles (e.g., 2 and 3 methyl-butanal and 3 methyl-butanol γ-n-caprolactone, pentofuran), depending on genotype and year. A higher ratio of saturated fatty acids negatively influenced the flavour and odour characteristics. In the headspace volatiles, these features correlated negatively with 2-pentylfuran and hexanal. The oil content of poppy flour has a positive effect on colour, appearance, tactility and poppy flavour. Our results support a goal-oriented use of poppy genotypes for high-quality dietary products.

First report of ‘Candidatus Phytoplasma australasia’ related strain associated with opium poppy phyllody and stunting in India

First report of ‘Candidatus Phytoplasma australasia’ related strain associated with opium poppy phyllody and stunting in India

Influence of fermentation and storage on the content of opium alkaloids in poppy seed yoghurt

There is a current trend to make yoghurts with seeds such as poppy seeds to enhance their nutritional benefits. These seeds may be contaminated with opium alkaloids (OAs) present in the own latex of the plant (Papaver somniferum L.). Food processing such as heat treatment, grinding or washing may reduce them, but lactic fermentation has not been studied. In this work, an analytical methodology was optimised based on a solid-liquid extraction (SLE) with water, a purification by magnetic solid-phase extraction (MSPE) with a mesostructured silica magnetic composite with β-cyclodextrin (Fe3O4 @SiO2 @mSiO2 @β-CD) and subsequent analysis by liquid chromatography coupled to a tandem mass detector (HPLC-MS/MS). The methodology was successfully validated in terms of linearity, limits of detection and quantification, matrix effect, precision, recovery tests, and selectivity. Therefore, it was applied to determine OAs in commercial yoghurts, detecting morphine, papaverine and noscapine in all of them but below the limit of quantification. Besides, the effect of fermentation was studied (6 and 18 h) and storage (1 week/ 4ºC), showing a considerable degradation effect (33–80%) in the first hours.

Investigation of the Effects of Opioids on Microglial Nitrite and Nitric Oxide Synthase (iNOS) Production and Phagocytosis during Inflammation.

This study aimed to investigate how opioids affect phagocytosis and microglial nitrite and nitric oxide synthase (iNOS) production during inflammation. Opioids are a group of chemicals that are naturally found in the opium poppy plant and exert a variety of effects on the brain, including pain alleviation in some cases. They are commonly used in surgery and perioperative analgesia. However, research on the impact of opioids on microglial inflammatory factor production and phagocytosis is limited. This study was designed to investigate the effects of opioids on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) generation. Moreover, the influence of opioids on the engulfment of C8-B4 microglial cells after stimulation with LPS was also examined. C8-B4 mouse microglial cells were exposed to various concentrations of opioids after stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Nitrite production was assayed. The iNOS and Cox-2 were determined by Western blotting, and fluorescent immunostaining was performed to assess the percentage of microglia that engulfed fluorescent microspheres in total microglia cultivating with opioids after being activated by LPS. After LPS and IFN-γ stimulation, microglia produced lower amounts of nitric oxide (NO) production with buprenorphine, salvinorin A, and naloxone (P<0.05). When combined with naloxone, no significant differences were found than buprenorphine. It was observed that buprenorphine and salvinorin A could suppress iNOS expression activated by LPS and IFN-γ. Phagocytosis was greatly increased after LPS stimulation, and a significant increase was observed after adding salvinorin A. Buprenorphine and salvinorin A were found to reduce NO production and iNOS induction in microglial cells activated by LPS and IFN-γ. Salvinorin A promoted the phagocytosis of microglia cells treated by LPS.

Oxidative stress caused by a commercial presentation of glyphosate in two indigenous fish species of importance in Colombia

The use of glyphosate to eradicate poppy (Papaver somniferum) and coca (Erythroxylon coca) plants is of great concern in Colombia due to potential effects on the environment. Juveniles of white cachama (n=36) (Piaractus brachypomus) (22.7 ± 2.9 g) and yamú (Brycon amazonicus) (n=36) (11.7 ± 1.1 g) were exposed for 96 h to three glyphosate concentrations (0, 5 and 15 ppm, v/v, as Roundup®). Enzymes linked to oxidative stress in liver and gills were measured after the exposure. The main oxidative stress changes happened in the gills of glyphosate-exposed cachama and liver of both species. There was a significant decrease in reduced glutathione (GSH) and glutathione-s-transferase (GST) activity of both species. Catalase activity was significantly reduced in livers of exposed cachama. Lipid peroxidation had a significant increase in glyphosate-exposed cachama (liver and gills) and yamú (liver). The biochemical changes found in both species and both organs indicate the oxidative effects of glyphosate as Roundup® despite the asymptomatic and non-lethal exposures.

Unearthed opium: development of a UHPLC-MS/MS method for the determination of Papaver somniferum alkaloids in Daunian vessels.

Introduction: The analysis of organic residue in ancient vessels to investigate early-age civilization habits is an important archeological application that needs advanced analytical methods. However, these procedures should meet inherent requisites such as low sampling invasiveness and high sensitivity for trace analysis. This study deals with the development of advanced analytical methods for the detection of opium alkaloids in ceramic vessels and its first application to the study of Daunian pots dating back to the VIII-IV sec BC. Methods: All the stages of the analytical procedure, from sampling to analysis, were carefully optimized. Concerning sampling, the traditional scraping approach was compared with a swabbing strategy which permitted minimizing sample encroachment. Extraction was based on pressurized liquid extraction or ultrasound-assisted liquid extraction, followed by dispersive liquid-liquid microextraction, which allowed concentration enrichment. On the other hand, a UHPLC-MS/MS method was specifically developed and validated to obtain reliable data. Some Daunian pots, belonging to the Ceci-Macrini private archeological collection, were selected for sample withdrawal as their iconography could suggest opium usage. Results: Several of the analyzed samples resulted positive to thebaine and less frequently to morphine and codeine; furthermore, 70% of the analyzed items tested positive for at least one opium alkaloid. Positive findings were common to all the samples collected in the pots, suggesting that scraping and swabbing provided comparable results and validating this unusual sampling strategy. All samples were additionally analyzed by UHPLC-HRMS to further improve the confidence level of the identified compounds. The obtained results shed new light on the hypothesis of opium usage by the ancient Daunian civilization. Furthermore, this study provided suitable analytical tools for further investigations on the same topic, with a good level of confidence in the quality of the results.

A New Protocol of Methamphetamine Dependence Treatment with Taper-Up-Off Treatment of Opium Tincture, a New Hope to Cure the Methamphetamine Addiction

Methamphetamine is a neurotoxic drug and highly addictive stimulant, which causes a significant psychological dependence in use disorder and potential brain damage even in the first use disorder. Despite decades of research, no approved pharmacotherapy is available for methamphetamine (METH) use disorder, and behavioral therapies are faced with a great lack of long-term recovery and a high rate of relapse. Opium tincture is air-dried Papaver somniferum latex, formulated for oral administration. The present study aimed to evaluate the effectiveness of the new protocol for taper up-off method of opium tincture used for treatment of methamphetamine addiction in Iran, for more than 10 years. In the present study, the effectiveness of the Opium tincture taper-up-off treatment method for methamphetamine dependence called “Dezhakam step time (DST) for methamphetamine” was assessed. We used data collected via the “Congress 60” a nongovernmental organization in Iran, dedicated to addiction treatment with the DST method, from Jan 2018 until December 2020. We evaluated the treatment safety, success, and relapse rate in methamphetamine dependents treated in the “Congress 60” organization with the DST for methamphetamine method. All subjects were tested using Urine drug monitoring for both opioid and methamphetamine use after the treatment period and during the next two years as a follow-up. Findings revealed 89 percent of successful treatments for methamphetamine dependence and only 11 percent of substance abuse relapses in two years follow up. Also, less than one percent of the subjects that finished the treatment program abused opioids in two years follow up. Findings suggest the safety and effectiveness of the Opium tincture taper-up-off method in the treatment of methamphetamine dependence. The findings of the study may help to a better understanding of a safe potential novel method for methamphetamine dependence treatment and its effects on psychological dependence on psychostimulants.

Ahifen: A critical review

Poppy, a plant belonging to the papaveraceae family, is the source of opium.It is a plant that blooms. It has sedative, somniferous, and neurotoxic properties in addition to being cerebrally poisonous. Due to its neurotoxic nature, opium causes a variety of adverse effects, including anxiety, seizures, hallucinations, sleepiness, giddiness, and many more. In order to create various types of analgesic medications to cure pain and promote sleep, this poppy is grown as an agricultural crop. The main source of opium, or dried latex made by the seed pods, is the opium poppy, as its name suggests. Because opium has sexual properties, many people use it for extended periods of time before becoming addicted.

Between necessity and compulsion: opium poppy cultivation and the exigencies of survival in Badakhshan, Afghanistan

ABSTRACT Drawing on long-term fieldwork in Badakhshan, a borderland province in the northeast of Afghanistan, the paper explores the role that opium poppy cultivation has played in a marginal high-altitude economy. Framed by the analytic of ‘narco-frontiers’ and the puzzle of the persistence of small farmers in uneven agrarian transitions, the paper investigates the diversity of market and non-market institutions that operate across the means of production of opium. Rather than seeing opium poppy production as the vanguard of an agrarian transition, it is suggested that it is more of a rearguard action to ensure survival.

Morphometrics of waterlogged archaeological seeds give new insights into the domestication and spread of Papaver somniferum L. in Western Europe.

Domesticated opium poppy Papaver somniferum L. subsp. somniferum probably originated in the Western Mediterranean from its possible wild progenitor, Papaver somniferum L. subsp. setigerum and spread to other European regions. Seeds of opium poppy have been identified in different European regions since the Early Neolithic (from the 6th millennium cal. BC onwards) period. However, until recently, the absence of morphological identification criteria has prevented the discrimination between wild and domestic morphotypes. New morphometric approaches to distinguish modern subspecies have been proven to be applicable to waterlogged archaeological remains, opening the possibility of understanding the process of domestication of the plant in both time and space. This paper applies seed outline analyses, namely elliptic Fourier transforms, combined with size and number of cells to archaeological waterlogged Papaver seeds throughout the Neolithic period in the NW Mediterranean and the surroundings of the Alps. Furthermore, one example from the Late Bronze Age (LBA) was added to see what kind of differences appeared during the >1000 years between the end of the Neolithic and the LBA. The aim of the study is to classify the archaeological seeds as domestic or wild morphotypes and observe morphometric changes in connection to geographical and chronological patterns that can explain the spread and domestication process(es) of this important crop. A total of 295 archaeological seeds coming from 10 waterlogged sites dating between 5300-2300 cal. BC (Neolithic), and one LBA site dating to 1070 cal. BC were analysed. The results indicate the presence of seeds, similar to the wild morphotype, in the Mediterranean sites and larger seeds, similar to the domestic morphotype, in the regions surrounding the Alps. The number of cells mainly increased during the Late Neolithic (3300 to 2300 cal. BC) and, finally, in the Late Bronze Age (ca. 1050-800 cal. BC), larger, morphologically domesticated seeds are clearly predominant. A change in the shape of the seeds is only clearly visible in the LBA material. Altogether our results suggest that opium poppy seeds show no sign of domestication in the early periods of the Neolithic, despite the fact that the plant was very probably already cultivated at that time in the western Mediterranean region.

Morphology, Taxonomy, Anatomy, and Palynology of the Opium Poppy (Papaver somniferum L.) Cultivation in Northern Thailand.

In this paper, we present the morphology, taxonomy, anatomy, and palynology of Papaver somniferum. A detailed morphological description and illustrations of the species are provided, along with information about the identification, distribution, cultivation areas, habitats, pollinators, specimens examined, growing periods, phenology, etymology, vernacular name, and uses. The species can be characterized as a glabrous and glaucous herb with unlobed or pinnately lobed leaves, and an amplexicaul base; variations in color and morphological characteristics of petals; and white filaments, occasionally purple with a white basal part, broadened at the apical part. Two rings of discontinuous and widely spaced collateral vascular bundles are recognized in the transverse section of the stems. The shape of epidermal cells on the adaxial surface is polygonal, while that on the abaxial surface is polygonal or irregular. The anticlinal cell walls of the epidermal cells on the adaxial surface are straight or slightly curved, while those on the abaxial surface are straight, slightly curved, sinuate, or strongly sinuate. The stomata are anomocytic and are confined to the lower epidermis. The stomatal density is 54-199/mm2 (with a mean of 89.29 ± 24.97). The mesophyll is not distinctly differentiated into palisade and spongy regions. Laticifers are found in the phloem areas of the stems and leaves. The pollen grains can be spheroidal or prolate spheroidal in shape, sometimes oblate spheroidal [polar axis (P) diameter/equatorial axis (E) diameter ratio = 0.99-1.12 (with a mean of 1.03 ± 0.03)]. The pollen aperture is tricolpate and the exine sculpturing is microechinate.

Rational Engineering of (S)-Norcoclaurine Synthase for Efficient Benzylisoquinoline Alkaloids Biosynthesis.

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics/Molecular Mechanics (QM/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale.

Genetic variability for qualitative and quantitative characters and study of character association for their exploitation in genetic improvement of opium poppy (Papaver somniferum L.)

The goal of this study was to characterize forty genotypes of Papaver somniferum L. and assess the genetic variability using data from morphological as well as biochemical studies. For the characterization, the morphological characters viz., plant height, primary branch, peduncle length, days to maturity, number of selfed-capsules, weight of selfed-capsule, number of open-pollinated capsule, weight of open pollinated capsule were complimented with five biochemical alkalodis morphine, codeine, thebaine, papaverine and narcotine. The results show that morphine and codeine had highly significant positive correlation (0.68 **). Similarly, a highly positive significant correlation (0.63 **) was established between morphine and narcotine. Further, all the 40 genotypes were subjected to cluster analysis where eight primary clusters were obtained using morphological analysis, whereas nine clusters were formed based on biochemical analysis. On the basis of morphological analysis, 32 genotypes were assigned to a one, large cluster which was further organized into 12 sub-clusters. However, clustering based on biochemical analysis yielded one, large cluster with 25 genotypes, which was further subdivided into eight subclusters. The findings from the present study can be successfully employed for developing superior lines of opium poppy.

Metabolic Changes of Active Components of Important Medicinal Plants on the basis of Traditional Chinese Medicine under Different Environmental Stresses

Abstract: Traditional Chinese medicine is an ancient system of wellness and health that has been used in almost all countries of the world, specially in Asia for thousands of years. : The growth, development, final yield and chemical compounds of medicinal plants can be negatively influenced by different kinds of biotic and abiotic stresses. Abiotic stress signals are chemical stress (Mineral salts, heavy metal, aerosols, gaseous toxins, pesticides, and pollutants), salinity (salt), temperature (Heat, cold), radiation (Ionisation radiation, light and UV), water (Flooding, drought) and mechanical stress (Submergence, wind, soil movement). Relevant literature has been obtained using the keywords “Traditional Chinese Medicine”, “Abiotic Stress”, “Biotic Stress”, “Ginseng”, “Ginger”, “Goji berry”, “Astragalus”, “Ginkgo”, “Artemisia annua L.”, “LC-MS”, “GC-MS”, and “NMR” in scientific information, namely “Web of Science”, “PubMed”, “SciFinder”, and “Elsevier”. Some of the plants’ secondary metabolites under different growth conditions are Camptothecin (Camptotheca acuminata), Capsaicin (Capsicum sp.), Rosmarinic acid (Salvia miltiorrhiza), Codeine (Papaver somniferum), Resveratrol (Grapes, groundnut), Artemisinin (Artemesia annua), Allicin (Allium sativum), Rohitukine (Dysoxylum binectariferum), Stevioside (Stevia rebaudiana), Andrographolide (Andrographis paniculata), Saikosaponins (Bupleurum chinense), Sennosides (Cassia augustifolia), Rutin (Dimorphandra mollis), Valepotriates (Valeria species), Indole alkaloids (Catharanthus roseous), and Furanocoumarins (Bituminaria bituminosa). : The aim of this article is a survey of active chemical compounds and metabolic changes of some of the most important medicinal plants in traditional Chinese medicine (TCM) in both abiotic and biotic stresses. : Future research is needed to evaluate the effects of biotic and abiotic stresses on chemical compounds and active metabolites of medicinal plants specially traditional Chinese medicine, and more surveys on the roles of LC-MS, GC-MS and NMR techniques for a better understanding of chemical components of medicinal plants.

Preliminary study on the effective site and mechanism of action of Meconopsis quintuplinervia Regel in alleviating acute alcoholic liver injury in mice.

Meconopsis quintuplinervia Regel (MQR) belongs to the opium poppy tree plant species, and it has heat purging, detoxification, diuretic, anti-inflammatory, and analgesic effects. MQR has liver-protective properties and can alleviate liver heat. Therefore, this study aimed to observe the effect of MQR extract on acute alcoholic liver injury in mice and explore the mechanism of action of ethyl acetate extract of MQR (MQR-E) on alcohol-induced liver injury in combination with the network pharmacology. To induce acute alcoholic liver injury, 52% of edible wine was administered at 12mL/kg for 14 days. The pharmacodynamic results were used to screen the active site. MQR-E composition was analyzed based on UPLC-Q-TOF-MS, and relevant MQR-E and alcoholic liver disease (ALD) targets were screened using an online database. Then, Venn analysis of drug and disease-related targets was performed to obtain cross-targets. We investigated the protein-protein interaction network (PPI) of overlapping targets, the core targets were screened using the STRING database, and the DAVID database was chosen for GO and KEGG enrichment analysis of the central targets. Each of the four MQR extracts ameliorated alcoholic liver injury to varying degrees; the best results were achieved with MQR-E. MQR-E reduces liver index, serum transaminases, and fat accumulation, and attenuates ethanol-induced histopathological changes. The activities of hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased, the content of malondialdehyde (MDA) was significantly reduced compared to the EtOH group, and MQR-E effectively mitigated the oxidative stress induced by ethanol in the liver. Thirty-six compounds were identified, and flavonoids were the most abundant. PPI network topology analysis was employed to assess 32 core targets: IL-6, TNF, STAT3, PPARA, and other inflammation and lipid metabolism related genes. Pathway analysis of GO and KEGG enrichment showed that the regulation of inflammatory factors and lipid metabolism were primarily involved. We concluded that MQR-E had protective effects against acute alcohol-induced liver injury in mice, and the mechanism could be linked to the inhibition of lipid peroxidation and oxidative stress. The mechanism by which MQR-E ameliorated ALD primarily involved regulating inflammatory factors and lipid metabolism based on the prediction of the network pharmacology.

Yield and Yield Components of Winter Poppy (Papaver somniferum L.) Are Affected by Sowing Date and Sowing Rate under Pannonian Climate Conditions

Poppy cultivation has a long tradition in Central Europe. Growing winter poppy instead of the commonly grown spring poppy might increase seed yield, especially in the face of changing climatic conditions. However, knowledge regarding optimum sowing date and optimum sowing rate for winter poppy under Pannonian climate conditions in Central Europe is missing. Therefore, a two-year field experiment was performed in Eastern Austria with four sowing dates ranging from early September to mid/end of October and two sowing rates with 50 or 100 mg seeds m−2. Seed yields were considerably higher than values reported for spring poppy throughout all sowing dates, mainly due to a higher number of seeds capsule−1 and, thereby, a higher seed yield capsule−1. The highest seed yields were obtained by sowing in early October, while the earliest and especially the latest sowing date resulted in lower seed yields. Consequently, the optimum sowing date for winter poppy under Pannonian climate conditions in Central Europe is early October but sowing can be performed over a wider range of dates. No seed yield differences were observed between sowing rates. Consequently, the sowing rate can be much lower than the recommended sowing rate for spring poppy.

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport.

Opioids are substances derived from opium (natural opioids). In its raw state, opium is a gummy latex extracted from Papaver somniferum. The use of opioids and their negative health consequences among people who use drugs have been studied. Today, opioids are still the most commonly used and effective analgesic treatments for severe pain, but their use and abuse causes detrimental side effects for health, including addiction, thus impacting the user's quality of life and causing overdose. The mesocorticolimbic dopaminergic circuitry represents the brain circuit mediating both natural rewards and the rewarding aspects of nearly all drugs of abuse, including opioids. Hence, understanding how opioids affect the function of dopaminergic circuitry may be useful for better knowledge of the process and to develop effective therapeutic strategies in addiction. The aim of this review was to summarize the main features of opioids and opioid receptors and focus on the molecular and upcoming epigenetic mechanisms leading to opioid addiction. Since synthetic opioids can be effective for pain management, their ability to induce addiction in athletes, with the risk of incurring doping, is also discussed.

Applicability of LC-QToF and Microscopical Tools in Combating the Sophisticated, Economically Motivated Adulteration of Poppy Seeds.

Morphine and codeine are the two principal opiates found in the opium poppy (Papaver somniferum L.) and are therapeutically used for pain management. Poppy seeds with low opiates are primarily used for culinary purposes due to their nutritional and sensory attributes. Intentional adulteration of poppy seeds is common, often combined with immature, less expensive, exhausted, or substituted with morphologically similar seeds, viz., amaranth, quinoa, and sesame. For a safer food supply chain, preventive measures must be implemented to mitigate contamination or adulteration. Moreover, the simultaneous analysis of P. somniferum and its adulterants is largely unknown. Pre- and post-processing further complicate the alkaloid content and may pose a significant health hazard. To address these issues, two independent methods were investigated with eight botanically verified and fifteen commercial samples. Microscopical features were established for the authenticity of raw poppy seeds. Morphine, codeine, and thebaine quantities ranged from 0.8-223, 0.2-386, and 0.1-176 mg/kg, respectively, using LC-QToF. In most cases, conventional opiates have a higher content than papaverine and noscapine. The analytical methodology provided a chemical profile of 47 compounds that can be effectively applied to distinguish poppy seeds from their adulterants and may serve as an effective tool to combat ongoing adulteration.

Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application.

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.

Pathway elucidation and microbial synthesis of proaporphine and bis-benzylisoquinoline alkaloids from sacred lotus (Nelumbo nucifera)

Sacred lotus (Nelumbo nucifera) has been utilized as a food, medicine, and spiritual symbol for nearly 3000 years. The medicinal properties of lotus are largely attributed to its unique profile of benzylisoquinoline alkaloids (BIAs), which includes potential anti-cancer, anti-malarial and anti-arrhythmic compounds. BIA biosynthesis in sacred lotus differs markedly from that of opium poppy and other members of the Ranunculales, most notably in an abundance of BIAs possessing the (R)-stereochemical configuration and the absence of reticuline, a major branchpoint intermediate in most BIA producers. Owing to these unique metabolic features and the pharmacological potential of lotus, we set out to elucidate the BIA biosynthesis network in N. nucifera. Here we show that lotus CYP80G (NnCYP80G) and a superior ortholog from Peruvian nutmeg (Laurelia sempervirens; LsCYP80G) stereospecifically convert (R)-N-methylcoclaurine to the proaporphine alkaloid glaziovine, which is subsequently methylated to pronuciferine, the presumed precursor to nuciferine. While sacred lotus employs a dedicated (R)-route to aporphine alkaloids from (R)-norcoclaurine, we implemented an artificial stereochemical inversion approach to flip the stereochemistry of the core BIA pathway. Exploiting the unique substrate specificity of dehydroreticuline synthase from common poppy (Papaver rhoeas) and pairing it with dehydroreticuline reductase enabled de novo synthesis of (R)-N-methylcoclaurine from (S)-norcoclaurine and its subsequent conversion to pronuciferine. We leveraged our stereochemical inversion approach to also elucidate the role of NnCYP80A in sacred lotus metabolism, which we show catalyzes the stereospecific formation of the bis-BIA nelumboferine. Screening our collection of 66 plant O-methyltransferases enabled conversion of nelumboferine to liensinine, a potential anti-cancer bis-BIA from sacred lotus. Our work highlights the unique benzylisoquinoline metabolism of N. nucifera and enables the targeted overproduction of potential lotus pharmaceuticals using engineered microbial systems.