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Uncontrolled hemorrhage remains a critical threat in trauma and surgery. This study developed a novel hemostatic composite by encapsulating Peganum harmala L. seed extract (PH) with known hemostatic properties into lipid nanocapsules (PH-LNCs) and then embedding them within a polyvinyl alcohol-chitosan-polyethylene glycol-glycerol (PVA-CS-PEG-G) matrix. The composite was physically crosslinked via the dual processes of freezing-thawing and thermal crosslinking and exhibited robust mechanical properties reaching 0.434 ± 0.014 MPa and elasticity of 40.685 % ± 4.04. It also demonstrated excellent biocompatibility, surface morphology, physical stability, and ex-vivo skin deposition/permeation were assessed. The characterization of PH-LNCs revealed optimal PH-LNC formation and successful integration into the composite with particle size, zeta potential, and PDI were approximately 45.45 ± 24 nm, -16.3 ± 1.4 mV, and 0.374 ± 0.1, respectively. In vitro studies highlighted enhanced blood clotting and platelet adhesion, while in vivo experiments confirmed superior hemostatic efficacy in a mouse tail amputation model. The composite's soft texture, conformability, and mechanical strength make it a promising candidate for effective traumatic wound management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endogenous hypochlorous acid (HOCl) is one of the most important reactive oxygen species (ROS) and acts as a distinct biomarker that is involved in various inflammatory responses including rheumatoid arthritis (RA). Therefore, it's crucial to develop an efficient method for the tracking and analysis of HOCl levels in vivo. Natural products continue to be compounds of interest, because they not only offer diverse and specific molecular scaffolds but also provide invaluable sources for new drug discovery. Herein, we firstly demonstrated harmaline (HML), a natural alkaloid mainly found in Peganum harmala L, could be acted as a novel fluorescent probe for HOCl with exceptional precision and responsiveness. Remarkably, this probe not only specifically tracked HOCl levels in cells and inflammatory RA mouse models, but also exhibited effective anti-inflammatory effects on RAW264.7 cells and anti-proliferative effects on fibroblast-like synoviocytes. Furthermore, HML has the potential to alleviate LPS-induced inflammation by inhibiting the NF-κB signaling pathway. This study represents the first example of a natural product that can simultaneously act as a fluorescent probe for specific ROS and a promising therapeutic candidate for a specific disease, which will undoubtedly extend the application of fluorophore-rich natural products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Peganum harmala L., a traditional Uyghur ethnic medicine widely used in China, is commonly used in the treatment of conditions such as hemiplegia, forgetfulness, cough, and asthma. Harmine and other β-carboline alkaloids, one of the main active ingredients in P. harmala, have exhibited various pharmacological activities, including anti-Alzheimer's, antidepressant, anti-inflammatory, and antioxidant effects. However, the effects and underlying mechanisms of harmine on improving ethanol-induced memory impairment remain unclear., Aim of the Study: This study aimed to investigate the effects of harmine on ameliorating ethanol-induced memory impairment, and to explore potential mechanisms., Materials and Methods: Ethanol (30%, i. g.) was used to induce memory impairment model. The effect of harmine on memory impairment was evaluated by Morris water maze (MWM). The histopathological analysis, immunofluorescence staining, RT-qPCR and UHPLC-MS/MS methods were performed to further investigate the underlying mechanisms., Results: MWM experiments showed that harmine significantly improved ethanol-induced spatial learning memory deficit. Harmine exhibited anti-inflammatory effect by downregulating inflammatory factors such as IL-6, IL-1β and tumor necrosis factor-α (TNF-α) induced by ethanol. Harmine also upregulated brain-derived neurotrophic factor (BDNF) levels to exert neuroprotective effect. Moreover, harmine protected neuronal cells and increased the protein expression of myelin basic protein (MBP). The cellular results indicated that harmine protected SH-SY5Y cells from ethanol-induced cytotoxicity and upregulated the relative mRNA expression of synaptosome associated protein 25 (SNAP25), syntaxin 1 A (STX1A), vesicle associated membrane protein 2 (VAMP2), synaptotagmin 1 (SYT1) and synaptophysin (SYP)., Conclusions: Harmine improved ethanol-induced memory impairment by ameliorating inflammation, increasing BDNF levels, promoting synaptic vesicle fusion, protecting myelin sheath, and modulating neurotransmitter levels. These findings provided a scientific basis for development of therapeutic drugs for alcohol-induced memory impairments and other related disorders., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Leading by the antiviral activities against HSV-2 virus, bioactivity-guided the fraction of crude alkaloids from seeds of Peganum harmala led to the isolation of nine structurally novel indole alkaloids, pegaharolines A - I (1-9), and 11 known ones (10-20). Compound 3 was an unusual 6/5/5/5 spirotetracyclic indole-derived alkaloids featuring a classic bicyclic indole unit fused with an additional pyrrolizine ring via a spiral atom (C-3). Compound 4 was determined as a novel indole alkaloid, characterized with a rare hexacyclic 6/5/6/5-6/6 ring system, by a single-crystal X-ray diffraction. Compounds 5 and 6 were peculiar indole dimers featuring with the rare carbon skeleton of an octacyclic scaffold. Compounds 1-6 were six racemates. Most compounds exhibited different levels of antiviral activities against HSV-2. Especially, the anti-HSV-2 activity of compound 1 (IC 50  = 0.90 ± 0.10 μM) was much better than that of the positive control (acyclovir, IC 50  = 1.12 ± 0.15 μM). In this study, the discovery of anti-HSV-2 components from the seeds of P. harmala, could benefit development and utilization of this plant in antiviral medicinal products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is a mental disorder characterised by persistent low mood, anhedonia and cognitive impairment that affects an estimated 3.8% of the world's population, including 5% of adults. Peganum harmala L. (P. harmala) is a medicinal plant and has been reported to be effective against Alzheimer's disease, Parkinson's disease and depression. The present study was aimed to evaluate the behavioral and pharmacological effects of P. harmala seed extract in rats exposed to chronic unpredictable mild stress (CUMS) in vivo and to investigate the mechanism of action. CUMS-exposed rats were treated with P. harmala extract (75 and 150 mg/kg, i.p.) for 2 weeks. HPLC analysis was used to determine the concentration of harmaline and harmine alkaloids in the extract. Heavy metal analysis in seeds was performed by ICP-MS. Our results showed that P. harmala at the dose of 150 mg/kg significantly reduced the depressive-like behaviors in CUMS-exposed rats, as evidenced by increased sucrose consumption in the sucrose preference test (SPT), decreased immobility time in the forced swim test (FST) and plasma corticosterone levels, increased the time spent in open arms in the elevated plus maze (EPM), and improved memory and learning in the passive avoidance test (PAT). In addition, P. harmala decreased monoamine oxidase-A (MAO-A) levels, and increased serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels in the brains of rats exposed to CUMS. P. harmala decreased the expression of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB), and increased the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) in rat brain. Furthermore, P. harmala improved brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression in rat brain. In conclusion, P. harmala at a dose of 150 mg/kg is more effective in preventing depressive-like behavior in CUMS-exposed rats by improving neurotransmitter levels, reducing oxidative stress, suppressing neuroinflammation and activating the BDNF/TrkB pathway, all of which are important in the pathogenesis of depression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Peganum harmala L. is used in traditional medicine to treat several health ailments. Hence, the present work aimed to investigate the DPPH free radical scavenging, α-amylase, cytotoxic, and antifibrotic effects of the hydrophilic extract and fixed oil obtained from P. harmala seeds., Methods: The hydrophilic extract and fixed oil of P. harmala were assessed for their abilities to scavenge DPPH free radicals and inhibit α-amylase using reference bioassays. The cytotoxicity was assessed on several cancer and normal cell lines, including B16F1, Caco-2, COLO205, HeLa, Hep 3B and Hep G2, MCF-7, and HEK-293 T cells. The MTS assay was used to evaluate the antifibrotic capabilities utilizing the human hepatic stellate (LX-2) cell line., Results: P. harmala plant fixed oil has potent DPPH free radical scavenging activity with an IC 50 dose of 79.43 ± 0.08 µg/ml. Besides, the hydrophilic extract has a poor anti-α-amylase effect compared with the antidiabetic drug Acarbose, with IC 50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively. In addition, the growth of MCF-7, Hep3B, HepG2, HeLa, COLO205, CaCo2, B16F1, and HeK293t was inhibited by P. harmala hydrophilic extract with IC 50 doses of 121.34 ± 1.71, 268.3 ± 0.75, 297.20 ± 1.00, 155.60 ± 1.14, 150.01 ± 0.51, 308.35 ± 0.53, 597.93 ± 1.36, and 5.38 ± 0.99 µg/ml, respectively. In addition, at 1000 µg/ml, 5-Fluorouracil reduced fibrosis cells by 0.089%, while the hydrophilic extract decreased the number of LX-2 cells by 5.81%., Conclusion: P. harmala plant-fixed oil exhibits potential antioxidant properties. While the hydrophilic extract showed limited effectiveness as an anti-α-amylase agent and demonstrated notable cytotoxic effects against various tested cancer cell lines. Furthermore, this extract significantly reduces the number of LX-2 fibrotic cells. These findings emphasize the therapeutic potential of these products in managing various health disorders and warrant further investigation into their mechanisms of action and clinical applications., (© 2024. The Author(s).)

Peganum harmala L., a traditional medicinal plant in China, is renowned for its significant alkaloid content in seeds and roots exhibiting a wide range of pharmacological activities, including antidepressant, antiseptic, and antiviral. However, the volatile composition of the herb remained unclear. Apart from that, the extraction of volatile compounds through essential oil presents challenges due to the low yield and the degradation of volatile active compounds at high temperatures. This study used multiple sample preparation methods including headspace (HS), needle trap device (NTD), and liquid-liquid extraction (LLE) coupled with gas chromatography-mass spectrometry (GC-MS) to analyze the volatile compounds from the areal part of P. harmala L.. A total of 93 compounds were identified with NTD facilitating the first detection of harmine among the volatile organic compounds. Through network pharmacology and protein interaction analysis, the compounds' potential therapeutic targets of the compounds were explored, and 23 key targets were obtained (AKT1, ALB, PTGS2, MAOA, etc). KEGG pathway enrichment analysis indicated significant involvement in neuroactive ligand-receptor interactions and serotonergic synapses. The results enhanced the understanding of P. harmala's pharmacological mechanisms and supported its ethnopharmacological use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The present study aimed to elucidate the potential anticancer activity and mechanism of P. harmala's alkaloid extract, harmine (HAR), and harmaline (HAL) in HCT-116 colorectal cancer cells., Methods and Results: P. harmala's alkaloid was extracted from harmala seeds. HCT-116 cells were treated with P. harmala's alkaloid extract, HAR and HAL. Cytotoxicity was determined by MTT assay, apoptotic activity detected via flow cytometry and acridine orange (AO)/ethidium bromide (EB) dual staining, and cell cycle distribution analyzed with flow cytometry. The mRNA expression of Bcl-2-associated X protein (Bax) and glycogen synthase kinase-3 beta (GSK3β) was measured by real-time PCR. Furthermore, the expression of Bax, Bcl-2, GSK3β and p53 proteins, were determined by western blotting. The findings indicated that, P. harmala's alkaloids extract, HAR and HAL were significantly cytotoxic toward HCT116 cells after 24 and 48 h of treatment. We showed that P. harmala's alkaloid extract induce apoptosis and cell cycle arrest at G2 phase in the HCT116 cell line. Downregulation of GSK3β and Bcl-2 and upregulation of Bax and p53 were observed., Conclusion: The findings of this study indicate that the P. harmala's alkaloid extract has anticancer activity and may be further investigated to develop future anticancer chemotherapeutic agents., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Peganum harmala has been extensively employed in Algerian traditional medicine practices. This study aimed to explore the impact of n-butanol (n-BuOH) extract sourced from Peganum harmala seeds on cell proliferation, cell migration, and angiogenesis inhibition. Cytotoxic potential of n-BuOH extract was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide) assay against human breast adenocarcinoma MCF-7 cells, cell migration was determined using scratch assay, and anti-angiogenic effect was evaluated through macroscopic and histological examinations conducted on chick embryo chorioallantoic membrane. Additionally, this research estimated the phytochemical profile of n-BuOH extract. Fifteen phenolic compounds were identified using Ultra-performance liquid chromatography UPLC-ESI-MS-MS analysis. In addition, the n-BuOH extract of P. harmala exhibited potent antioxidant and free radical scavenging properties. The n-BuOH extract showed potent cytotoxicity against MCF-7 cell with an IC 50 value of 8.68 ± 1.58 μg/mL. Furthermore, n-BuOH extract significantly reduced migration. A strong anti-angiogenic activity was observed in the groups treated with n-BuOH extract in comparison to the negative control. Histological analysis confirmed the anti-angiogenic effect of the n-BuOH extract. This activity is probably a result of the synergistic effects produced by different polyphenolic classes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study reports the isolation of four new β-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these compounds, 1 and 2 were characterized as rare β-carboline-quinazoline dimers exhibiting axial chirality. Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring, and compound 4 was a novel annomontine β-carboline. The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations. The biosynthetic pathways of 1-3 were proposed. Additionally, the cytotoxicity of some isolates against four cancer cell lines (HL-60, A549, MDA-MB-231, and DU145) was evaluated. Notably, compound 4 exhibited significant cytotoxicity against HL-60, A549, and DU145 cells with IC 50 values of 12.39, 12.80, and 30.65 μmol·L -1 , respectively. Furthermore, compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC 50 value of 17.32 μmol·L -1 ., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Peganum harmala L. is a perennial herb of Peganum in Zygophyllaceae family. It has been used as a national medicinal herb with the efficacy of strengthening muscle, warming stomach, dispelling cold, and removing dampness in Chinese folk. Clinically, it is mainly used to treat diseases such as weak muscles and veins, joint pain, cough and phlegm, dizziness, headache, and irregular menstruation., Methods: The relevant information about P. harmala L. in this review is based on online databases, including Elsevier, Willy, Web of Science, PubMed, ScienceDirect, SciFinder, SpringLink, Google Scholar, Baidu Scholar, ACS publications, SciHub, Scopus, and CNKI. The other information was acquired from ancient books and classical works about P. harmala L., Results: P. harmala L. is an important medicinal plant with a variety of traditional uses according to the theory of Chinese medicine. Phytochemical research revealed that P. harmala L. contained alkaloids, volatile oils, flavonoids, triterpenoids, coumarins, lignins, anthraquinones. Modern studies showed P. harmala L. possessed multiple bioactivities, including anti-cancer, neuroprotective, anti-bacterial, anti-inflammatory, hypoglycemic, anti-hypertensive, anti-asthmatic, and insecticidal activities. Furthermore, the contents of the quality marker and toxicity of P. harmala L. were summarized and analyzed in this review., Conclusion: The botany, traditional use, phytochemistry, pharmacology, quality marker, and toxicity of P. harmala L. were reviewed in this paper. It will not only provide an important clue for further studying P. harmala L., but also supply an important theoretical basis and valuable reference for in-depth research and exploitations of this plant in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Harmaline and harmine are naturally occurring closely related β-carboline alkaloids found in Peganum and Banisteriopsis plants. They have historical significance in traditional practices due to their potential psychoactive and therapeutic properties. Herein, a highly sensitive spectrofluorometric method was developed for the quantifying of harmaline and harmine in diverse matrices, including pure forms, seed samples, and spiked plasma. The procedures lie in addressing the challenge of overlapping fluorescence spectra exhibited by harmaline and harmine through the incorporation of hydroxypropyl-β-cyclodextrin, altering their chemical properties and fluorescence characteristics. Synchronous fluorescence measurements coupled with first derivative mathematical technique make it possible to distinguish between the harmaline and harmine at 419 and 456 nm, respectively. The method effectiveness is demonstrated through spectral analysis, optimization of the measurement conditions, adopting validation parameters and application to the pure form, seed samples and spiked human plasma. This methodology facilitates accurate determination of these alkaloids over the concentration range of 10─200 ng/mL. Thus, the developed approach provides a robust mean for the precise determination of harmaline and harmine, contributing to analytical chemistry's ongoing efforts to address complex challenges in quantification across diverse matrices., (© 2023. The Author(s).)

Ethnopharmacological Relevance: Peganum harmala L. is a traditional medicinal plant used for centuries in folk medicine. It has a wide array of therapeutic attributes, which include hypoglycemic, sedative, anti-inflammatory, and antioxidant properties. The fruit decoction of this plant was claimed by Avicenna as traditional therapy for urolithiasis. Also, P. harmala seed showed a clinical reduction in kidney stone number and size in patients with urolithiasis., Aim of the Study: In light of the above-mentioned data, the anti-urolithiatic activities of the seed extracts and the major β-carboline alkaloids of P. harmala were investigated., Materials and Methods: Extraction, isolation, and characterization of the major alkaloids were performed using different chromatographic and spectral techniques. The in vivo anti-urolithiatic action was evaluated using ethylene glycol (EG)-induced urolithiasis in rats by studying their mitigating effects on the antioxidant machinery, serum toxicity markers (i.e. nitrogenous waste, such as blood urea nitrogen, uric acid, urea, and creatinine), minerals (such as Ca, Mg, P, and oxalate), kidney injury marker 1 (KIM-1), and urinary markers (i.e. urine pH and urine output)., Results: Two major alkaloids, harmine (P1) and harmalacidine HCl (P2), were isolated and in vivo evaluated alongside the different extracts. The results showed that P. harmala and its constituents/fractions significantly reduced oxidative stress at 50 mg/kg body weight, p.o., as demonstrated by increased levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and catalase (CAT) in kidney homogenate as compared to the EG-treated group. Likewise, the total extract, pet. ether fraction, n-butanol fraction, and P1, P2 alleviated malondialdehyde (MDA) as compared to the EG-treated group. Serum toxicity markers like blood urea nitrogen (BUN), creatinine, uric acid, urea, kidney injury molecule-1 (Kim-1), calcium, magnesium, phosphate, and oxalate levels were decreased by total extract, pet. ether fraction, n-butanol fraction, P1, and P2 as compared to the EG-treated group. Inflammatory markers like NFκ-B and TNF-α were also downregulated in the kidney homogenate of treatment groups as compared to the EG-treated group. Moreover, urine output and urine pH were significantly increased in treatment groups as compared to the EG-treated group deciphering anti-urolithiatic property of P. harmala. Histopathological assessment by different staining patterns also supported the previous findings and indicated that treatment with P. harmala caused a gradual recovery in damaged glomeruli, medulla, interstitial spaces and tubules, and brown calculi materials as compared to the EG-treated group., Conclusion: The current research represents scientific evidence on the use of P. harmala and its major alkaloids as an effective therapy in the prevention and management of urolithiasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Two pairs of unprecedented β-carboline-phenylpropanoid heterogeneous alkaloids, (±)-pheharmines A-B (1-4), characterized by a morpholino[4,3,2- hi ]β-carboline core with two chiral centers, were isolated from the roots of Peganum harmala . The structures, including their absolute configurations, were identified using spectroscopic analyses and electronic circular dichroism (ECD) calculations. The biosynthetic hypothesis for the formation of pheharmines A-B was proposed. Compounds 1-4 exhibited moderate cytotoxic activities against HL-60 cell lines.

Peganum genus is rich with its high phytochemical and botanical variability. Peganum species have been used as a sedative, antitumor, analgesic and antidepressant. This paper aims to study the molecular diversity of Peganum genus and to shed more light on the structure-activity relationship of the alkaloids isolated from Peganum genus. All Peganum alkaloids were grouped according to their structural properties. A chemoinformatic approach (SwissTargetPrediction) was used to determine the molecular targets of these alkaloids. To analyze and visualize the results, R software was used to generate hierarchical clustering heatmaps. The results of this study can help researchers to better understand the structure-activity relationship of Peganum alkaloids and how substitution can affect the biological activity of those alkaloids., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Six alkaloids peharmalines F-K, along with 14 known ones, were isolated from the aerial part of Peganum harmala L.. The structures of the isolated compounds were determined based on their HR-ESI-MS data, extensive NMR spectroscopic analyses, and ECD calculations. 3-(4-Hydroxyphenyl)quinoline exhibited potent antiproliferative activity against the HepG-2 cell lines with an IC 50 value of 3.05 μM. Norharmane displayed a moderate inhibition against A549 and HepG-2 cells with IC 50 values of 16.45 μM and 17.27 μM, respectively., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Biofilm formation of the opportunistic pathogen Pseudomonas (P). aeruginosa is one of the major global challenges to control nosocomial infections due to their high resistance to antimicrobials and host defense mechanisms. The present study aimed to assess the antibacterial and the antibiofilm activities of Peganum (P). harmala seed extract against multidrug-resistant P. aeruginosa isolates. Chemical identification of the active compound and determination of its molecular mechanism of action were also investigated. Results showed that P. harmala n-butanol "n-BuOH" extract exhibited antibacterial activity against multidrug-resistant P. aeruginosa isolates. This extract was even more active than conventional antibiotics cefazolin and vaamox when tested against three P. aeruginosa multidrug-resistant isolates. In addition, P. harmala n-BuOH extract exhibited potent bactericidal activity against PAO1 strain at MIC value corresponding to 500 µg/mL and attained 100% killing effect at 24 h of incubation. Furthermore, P. harmala n-BuOH extract showed an antibiofilm activity against P. aeruginosa PAO1 and exhibited 80.43% inhibition at sub-inhibitory concentration. The extract also eradicated 83.99% of the biofilm-forming bacteria. The active compound was identified by gas chromatography-mass spectrometry as an indole alkaloid harmaline. Transcriptomic analysis showed complete inhibition of the biofilm-related gene pilA when PAO1 cells were treated with harmaline. Our results revealed that P. harmala seed extract and its active compound harmaline could be considered as a candidate for a new treatment of multidrug-resistant P. aeruginosa pathogens-associated biofilm infections., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Objective: Peganum harmala has been traditionally used to manage rheumatoid arthritis (RA) and other inflammatory conditions. However, its use against RA has not been scientifically evaluated. The current study was designed to assess the anti-arthritic and anti-inflammatory activities of the methanolic extract of P. harmala leaves by in vitro and in vivo methods., Methods: The in vitro assays were carried out to determine the effect of plant extract on inhibition of egg albumin denaturation and human red blood cell membrane (HRBC) stabilization. Moreover, 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity was performed to determine the antioxidant potential. In vivo anti-arthritic activity was performed by determining the curative effect against Complete Freund's adjuvant (0.1 ml). The plant extract was administered to rats orally at 200, 400 and 600 mg/kg/day for 21 days., Results: The values of IC50 of plant extract in protein denaturation, stabilization of HRBC and DPPH assays were 77.54 mg/ml, 23.90 mg/ml and 58.09 μg/ml, respectively. Moreover, the plant extract significantly attenuated the poly-arthritis and weight loss, anemia and paw edema. The plant extract restored the level of C-reactive protein, rheumatoid factor, alanine transaminase, aspartate transaminase and alkaline phosphatase in poly-arthritic rats. Moreover, the plant extract restored the immune organs' weight in treated rats. Treatment with P. harmala also significantly subdued the oxidative stress by reinstating superoxide dismutase, reduced glutathione, catalase and malondialdehyde in poly-arthritic rats. The plant extract notably restored the prostaglandin-E2 and tumor necrosis factor (TNF)-α in the serum of poly-arthritic rats., Conclusion: It was concluded that P. harmala extract had potential antioxidant, anti-inflammatory and antiarthritic activities, which primarily might be attributed to alkaloids, flavonoids and phenols., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Harmine is a β-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Extract of natural plants is one of the most important metallic corrosion inhibitors. They are readily available, nontoxic, environmentally friendly, biodegradable, highly efficient, and renewable. The present project focuses on the corrosion inhibition effects of Peganum Harmala leaf extract. The equivalent circuit with two time constants with film and charge transfer components gave the best fitting of impedance data. Extraction of active species by sonication proved to be an effective new method to extract the inhibitors. High percent inhibition efficacy IE% of 98% for 283.4 ppm solutions was attained using impedance spectroscopy EIS measurements. The values of charge transfer R ct increases while the double layer capacitance C dl values decrease with increasing Harmal extract concentration. This indicates the formation of protective film. The polarization curves show that the Harmal extract acts as a cathodic-type inhibitor. It is found that the adsorption of Harmal molecules onto the steel surface followed Langmuir isotherm. Fourier-transform infrared spectroscopy FTIR was used to determine the electron-rich functional groups in Harmal extract, which contribute to corrosion inhibition effect. Scanning electron microscopy SEM measurement of a steel surface clearly proves the anticorrosion effect of Harmal leaves.

Peganum harmala ( P. harmala ) belongs to the family Zygophyllaceae , and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent-solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC 50 of 49 µg/mL as compared to the standard quercetin with an IC 50 of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD 50 ) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala , which justifies its use in folk medicine.

Synthesis and investigation of biological activity of Peganum harmala smoke-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Peganum harmala smoke-loaded PLGA nanoparticles (PHSE-PNP) were produced by double emulsion solvent evaporation method and characterised by scanning electron microscopy (SEM), dynamic light scattering (DLS), and ζ -potential. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for toxicity evaluation, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assay for antioxidant power, chorioallantoic membrane (CAM), qPCR, and scratch assay for angiogenesis and mouse cancer model for antitumor effects of PHSE-PNP's were used. PHSE-PNP with a size of 216.33 nm, polydispersity index (PDI): 0.22 and ζ -potential: -25.41 mV inhibited A2780, PC3, A549, HepG2, Mda-mb-231, HT-29 as cancer cells and HUVEC as an normal cells with half-maximal inhibitory concentration (IC 50 ) at about 208.62, 479.05, 1092.6, 1103.9, 1299.21, 3467.5, and <4000 µg/ml, respectively. Also PHSE-PNP inhibited ABTS (IC 50 : 0.720 mg/ml), DPPH (IC 50 : 1.36 mg/ml) free radicals and decreased the size of murine tumours (88.3% in 11 days) and suppressed angiogenesis in the CAM and scratch assays. PHSE-PNP can be considered as a potential chemopreventive agent in cancer therapy.

The genus Peganum includes four species widely distributed in warm temperate to subtropical regions from the Mediterranean to Mongolia as well as certain regions in America. Among these species, Peganum harmala L., distributed from the Mediterranean region to Central Asia, has been studied and its phytochemical profile, traditional folk use, and application in pharmacological and clinical trials are well known. The review is aimed at presenting an insight into the botanical features and geographical distribution of Peganum spp. along with traditional folk uses. This manuscript also reviews the phytochemical profile of Peganum spp. and its correlation with biological activities evidenced by the in vitro and in vivo investigations. Moreover, this review gives us an understanding of the bioactive compounds from Peganum as health promoters followed by the safety and adverse effects on human health. In relation to their multipurpose therapeutic properties, various parts of this plant such as seeds, bark, and roots present bioactive compounds promoting health benefits. An updated search (until December 2020) was carried out in databases such as PubMed and ScienceDirect. Chemical studies have presented beta-carboline alkaloids as the most active constituents, with harmalol, harmaline, and harmine being the latest and most studied among these naturally occurring alkaloids. The Peganum spp. extracts have shown neuroprotective, anticancer, antimicrobial, and antiviral effects. The extracts are also found effective in improving respiratory disorders (asthma and cough conditions), dermatoses, and knee osteoarthritis. Bioactivities and health-enhancing effects of Peganum spp. make it a potential candidate for the formulation of functional foods and pharmaceutical drugs. Nevertheless, adverse effects of this plant have also been described, and therefore new bioproducts need to be studied in depth. In fact, the design of new formulations and nanoformulations to control the release of active compounds will be necessary to achieve successful pharmacological and therapeutic treatments., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Javad Sharifi-Rad et al.)

Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer's disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl 3 ; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl 3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl 3 . Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.

In the present study, a magnetic molecularly imprinted polymer (MMIP) was synthesized for the extraction of harmaline from Peganum harmala by dispersive solid-phase microextraction (DSPME). The MMIP for selective and intelligent extraction of harmaline with excellent functionality and high selectivity was synthesized using the sol-gel method with functionalized superparamagnetic core-shell nanoparticles, ethylene glycol dimethacrylate (EDMA) as a cross-linker, methacrylic acid (MAA) as a functional monomer, and 2,2-azobisisobutyronitrile (AIBN) as a porogen. To study the properties and morphology of the coated polymer, FT-IR spectroscopy, FESEM, TEM images, and VSM were used. The DSPME-HPLC-UV equipment was used to quantify and analyze the data obtained from harmaline extraction. In this research, the efficiency of the synthesized polymer in harmaline extraction was modeled and optimized using the response surface methodology based on central composite design (RSM-CCD). In addition, for modeling the isotherm of harmaline sorption by the MMIP, Langmuir and Freundlich isotherm equations were used. The obtained results showed that the extraction of harmaline with the MMIP was well described with Freundlich isotherm. The results of the validation of the method showed that the measurement of harmaline in the concentration range of 1.0-4000 ng mL -1 followed a linear relationship (R 2  = 9986.0). Moreover, the accuracy or repeatability index (% RSD) was determined to be < 10, and the LOQ and LOD values were 0.526 and 0.158 ng mL -1 , respectively. The results of this study showed that the DSPME technique by using the synthesized MMIP as an effective sorbent with high efficiency and capacity could be utilized for pre-concentration and extraction of harmaline from real and complex samples., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The free online trading of herbal mixtures useful for various purposes facilitates the circulation of dangerous herbs or plant parts. This is the case, for example, of the illegal trade in seeds of Peganum harmala ( Pgh ), which contain alkaloids capable of inhibiting monoamine oxidase (MAO) and are therefore used in hallucinogenic preparations, such as the psychedelic drink ayahuasca . The precise identification of these seeds and their distinction from other very similar but not dangerous seeds are necessary for forensic purposes and represents an advance in avoiding the adulteration of mixtures. In this work, we show the qualitative identification of Pgh seeds by optical and electron microscopy and the parallel development of a real-time qPCR test, which reveals, in a species-specific manner, the presence of Pgh DNA up to quantities lower than 1 pg. In addition to the species specificity and high sensitivity, the reaction accurately quantifies the presence of seeds or parts of seeds of Pgh in complex herbal mixtures, thus giving an indication of the danger or otherwise of the product.

Aims: Natural products still serves as a hope for some illnesses which modern medicine fails to cure. Many people, either knowing their effects or not, are using these herbal products. Treatment of chronic heart failure (CHF) is yet a complicated clinical challenge and there is need to improve or make new therapeutic targets. Finding new agents for CHF is an important subject in cardiovascular drug research. In this study, we evaluated the effects of ten herbals on treatment of CHF on isoproterenol-induced model., Methods and Results: Ninety-six male Wistar rats (16 weeks old) were used in 12 groups. Transthoracic echocardiography was performed on the rats for confirmation of CHF model by decreasing ejection fraction. After 4 weeks' treatment, hearts were removed and blood samples were collected in tubes to measure plasma levels of laboratory findings. Our results showed that the mean of ejection fraction in model rats was 51.82 ± 3.49 percent and all of our used natural products could significantly increase the ejection fraction (P < 0.01). The most effective herbals in improving the ejection fraction were Allium sativum (30.69 %), Peganum harmala (26.08 %) and Apium graveolens (24.09 %). The best results in decreasing NT-ProBNP, was obtained from Allium sativum, Peganum harmala and Berberis vulgaris respectively. Our results showed that none of natural products had toxic effect on renal and liver tissues., Conclusion: Our results showed that Allium sativum, Peganum harmala and Berberis vulgaris could significantly improve cardiac function by improvement of left ventricular remodeling, lowering hs-CRP and NT-ProBNP and echocardiographic indexes without liver or renal side effects., (Copyright © 2020. Published by Elsevier Masson SAS.)

Di(2-ethylhexyl) adipate (DEHA) is a widely used plasticizer and prevalent environmental contaminant. In this study, DEHA concentrations in the milk, cheese, and butter samples wrapped with food-grade commercial polyethylene films and stored at 4 °C for 30 days were detected using gas chromatographic analysis. Also, the effects of exposure to a high dose of DEHA for a long duration on the liver, brain, and heart of Wistar rats were assessed. Besides, the possible beneficial effect of Peganum harmala oil (PGO), in relieving DEHA induced adverse effects was explored. For this purpose, four groups (8 rats/group) were orally given physiological saline, PGO (320 mg/kg bwt), DEHA (2000 mg/kg bwt), or PGO + DEHA for 60 days. The results revealed that the DEHA concentrations in the tested dairy products were ordered as follows: (butter > cheese > milk). Notably, the detected levels in butter were higher than the specific migration limit in foods. DEHA induced a significant increase in the serum levels of glucose, alanine transaminase, aspartate transaminase, acetylcholine esterase, creatine kinase-myocardium bound, malondialdehyde, tumor necrosis factor-α, and interleukin-1β. But, significant hypoproteinemia, hypoalbuminemia, hypoglobulinemia, and hypocholesterolemia were evident following DEHA exposure. A significant reduction in the serum level of superoxide dismutase, reduced glutathione, and brain-derived neurotrophic factor was recorded. Besides, a significant downregulation in hepatic CYP2E1, brain glial fibrillary acidic protein, and cardiac troponin I gene expression was noticed. Moreover, DEHA exposure induced a significant decrease in Bcl-2 immunolabeling, but Caspase-3 immunoexpression was increased. On the contrary, PGO significantly recused DEHA injurious impacts. Therefore, PGO could represent a promising agent for preventing DEHA-induced hepatotoxicity, neurotoxicity, and cardiotoxicity., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Predominant molecules in Peganum harmala leaves were detected using gas chromatography-mass spectrometry (GC-MS). Based on the results of this analysis, most alkaloids, flavonoids and triterpenoids in found P. harmala was compiled from the literature in order to develop and lead the production of effective inhibitor drugs for ACE2, main protease, and RNA dependent RNA polymerase (RdRp) proteins of SARS-CoV-2 virus, which is today's most contagious and deadly disease., Aim: By comparing FDA-approved drugs used in the treatment of COVID-19, we aimed to determine whether the molecules in P. harmala are effective against SARS CoV-2 in silico., Results and Conclusion: P. harmala molecules were selected as drug candidates from the PubChem web tool. Afterwards, molecular docking calculations of these inhibitor molecules were made with Maestro Molecular modeling program by Schrödinger. The comparison of molecules with high inhibitory activities with FDA-approved drugs was made. With molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations, docking calculations of molecules that have high inhibitory activity, were tried to be verified by calculations in the range of 0-100 nanoseconds (Tab. 4, Fig. 6, Ref. 53).

Harmine is isolated from the seeds of the medicinal plant, Peganum harmala L., and has been used for thousands of years in the Middle East and China. Harmine has many pharmacological activities including anti-inflammatory, neuroprotective, antidiabetic, and antitumor activities. Moreover, harmine exhibits insecticidal, antiviral, and antibacterial effects. Harmine derivatives exhibit pharmacological effects similar to those of harmine, but with better antitumor activity and low neurotoxicity. Many studies have been conducted on the pharmacological activities of harmine and harmine derivatives. This article reviews the pharmacological effects and associated mechanisms of harmine. In addition, the structure-activity relationship of harmine derivatives has been summarized.

Huntington's disease (HD) is a relentlessly progressive neurodegenerative disease featured by the over-expanded polyglutamine (polyQ)-induced protein aggregation. Using Caenorhabditis elegans (C. elegans) as a model system, we show that water soluble polysaccharide extracted from the herb Peganum harmala L. (PS1) not only reduces polyQ aggregation but also alleviates the associated neurotoxicity. Genetic and pharmacologic analysis suggested that PS1 treatment acts though proteasome-mediated protein degradation pathway to inhibit polyQ aggregation. Notably, the efficacy of PS1 is aroused specifically by co-incubation with live Escherichia coli OP50, which is the sole food source for worms. Further UPLC-Q-TOF/MS analysis determined the bioactivity of polyQ inhibition, which is composed of several oligosaccharides, including stachyoses, verbascoses, trisaccharides and tetrasaccharides composed of galacturonic acids. Together, our study revealed a potential drug target for further HD treatment and pinpointed the possibility that the secreted metabolites produced from bacteria treated with various compounds may provide direct beneficial effect to human bodies., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020. Published by Elsevier B.V.)

This investigation included the chemical analysis of Peganum harmala ( P. harmala ) seed oil and its antifungal properties against 10 fungal species. Seed oils of six populations were analyzed using high performance liquid chromatography (HPLC) and gas chromatograph/mass spectrometry (GC-MS). The HPLC analysis indicated that P . harmala seed oil exhibited a very high level of tocopherol contents, with values in the range of 2385.66-2722.68 mg/100 g. The most abundant tocopherol isomer was δ-tocopherol (90.39%), followed by γ-tocopherol (8.08%) and α-tocopherol (1.14%). We discovered for the first time the presence of tocotrenols in P. harmala seed oils of the six populations studied. The GC-MS analyses revealed that linoleic acid was the main fatty acid (65.17%), followed by oleic acid (23.12%), palmitic acid (5.36%) and stearic acid (3.08%). We also studied the antifungal activity of seed oil of the Medenine (MD) population on ten fungal pathogens. The antifungal effects differed among pathogens and depended on oil concentrations. Seed oil of the MD population caused a significant decrease in mycelial growth of all fungi tested, with values ranging 31.50-82.11%, except for Alternaria sp., which showed no inhibition. The antifungal activity against the 10 selected fungi can be explained by the richness in tocols of the extracted oil and make P. harmala a promising crop for biological control. Furthermore, the importance of fatty acids and the wide geographic spread in Tunisia of this species make this crop a potential source of renewable energy.

Two nonbiaryl axially chiral β-carboline-quinazoline dimers, pegaharmols A ( 1 ) and B ( 2 ), were isolated from the roots of Peganum harmala . Their planar structures were elucidated by the spectroscopic methods of high-resolution mass spectrometry and 1D and 2D nuclear magnetic resonance (NMR). The stereochemistry was established by a comparison between the experimental data of NMR and electronic circular dichroism and the computed data by quantum mechanical calculations. It is discovered for the first time that the β-carboline at the C-8 position is bonded to the vasicine at the C-9 position. 1 exhibited moderate cytotoxic activity against HL-60 and A549 cell lines.

Pegaharines A-G ( 1 - 6 ), six novel β-carboline alkaloids representing three types of skeleton, were isolated from the seeds of Peganum harmala . Compound 1 is a peculiar β-carboline alkaloid characterized by the unprecedented carbon skeleton of an azepine-indole system. Compounds 3 - 6 represent the first examples of heterodimers constructed from rare tetracyclic β-carboline and classic tricyclic β-carboline alkaloids. Compounds 1 and 2 were characterized by X-ray crystallography. Compound 4 exhibited strong antiviral activity against HSV-2, with an IC 50 value of 2.12 ± 0.14 μM.

Many substances of secondary plant metabolism have often attracted the attention of scientists and the public because they have certain beneficial effects on human health, although the reason for their biosynthesis in the plant remains unclear. This is also the case for alkaloids. More than 200 years have passed since the discovery of the first alkaloid (morphine), and several thousand substances of this character have been isolated since then. Most often, alkaloid-rich plants are part of folk medicine with centuries-old traditions. What is particularly important to monitor for these herbal products is the spectrum and concentrations of the present active substances, which decide whether the product has a beneficial or toxic effect on human health. In this work, we present a fast, reliable, and robust method for the extraction, preconcentration, and determination of four selected alkaloids with an indole skeleton, i.e., harmine, harmaline, yohimbine, and ajmalicine, by ultra-high performance liquid chromatography coupled with tandem mass spectrometry. The applicability of the method was demonstrated for tobacco and Tribulus terrestris plant tissue, the seeds of Peganum harmala, and extract from the bark of the African tree Pausinystalia johimbe .

Background: Aerial parts of Peganum harmala Linn is used as a traditional medical herb for treatment of amnesia in Uighur medicine in China. Deoxyvasicine (DVAS) is one of the chief active ingredients in P. harmala, it possesses strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in vitro, but the therapeutic effect and mechanisms on amnesia in vivo are unclear., Purpose: The objective of this study was to investigate the improvement effect of DVAS from P. harmala in learning and memory deficits of scopolamine-induced mice and elucidate the underlying mechanisms involved., Methods: Mice were pretreated with DVAS (5, 15 and 45 mg/kg) and huperzine-A (0.2 mg/kg) by gavage for 7 days, and subsequently were daily intraperitoneally injected with scopolamine (1 mg/kg) to induce learning and memory deficits and behavioral performance was assessed by Morris water maze. To further evaluate the potential mechanisms of DVAS in improving learning and memory capabilities, pathological change, levels of various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation were examined., Results: The results showed that DVAS could alleviate learning and memory deficits in scopolamine-treated mice. DVAS could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities and protein expressions. DVAS could induce brain-derived neurotrophic factor and protect hippocampal pyramidal cells against neuronal damage. DVAS also enhanced antioxidant defense via increasing the antioxidant enzyme level and activity of glutathione peroxidase, and anti-inflammatory function through suppressing tumor necrosis factor-α. Additionally, DVAS could regulate the neurotransmitters by elevating acetylcholine, 5-hydroxytryptamine, γ-aminobutyric acid and reducing 5-hydroxyindole-3-acetic acid and glutamic acid., Conclusion: Results illustrated that DVAS may be a promising candidate compound against amnesia via restoration of cholinergic function, regulating neurotransmitters, attenuating neuroinflammation and oxidative stress., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Bioanalytical questions are more and more solved by bioassays directly in situ the planar separation. If compared to chemical derivatization in situ, several reagent applications on the same chromatogram make the workflow for enzymatic and biological assays more complex. Hence, if compared to piezoelectric spraying of chemical derivatization reagents, an assay transfer to the piezoelectric spraying technique was much more challenging. Important aspects were investigated, i.e., plate pre-wetting, spraying nozzle type and applied volumes for microorganism suspension as well as enzyme and substrate-chromogenic solutions. Finally, with the newly developed piezoelectric spraying procedures for the application of biological (Aliivibrio fischeri) and enzymatic (acetyl- and butyrylcholinesterase) assays, several obstacles of the state-of-the-art automated immersion were avoided such as the (1) required high volumes of solutions, (2) tailing of highly water-soluble zones upon slow plate withdrawal, (3) zone distortion or shift observed after previous buffer salt applications or long/slow immersion times/speeds, (4) gradual inactivation of the enzyme solution along with its ongoing re-use, and (5) lack of covering the whole plate surface. The benchmarking of both techniques also showed that simplicity remains the key argument for immersion. As proof of concept, piezoelectrically sprayed autograms were compared with those of immersion, by taking the example of Peganum harmala (P. h.) seed extract. The plate background and thus homogeneity of the applied solutions were found to be almost comparable. Three bands among the pronounced fluorescent bands were responsible for the most antibacterial activity of P. h. seed extract in the A. fischeri bioassay and were also inhibiting the AChE. These AChE and three further BChE inhibitors were detected, whereby the AChE inhibition was twice as strong as the BChE inhibition. By their in situ HRMS spectra, the active zones in the P. h. seed extract were assigned to be the AChE-inhibiting β-carboline alkaloids, harmine, harmaline and ruine, as well as the BChE-inhibiting quinazoline alkaloids, vasicine and deoxyvasicine, and the β-carboline alkaloid harmol. For the first time, the found inhibitors were calculated equivalently to the well-known ChE-inhibitor physostigmine, and thus, piezoelectric spraying was proven to be suited for quantifications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Shape, size, and homogeneity affect the biological activity of gold nanoparticles (AuNPs) in nanomedicine and catalytic applications. Here we biosynthesized monodispersed isotropic and polydispersed anisotropic spherical AuNPs from leaf and seed extract broths of the medicinal plant Peganum harmala L. (Ph. L). Synthesized AuNPs were characterized by ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy (FT-IRS), field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM). The antimicrobial activity of AuNPs against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) human pathogens was also assessed. Leaf- and seed-derived AuNPs had characteristic localized surface plasmon resonances of 530 and 578 nm, respectively. TEM, FE-SEM, EDX, and XRD revealed the formation of elemental face-centered cubic spherical monodispersed isotropic AuNPs of average size 43.44 nm and polydispersed anisotropic AuNPs of average size 52.04 nm from leaf and seed extract broths, respectively. FT-IR revealed polyphenols and alcohols as responsible for AuNP capping, reduction, and protection. Anisotropic AuNPs showed no antibacterial activity, whereas isotropic AuNPs showed good inhibition of both E. coli and S. aureus. This represents a simple and ecofriendly protocol for the green synthesis of monodispersed isotropic spherical AuNPs, which may have value in a variety of applications., (© 2019 International Union of Biochemistry and Molecular Biology, Inc.)

Ethnopharmacological Relevance: Aerial parts of Peganum harmala Linn are a Uighur traditional medicinal herb in China used to treat amnesia, bronchial asthma, and cough. Deoxyvasicine (DVAS), a potent cholinesterase inhibitor exhibiting anti-senile dementia activity, is one of the chief active ingredients in aerial parts of P. harmala and plays a key role in mediating the pharmacological effects of P. harmala. However, the metabolic profiling and in vivo pharmacokinetic characteristics of DVAS still remain unknown., Aim of the Study: The aim of this present study was to investigate the metabolism and pharmacokinetic properties of DVAS in rats by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method., Materials and Methods: The metabolic profiling of DVAS was evaluated in vitro and in vivo by rat liver microsomes (RLMs) incubation and by rat bio-specimens, such as urine, feces, plasma, and bile, after the oral administration of 45 mg/kg DVAS. An efficient and sensitive UPLC-ESI-MS/MS method was developed and validated to simultaneously determine DVAS and its major four metabolites, namely, vasicine, deoxyvasicinone, vasicinone, and 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-β-D-glucuronide in rat plasma. For pharmacokinetic studies, 32 Sprague-Dawley rats were randomly divided into four groups, namely, intravenous dosage group (2 mg/kg DVAS) and three oral dosage groups (5, 15, and 45 mg/kg DVAS). In addition, the activity of the components in plasma after intravenous administration of DVAS was evaluated by in vitro anti-butyrylcholinesterase (BChE) assays., Results: A total of 23 metabolites were found in RLMs, plasma, urine, feces, and bile by UPLC-ESI-QTOF-MS. The metabolic pathway of DVAS in vivo and in vitro mainly involved hydroxylation, dehydrogenation, acetylation, methylation, glucuronidation, and O-sulphate conjugation, and the C-3 and C-9 sites were the main metabolic soft spots. All 23 metabolites were detected in the urine sample, and 13, 8, 22, and 6 metabolites were identified from rat feces, plasma, bile, and RLMs, respectively. The standard curves of DVAS and four metabolites in rat plasma showed good linearity in the concentration range of 0.82-524.00 ng/mL with acceptable selectivity, precision, accuracy, recovery, and stability. DVAS exhibited linear dose-proportional pharmacokinetics at doses of 5, 15, and 45 mg/kg after oral administration, and the average oral absolute bioavailability of DVAS was 47.46%. The in vitro anti-BChE assays implied that the inhibitive activities were mainly due to the different concentrations of prototype DVAS., Conclusions: DVAS can be rapidly absorbed and excreted by blood, and it is also extensively metabolized in vivo, and the anti-BChE activity in blood is mainly attributed to DVAS. These findings can lay a foundation for new drug development for DVAS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To investigate the N-containing compounds in the seeds of Paganum harmala,fourteen compounds were finally isolated from the 95% Et OH extract of P. harmala seeds by using various chromatographic techniques including silica gel,MCI resin,and ODS column chromatography as well as the semi-preparative HPLC. Depending on spectroscopic techniques and comparison with the reported data in the literatures,the structures of all compounds were identified as N-[3-(2-amino-4-methoxyphenyl)-3-oxopropyl]acetamide(1),dehydroharmalacidine(2),harmalacidine(3),harmine N-oxide(4),harmine(5),tetrahydroharmine(6),demethylharmalacidine(7),harmol(8),tetrahydroharmol(9),harmindol β-D-glucopyranoside(10),tryptophyl β-D-glucopyranoside(11),pegamineβ-D-glucopyranoside(12),vasicol(13) and vasicinone(14). Among them,1 was a new compound,and 2 and 10 were obtained as natural products for the first time.

Background: The vernacular name 'Harmal' is used for two plant species in Saudi Arabia, i.e. Peganum harmala L. and Rhazya stricta Decne. Both are important medicinal plants which offer interesting pharmacological properties., Objective: This study aimed to evaluate the genetic diversity among different populations of harmal based on chemical variations of alkaloids and molecular polymorphism., Methods: Total alkaloids were extracted from plants of three populations of each species and estimated by using spectrophotometer and the chemical compounds were analyzed by Gas chromatography mass spectrometry (GC-MS). Molecular polymorphism was estimated by using the Inter Simple Sequence Repeat (ISSR) fingerprints., Results: The results showed that the alkaloids content of R. stricta was higher than P. harmala populations. The GC-MS analysis revealed the presence of (65-53) compounds in R. stricta and P. harmala, and the percentage of polymorphism was found to be 93.2%. Sixteen ISSR primers produced 170 scorable bands with an average of 9.6 bands per primer and 75%-100% polymorphism. The cluster analysis using the unweighted pair-group method of the arithmetic average (UPGMA) method based on combined data of GC-MS and ISSR markers divided the six harmal genotypes into two major groups., Conclusion: The existence of variations in chemical and genetic markers is useful for the selection of potential genotypes for medicinal use, and for breeding lines for medicinal substances production to spare wild plants from uncontrolled harvesting for folk medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

An orthogonal two dimensional analysis method based on high performance liquid chromatography (HPLC) separation and electrospray ionization-ion mobility spectrometry (ESI-IMS) detection was developed for the analysis of alkaloid compounds from Peganum harmala L. seeds. Reverse phase (RP) and hydrophilic interaction chromatography (HILIC) were compared for the most optimal performance using three different chromatographic columns. The experimental results suggest that HILIC mode is a better option for combining with the ESI-IMS system for higher sensitivity and ease in hyphenating. Under optimized conditions, alkaloids from different extraction phases were determined by means of the established HPLC-IMS method. More compounds from Peganum harmala L. seed extracts were differentiated on the HPLC-ESI-IMS system by their retention time and drift time than by HPLC or ESI-IMS alone, and thirteen alkaloids were tentatively identified based on m/z and fragment ions using ultra-high-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS). Hence, our results indicate that this method can be considered to be advantageous over traditional absorbance detection methods for resolving complex mixtures because of complementary separation steps, elevated peak capacity, and higher sensitivity., (Copyright © 2018. Published by Elsevier B.V.)

The revival of cultural heritage in a form of natural colorants for textile dyeing is gaining popularity due to their soothing nature and bright shades. The present study was conducted to explore the coloring potential of harmala (Peganum harmala) seeds and to improve color strength of dye using microwave radiations followed by a mordanting process. The results showed that harmala plant seeds could be an excellent source of natural dyes for cotton dyeing if the irradiated acidified methanolic extract (RE, 4 min) is used to dye un-irradiated fabric (NRC) at 85 °C for 45 min using a dye bath of pH 9.0 having salt concentration of 7 g/100 mL. Alum (1%) as pre-mordants and iron (7%) as post-mordants have improved the color strength in chemical mordanting more than other mordants employed. The bio-mordants employed reveal that 10% of acacia as pre-bio-mordants and 7% of acacia as post-bio-mordants are effective amounts to obtain high color strength. Suggested ISO standards for colorfastness illustrate that bio-mordanting has given more excellent rating as compared to chemical mordants. It is concluded that harmala seeds have a great potential to act as a source of natural colorant for cotton dyeing under the influence of microwave radiation.

Five pairs of new 2-oxoindole alkaloids, (±)-peganumalines A-E (1-5), and a new indole alkaloid, peganumaline F (6), along with two known analogues, were isolated from the seeds of Peganum harmala. Their structures and absolute configurations were elucidated through spectroscopic analyses and quantum chemistry calculations. Notably, (±)-peganumalines A (1) represent a pair of rare 2-oxoindole dimeric alkaloid enantiomer with the hitherto unknown carbon skeleton. All isolates were tested for antiproliferative and antibacterial activities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5-8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC 50 value of 15.41 μM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Monoamine oxidase (MAO) catalyzes the oxidative deamination of amines and neurotransmitters and is involved in mood disorders, depression, oxidative stress, and adverse pharmacological reactions. This work studies the inhibition of human MAO-A by Hypericum perforatum , Peganum harmala, and Lepidium meyenii, which are reported to improve and affect mood and mental conditions. Subsequently, the antioxidant activity associated with the inhibition of MAO is determined in plant extracts for the first time. H. perforatum inhibited human MAO-A, and extracts from flowers gave the highest inhibition (IC 50 of 63.6  μ g/mL). Plant extracts were analyzed by HPLC-DAD-MS and contained pseudohypericin, hypericin, hyperforin, adhyperforin, hyperfirin, and flavonoids. Hyperforin did not inhibit human MAO-A and hypericin was a poor inhibitor of this isoenzyme. Quercetin and flavonoids significantly contributed to MAO-A inhibition. P. harmala seed extracts highly inhibited MAO-A (IC 50 of 49.9  μ g/L), being a thousand times more potent than H. perforatum extracts owing to its content of β -carboline alkaloids (harmaline and harmine). L. meyenii root (maca) extracts did not inhibit MAO-A. These plants may exert protective actions related to antioxidant effects. Results in this work show that P. harmala and H. perforatum extracts exhibit antioxidant activity associated with the inhibition of MAO (i.e., lower production of H 2 O 2 ).

Background/aims: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a novel tumor suppressor gene that is critical for regulating tumor cell invasion and metastasis. The expression of RECK is dramatically down-regulated in human cancers. Harmine, a tricyclic compound from Peganum harmala, has been shown to have potential anti-cancer activity., Methods: Cell proliferation assay (CCK-8 cell viability assay), cell cycle analysis (detection by flow cytometry), apoptosis staining assay (TUNEL staining), cell migration assay and invasion assay (transwell assay) were carried out to investigate the Harmine's efficacy on non-small cell lung cancer (NSCLC) cells in vitro. A549-luciferase cell orthotropic transplantation xenograft mouse model was used to determine the effect of Harmine treatment on NSCLC in vivo. Western blotting analysis of cell growth and metastasis related signal pathways was conducted to investigate the molecular mechanism of Harmine's inhibitory effect on NSCLC., Results: Harmine treatment effectively inhibited cell proliferation and induced the G1/S cell cycle arrest of NSCLC cells. Further study proved that Harmine treatment led to apoptosis induction. Furthermore, treatment with NSCLC cells with Hamine resulted in decreased cell migration and cell invasion in vitro. More importantly, Harmine treatment significantly suppressed the NSCLC tumor growth and metastasis in mouse xenograft model in vivo. Mechanistically, in Harmine-treated NSCLC cells, RECK expression and its downstream signaling cascade were dramatically activated. As a consequence, the expression level of MMP-9 and E-cadherin were significantly decreased., Conclusion: These findings identify Harmine as a promising activator of RECK signaling for metastatic NSCLC treatment., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Genital herpes is a sexually transmitted disease caused by herpes simplex virus type 2 (HSV-2). Nucleoside analogues such as acyclovir (ACV) are the usual therapy for treating HSV infection. However, the overuse of this drug has led to the emergence of resistant strains. Therefore, the search for new alternative or complementary molecules to overcome this obstacle is needed. In this objective, Peganum harmala was investigated for its HSV-2 activity. The organic extracts of the different plant organs were evaluated for their cytotoxicity on Vero cells by the MTT test and anti HSV-2 activity by plaque reduction assay. Only the methanol seeds extract was active with a 50% inhibitory concentration (IC 50 ) and a selectivity index (SI) of 161 and 13.2 μg/mL, respectively. In addition, the study of the antiviral mode of action revealed that this extract exerts a virucidal action both during the entry of viruses and the release of the newly formed virions, whereas no cell protection effect was observed. The active compound was isolated by bio-guided purification using thin layer chromatography (TLC) and identified by GC-MS and HPLC-DAD-ESI-MS n as harmine. The combination of harmine standard compound with ACV showed a combination index (CI) of 0.5 indicating that these two compounds have a synergic effect. This data suggests that harmine could be associated to ACV to improve the treatment of genital herpes essentially for the immunocompromised patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this work, we characterized by high-performance liquid chromatography, the γ-tocopherol (573.66 μg/g), and by gas chromatography-mass spectrometry, the linoleic acid (62.05%) as major components from Peganum harmala L. seeds oil and evaluated their potential in vivo acute antiinflammatory, analgesic activities, and in vitro antioxidative capacity. The 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay showed an important antioxidant activity (62.50% with an IC50 of 4.8 mg/mL). In addition, the antiinflammatory effect of the formulation cream at 20% caused a reduction in inflammation at 5 hours after carrageenan application compared with diclofenac at 1% (60.4%; 45.65%; respectively). A slight potential peripheral analgesia was noted in plantar test in treated rats with cream (20 s). Therefore, our findings demonstrate that formulation cream of P. harmala seeds oil has an interesting antiinflammatory activity with a slight peripheral analgesic effect due mainly to its richness on linoleic acid, γ-tocopherol, and polyphenols and to its important antioxidant capacity.