Green Synthesis of Silver Nanoparticles Derived from Papaver rhoeas L. Leaf Extract: Cytotoxic and Antimicrobial Properties.

In the last few decades, the search for metal nanoparticles as an alternative to cancer treatments and antibiotics has increased. In this article, the spectroscopic (ultraviolet-visible (UV-vis), electron-dispersing X-ray (EDX), and Fourier transform infrared (FT-IR)), microscopic (field emission scanning electron microscope (FE-SEM), transmission electron microscope (TEM), and atomic force microscope (AFM)), structural (X-ray diffractometer (XRD) and zetasizer), and analytic (thermogravimetric/differential thermal analyzer (TGA-DTA)) characterization of the silver nanoparticles (AgNPs) produced from Papaver rhoeas (PR) L. leaf extract are presented. PR-AgNPs are generally spherical and have a maximum surface plasmon resonance of 464.03 nm. The dimensions of the manufactured nanomaterial are in the range of 1.47-7.31 nm. PR-AgNPs have high thermal stability and a zeta potential of -36.1 mV. The minimum inhibitory concentration (MIC) values (mg L-1) of PR-AgNPs on Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Candida albicans are 1.50, 0.75, 3.00, 6.00, and 0.37, respectively. In the study, the cytotoxic and proliferative effects of PR-AgNPs using the MTT (3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide) method on various cancer cell lines (CACO-2 (human colon adenocarcinoma cell), MCF-7 (human breast cancer cell), T98-G (glioblastoma multiforme cell), and healthy HUVEC (human umbilical vein endothelial cell)) cell lines are presented. After 24 and 48 h of the application, the half-maximum inhibitory concentration (IC50) values (µg mL-1) of PR-AgNPs on HUVEC, CACO-2, MCF-7, and T98-G lines are 2.365 and 2.380; 2.526 and 2.521; 3.274 and 3.318; 3.472 and 3.526, respectively. Comprehensive in vivo research of PR-AgNPs is proposed to reveal their potential for usage in sectors such as nanomedicine and nanochemistry.

Developing the evidence and associated service models to support older adults living with frailty to manage their pain and to reduce its impact on their lives: protocol for a mixed-method, co-design study (The POPPY Study).

INTRODUCTION: The Pain in Older People with Frailty Study is a mixed-method, co-design study, which aims to develop the content, implementation strategies, service and professional guidance to support older adults with frailty to manage their pain. METHODS AND ANALYSIS: The study has four phases: Phase 1, research evidence and information synthesis from randomised controlled trials of multicomponent pain management programmes and psychological therapies for community-dwelling older adults. Phase 2, qualitative interviews with 30 community-dwelling older adults (≥75 years) living with frailty and persistent pain, including dyadic interviews with a spouse or unpaid carer. Phase 3, qualitative interviews with healthcare professionals (HCPs) working within various pain service types; 5-8 HCPs per service and up to 12 services including primary care, secondary care, tertiary centres and services with voluntary sector input. Phase 4, co-design workshops with older adults, HCPs and commissioners. Inclusion criteria (Phase 2): community-dwelling older adults (≥75 years) living with frailty and persistent pain. Exclusion criteria (Phase 2): care home residents, a dementia or cancer diagnosis. Cancer survivors, ≥5 years cancer free, and not undergoing active cancer treatment can participate. Analysis for Phase 1 will use narrative synthesis, Phase 2 will use grounded theory analysis and Phase 3 will use thematic analysis. Oversight is provided from a patient and public involvement group and an independent steering committee. ETHICS AND DISSEMINATION: The protocol was approved by Leeds-East Research Ethics Committee on 28 April 2022 (22/YH/0080). Consent is sought if an individual is willing to participate (Phases 2-4) and has capacity. Findings will be disseminated at conferences, in newsletters and journals and to local authorities and charities.

Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence.

Papaver somniferum L. (Family: Papaveraceae) is a species well known for its diverse alkaloids (100 different benzylisoquinoline alkaloids (BIAs)). L-tyrosine serves as a precursor of several specific metabolites like BIAs. It has been used as an antitussive and potent analgesic to alleviate mild to extreme pain since ancient times. The extraction of pharmaceutically important alkaloids like morphine and codeine from poppy plant reflects the need for the most suitable and standard methods. Several analytical and extraction techniques have been reported in open literature for morphine, codeine and other important alkaloids which play a vital function in drug development and drug discovery. Many studies suggest that opioids are also responsible for adverse effects or secondary complications like dependence and withdrawal. In recent years, opium consumption and addiction are the most important risk factors. Many evidence-based reviews suggest that opium consumption is directly linked or acts as a risk factor for different cancers. In this review, we highlight significant efforts related to research which have been done over the past 5 decades and the complete information on Papaver somniferum including its phytochemistry, pharmacological actions, biosynthetic pathways and analytical techniques of opium alkaloid extraction and the link between opium consumption and cancer-related updates.

Cohort profile: POPPY II - a population-based cohort examining the patterns and outcomes of prescription opioid use in New South Wales, Australia.

PURPOSE: The POPPY II cohort is an Australian state-based cohort linking data for a population of individuals prescribed opioid medicines, constructed to allow a robust examination of the long-term patterns and outcomes of prescription opioid use. PARTICIPANTS: The cohort includes 3 569 433 adult New South Wales residents who initiated a subsidised prescription opioid medicine between 2003 and 2018, identified through pharmacy dispensing data (Australian Pharmaceutical Benefits Scheme) and linked to 10 national and state datasets and registries including rich sociodemographic and medical services data. FINDINGS TO DATE: Of the 3.57 million individuals included in the cohort, 52.7% were female and 1 in 4 people were aged ≥65 years at the time of cohort entry. Approximately 6% had evidence of cancer in the year prior to cohort entry. In the 3 months prior to cohort entry, 26.9% used a non-opioid analgesic and 20.5% used a psychotropic medicine. Overall, 1 in 5 individuals were initiated on a strong opioid (20.9%). The most commonly initiated opioid was paracetamol/codeine (61.3%), followed by oxycodone (16.3%). FUTURE PLANS: The POPPY II cohort will be updated periodically, both extending the follow-up duration of the existing cohort, and including new individuals initiating opioids. The POPPY II cohort will allow a range of aspects of opioid utilisation to be studied, including long-term trajectories of opioid use, development of a data-informed method to assess time-varying opioid exposure, and a range of outcomes including mortality, transition to opioid dependence, suicide and falls. The duration of the study period will allow examination of population-level impacts of changes to opioid monitoring and access, while the size of the cohort will also allow examination of important subpopulations such as people with cancer, musculoskeletal conditions or opioid use disorder.

Ethnopharmacological evaluation of Poppy seed oil in combination with Tramadol on behavioral paradigm and on dopamine, and cytokines levels.

OBJECTIVE: The present study was taken up to evaluate the combination of two drugs in the management of behavioral disorders such as locomotor activity, muscle relaxation, analgesic, and anxiolytic activity. MATERIALS AND METHODS: In the methodology, Wistar rats weighing (150-180 g) were divided into six groups of 6 each (n=6). All the animals (groups II to VI) were subjected to stress and analyzed for anxiolytic activity using an elevated plus maze. The animals were treated for 28 days with poppy seed oil in lower and higher doses (1,000 and 2,000 mg/kg), tramadol in lower and higher doses (1.5 and 3 mg/kg) as individual groups, and one group with a combination of both drugs in lower doses. RESULTS: The results depicted showed that the combined treatment had significantly (**p <0.001) improvised behavior deficits, extemporized, and diminished anxiety-like attitude in rats, and showed the analgesic property in a significant manner. The pro-inflammatory cytokines TNF-α and IL-1ß were evaluated in the serum and were observed to be lessened the values of both in a significant manner with the co-administration of both the test drugs. The dopamine concentrations were also determined in the serum, which disclosed a decline (**p <0.001) significantly. CONCLUSIONS: It was concluded from the results that a combined effect of drugs might be beneficial in the management of behavioral disorders and pain management.

Investigating the Effects of Biogenic Zinc Oxide Nanoparticles Produced Using Papaver somniferum Extract on Oxidative Stress, Cytotoxicity, and the Induction of Apoptosis in the THP-1 Cell Line.

This study investigated the effect of novel zinc oxide nanoparticles (ZnO NPs) biosynthesized employing Papaver somniferum leaf on oxidative stress, necrosis, and apoptosis in the leukemia cancer THP-1 cell. The obtained ZnO was examined using SEM, AFM, and TEM microscopy, which revealed an irregular spherical morphology with a size ranging from 20 to 30 nm, and the UV-vis absorbance revealed a strong absorption peak in the range of 360-370, nm confirming the production of ZnO NPs. THP-1 cells were subjected to an MTT, an EdU proliferation, a lactate dehydrogenase release tests, a reactive oxygen species (ROS) induction experiment, a DAPI staining detection assay, and a flow cytometric analysis for Annexin V to measure the effects of ZnO NPs on cancer cell growth inhibition, apoptosis, and necrosis. Our results show that ZnO NPs inhibit THP-1 line in a concentration-dependent pattern. It was observed that ZnO NPs triggered necrosis (cell death) and apoptosis in the cell line. ZnO NPs massively improved the formation of intracellular ROS, which is crucial in deactivating the development of leukemic cells. In conclusion, ZnO nanoparticles synthesized using Papaver somniferum extract have the ability to inhibit proliferation leukemic cancer cells, making them potential anticancer agents.

Computational insights into diverse aspects of glutathione S-transferase gene family in Papaver somniferum.

Plant glutathione S-transferases are an ancient protein superfamily having antioxidant activity. These proteins are primarily involved in diverse plant functions such as plant growth and development, secondary metabolism, signaling pathways and defense against biotic and abiotic stresses. The current study aimed to comprehensively identify and characterize the GST gene family in the medicinally important crop Papaver somniferum. A total of 93 GST proteins were identified belonging to eight GST classes and found to be majorly localized in the cytoplasm. All GST genes were found on eleven opium chromosomes. Gene duplication analysis showed segmental duplication as a key factor for opium GST gene family expansion under strong purifying selection. Phylogenetic analysis with gymnosperm, angiosperm and bryophyte revealed the evolution of GSTs earlier than their division into separate groups and also prior to the divergence of monocot and dicot. The secondary structure prediction showed the dominance of α-helices indicative of PsomGSTs as structurally stable and elastic proteins. Gene architecture showed the conservation of number of exons across the classes. MEME analysis revealed only a few class specific and many across class conserved motifs. Ser was found to be the active site residue of tau, phi, theta and zeta class and Cys was catalytic residue of DHAR, lambda and GHR class. Promoter analyses identified many cis-acting regulatory elements related to hormonal, cellular, stress and light response functions. Ser was the key phosphorylation site. Only three glycosylation sites were found across the 93 PsomGSTs. 3D structure prediction was also performed and was validated. Interactome analyses revealed the correlation of PsomGSTs with glutathione metabolizing proteins. Gene enrichment analysis and KEGG pathway analyzed the involvement of PsomGSTs in three major pathways i.e. glutathione metabolism, tyrosine metabolism and ascorbate metabolism. The outcome revealed high model quality of PsomGSTs. The results of the current study will be of potential significance to understand the functional and structural importance of the GST gene family in opium, a medicinally important crop.

Depletion plays a pivotal role in self-incompatibility, revealing a link between cellular energy status, cytosolic acidification and actin remodelling in pollen tubes.

Self-incompatibility (SI) involves specific interactions during pollination to reject incompatible ('self') pollen, preventing inbreeding in angiosperms. A key event observed in pollen undergoing the Papaver rhoeas SI response is the formation of punctate F-actin foci. Pollen tube growth is heavily energy-dependent, yet ATP levels in pollen tubes have not been directly measured during SI. Here we used transgenic Arabidopsis lines expressing the Papaver pollen S-determinant to investigate a possible link between ATP levels, cytosolic pH ([pH]cyt ) and alterations to the actin cytoskeleton. We identify for the first time that SI triggers a rapid and significant ATP depletion in pollen tubes. Artificial depletion of ATP triggered cytosolic acidification and formation of actin aggregates. We also identify in vivo, evidence for a threshold [pH]cyt of 5.8 for actin foci formation. Imaging revealed that SI stimulates acidic cytosolic patches adjacent to the plasma membrane. In conclusion, this study provides evidence that ATP depletion plays a pivotal role in SI upstream of programmed cell death and reveals a link between the cellular energy status, cytosolic acidification and alterations to the actin cytoskeleton in regulating Papaver SI in pollen tubes.

Opium, Street Opium, and Cancer Risk.

Opium is defined as the air-dried latex obtained by incision from the unripe capsules of Papaver somniferum L. Opium is a complex mixture that contains approximately 10% morphine and 2% codeine. It is commonly used to prepare opium tinctures for people with chronic diarrhea. Morphine and related opioids are powerful but highly addictive analgesics; designing less addictive opioids is an active area of pharmaceutical research that may lead to significant improvements in chronic pain management. Recently, the International Agency for Research on Cancer (IARC) has classified opium consumption as carcinogenic to humans (Group 1) based on sufficient evidence of carcinogenicity in human studies. However, all human studies analyzed by the IARC Working Group included participants who consumed opium that was mixed, adulterated, and/or contaminated with known and probable human carcinogens (e.g., tarry residues of combusted opium, arsenic, lead, and chromium). The working group considered that these carcinogens were part of the complex mixture that opium is, rather than co-exposure or confounders. No evidence of carcinogenicity was available for pure opium in human, animal, or mechanistic studies. To avoid confusion and concern among health professionals and patients using medicinal opium preparations and in scientists involved in the design and development of new opium derivatives, opium should be classified in Group 3 (not classifiable as to its carcinogenicity to humans). The term 'street opium' could be used to refer to opium that probably contains human carcinogens not present in pure opium and should remain in Group 1 (carcinogenic to humans).

Total Phenolic Content and Antioxidant and Antimicrobial Activities of Papaver rhoeas L. Organ Extracts Growing in Taounate Region, Morocco.

The objective of this study is to valorize Papaver rhoeas L. from the Taounate region of Morocco by determining the total polyphenol content (TPC), the total flavonoid content (TFC) and the antioxidant and antimicrobial activities of four organs. The quantification of TPC and TFC in root, stem, leaf and flower extracts (RE, SE, LE and FE, respectively) was estimated by the Folin-Ciocalteu reaction and the aluminum trichloride method, respectively. Two tests were used to assess antioxidant power: the DPPH test and TAC assay. The antimicrobial activity was studied against five pathogenic bacteria and yeast, using two methods: disk diffusion and microdilution. The TPC in LE and LF was twice as high as that in RE and SE (24.24 and 22.10 mg GAE/g, respectively). The TFC values in the four extracts were very close and varied between 4.50 mg QE/g in the FE and 4.38 mg QE/g in the RE. The LE and FE showed low DPPH values with IC50 = 0.50 and 0.52 mg/mL, respectively. The TAC measurement revealed the presence of a significant amount of antioxidants in the studied extracts, mainly in LE and FE (6.60 and 5.53 mg AAE/g, respectively). The antimicrobial activity results revealed significant activity on almost all of the tested strains. The MIC of FE and SE against E. coli 57 was 1.56 and 0.78 mg/mL, respectively, while against the S. aureus it was 50 and 25 mg/mL, respectively. The low MLC value (1.56 mg/mL) was recorded against E. coli 57 by RE and SE.

Papaver Plants: Current Insights on Phytochemical and Nutritional Composition Along with Biotechnological Applications.

The genus Papaver is highly esteemed in the pharmacy industry, in the culinary field, and as ornamental plants. These plants are also valued in traditional medicine. Among all Papaver species, Papaver somniferum L. (opium poppy) is the most important species in supplying phytochemicals for the formulation of drugs, mainly alkaloids like morphine, codeine, rhoeadine, thebaine, and papaverine. In addition, Papaver plants present other types of phytochemicals, which altogether are responsible for its biological activities. Therefore, this review covers the phytochemical composition of Papaver plants, including alkaloids, phenolic compounds, and essential oils. The traditional uses are reviewed along with their pharmacological activities. Moreover, safety aspects are reported to provide a deep overview of the pharmacology potential of this genus. An updated search was carried out in databases such as Google Scholar, ScienceDirect, and PubMed to retrieve the information. Overall, this genus is a rich source of alkaloids of different types and also contains interesting phenolic compounds, such as anthocyanins, flavonols, and the characteristic indole derivatives nudicaulins. Among other pharmacological properties, numerous preclinical studies have been published about the analgesic, anticancer, antimicrobial, antioxidant, and antidiabetic activities of Papaver plants. Although it highlights the significant impact of this genus for the treatment of a variety of diseases and conditions, as a future prospect, characterization works accompanying preclinical studies are required along with clinical and toxicology studies to establish a correlation between the scientific and traditional knowledge.

Functional Studies of Plant Latex as a Rich Source of Bioactive Compounds: Focus on Proteins and Alkaloids.

Latex, a sticky emulsion produced by specialized cells called laticifers, is a crucial part of a plant's defense system against herbivory and pathogens. It consists of a broad spectrum of active compounds, which are beneficial not only for plants, but for human health as well, enough to mention the use of morphine or codeine from poppy latex. Here, we reviewed latex's general role in plant physiology and the significance of particular compounds (alkaloids and proteins) to its defense system with the example of Chelidonium majus L. from the poppy family. We further attempt to present latex chemicals used so far in medicine and then focus on functional studies of proteins and other compounds with potential pharmacological activities using modern techniques such as CRISPR/Cas9 gene editing. Despite the centuries-old tradition of using latex-bearing plants in therapies, there are still a lot of promising molecules waiting to be explored.

Determination of morphine, codeine, and thebaine concentrations from poppy seed tea using magnetic carbon nanotubes facilitated dispersive micro-solid phase extraction and GC-MS analysis.

With tightening enforcement and restrictions amid the opioid epidemic, poppy seed tea is consumed as an alternative to mitigate the withdrawal symptoms or as a home remedy to relieve pain and stress. Previously published studies suggested the potential danger of consuming tea brewed with a moderate to a large amount of poppy seed. In this study, the effects of small quantity and repeat brewing on opiate concentrations were evaluated. A dispersive-micro solid phase extraction facilitated by magnetic carbon nanotubes (Mag-CNTs/d-µSPE) was developed, optimized, successfully validated, and applied to ten poppy seed tea samples using gas chromatography-mass spectrometry (GC-MS) analysis. A total of ten poppy seed samples were evaluated in this work. Two grams of bulk poppy seeds were brewed with 6 mL of heated and acidified DI water three times. The brewed tea samples were subjected to the validated Mag-CNTs/d-µSPE/GC-MS analysis. The total mean opiate concentrations obtained from three brews were 1.1-1926, 20.2-311, and 9.0-100 mg/kg for morphine, codeine, and thebaine, respectively. The total opiate yields obtained from the small quantity brewing, i.e., 6 g seed in 18 mL tea, in this study may provide minimal analgesic and euphoric effects. Over 80% of the total opiate yield was extracted in the first brew with acidified deionized water from the 10 min brewing period, and opiate yields from the second and third brew were minimal. However, potential overdose could occur for some tea samples when scaled up to the starter quantity of seed suggested for new users.

Identification of novel anti-cancer agents by the synthesis and cellular screening of a noscapine-based library.

Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 µM and 1.5 µM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 µM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine.

Mineral Composition and Antioxidant Potential in the Common Poppy (Papaver rhoeas L.) Petal Infusions.

The flowers of the common poppy are used for medicinal purposes, both internally and externally. They are reported to have antispasmodic and antitussive properties, to alleviate inflammatory conditions and soothe anxiety-related digestive problems. The aim of the study was to determine the antioxidant potential and the content of vitamin C, polyphenols, and minerals in infusions made from the petals of the common poppy at different temperatures. The infusions were made at various temperatures (25 °C, 70 °C, 80 °C, and 90 °C). The antioxidant potential and the content of polyphenols and vitamin C were determined by spectrophotometric methods. The mineral content was determined using the ICP-OES method. The total polyphenol content ranged from 135.2 to 137.24 ppm and that of vitamin C-from 15.47 to 15.78 mg/100 mL. The temperature of the water used to make the infusions did not appear to have a significant effect on these parameters. The temperature did, however, significantly affect the antioxidant potential of the infusions-the highest antioxidant activity (71.21% DPPH inhibition) was observed in the infusion prepared using water at 80 °C. The infusions included in the study contained a number of minerals. No significant effect of temperature was found for the content of K, Zn, Cu, Fe, and Ni in the infusions. On the other hand, the content of Ca in the infusions was significantly correlated with the increasing temperature of the water. It was concluded that poppy petal infusions may serve as a valuable dietary supplement, providing antioxidants and minerals required by the human body to function properly.

Altered gene expression and root thebaine production in polyploidized and methyl jasmonate-elicited Papaver bracteatum Lindl.

Persian poppy (Papaver bracteatum Lindl.) is a perennial medicinal plant belonging to the Papaveraceae family that is endemic to the mountainous areas in Northern Iran. It is known for high amounts of the valuable benzylisoquinoline alkaloid thebaine. The effects of induced polyploidy as well as the effect of methyl Jasmonate (MeJA) elicitation on the root production of thebaine and on the expression of five alkaloid biosynthesis related genes were studied. The in vitro tetraploidy induction caused a significant increased expression of norcoclaurine synthase (NCS) and salutaridinol (SAT), and a significant decreased expression of berberine bridge enzyme (BBE) in the leaves. In the root tissues, the BBE, NCS, and SAT showed an increased expression in tetraploid plants, while codeinone reductase (COR) showed a decreased expression. A similar alteration pattern was found in mixoploid plants when compared to their diploid counterparts. MeJA at concentrations of 0.1 and 0.5 mM caused a remarkable increase in the thebaine content in the roots of treated plants, where the highest thebaine content was identified in plants elicited with 0.5 mM MeJA. Elicitation treatment caused a substantial increase in the expression of NCS and SAT in the leaves, while it had no major effect on BBE, codeine 3-O-demethylase (CODM) and COR. Expression analysis in the roots showed that MeJA caused a significant increase in the expression of only BBE and NCS, while expression of other studied genes remained unchanged. Our results may be exploited for improved thebaine production and the processing of Persian poppy.