Efficacy of Covexir® (Ferula foetida oleo-gum) treatment in symptomatic improvement of patients with mild to moderate COVID-19: A randomized, double-blind, placebo-controlled trial.

The SARS-CoV-2 COVID-19 pandemic has emerged as an unprecedented emergency state in healthcare system and global challenge. In recent decade, the function of exogenous H2 S in the treatment of respiratory diseases has been investigated using H2 S-donor agents. Ferula foetida is a medicinal plant that is traditionally used in respiratory diseases including asthma and viral respiratory diseases. The oleo-gum of this plant is a rich source of several organic sulfides including thiophenes, disulfides and polysulfide derivatives, which can act as H2 S-donor agents. The purpose of this study was to investigate the efficacy of Covexir® (F. foetida oleo-gum) treatment as a rich source of H2 S-donor compounds in clinical presentations of patients with COVID-19. The efficacy of Covexir® was evaluated in a randomized, double-blind, placebo-controlled trial in outpatients with COVID-19. Covexir® could significantly inhibit cough when compared to the placebo group (p < .01 and p < 001, respectively). Moreover, there was a significant difference (p < 001) between the two groups in dyspnea symptom at follow-up interval of 7 day after receiving Covexir®. Furthermore, on days 3 and 7, statistically significant differences were observed in myalgia, anorexia, anosmia, and sense of taste severity between two groups. Our findings revealed that Covexir® was very safe in the treatment of COVID-19 patients with mild to moderate symptoms and it can be recommended to improve clinical presentations of patients with COVID-19 such as cough, shortness of breath, myalgia, anorexia, anosmia, and sense of taste.

Metabolic differences of two Ferula species as potential sources of galbanum: An NMR-based metabolomics study.

INTRODUCTION: Ferula gummosa Boiss. and Ferula galbaniflua Boiss. & Buhse (Apiaceae) are two important Iranian plants that are considered as potential sources of galbanum (barijeh). Galbanum is traditionally used for treating different diseases including flatulence and memory impairment. OBJECTIVE: According to a phylogenetic analysis of the nrDNA ITS sequence and the Flora Iranica, F. gummosa has been considered as a synonym of F. galbaniflua. However, F. galbaniflua and F. gummosa grow in two different geographical locations and have different metabolic patterns. Some researchers believe that F. gummosa and F. galbaniflua are two distinct species. To discriminate these species, we compared metabolic profiles of F. gummosa and F. galbaniflua samples. METHODS: 1 H-NMR-based metabolomics analysis was used for classification of F. gummosa and F. galbaniflua samples collected from northeast Iran. The acquired data were analyzed using hierarchical cluster analysis (HCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). RESULTS: The result showed a clear separation between the two species that may be related to the quantity and diversity of their metabolites. Ferula gummosa had higher mogoltacin levels, while F. galbaniflua had higher feselol levels. Ligupersin A and conferdione were significantly detected in F. gummosa, whereas sterol compounds were significantly detected in F. galbaniflua. CONCLUSION: Our findings indicate that clear metabolomics discrimination of F. gummosa and F. galbaniflua makes their chemotaxonomic classification possible.

Antibacterial activity of flavonoids and their structure-activity relationship: An update review.

Based on World Health Organization reports, resistance of bacteria to well-known antibiotics is a major global health challenge now and in the future. Different strategies have been proposed to tackle this problem including inhibition of multidrug resistance pumps and biofilm formation in bacteria and development of new antibiotics with novel mechanism of action. Flavonoids are a large class of natural compounds, have been extensively studied for their antibacterial activity, and more than 150 articles have been published on this topic since 2005. Over the past decade, some promising results were obtained with the antibacterial activity of flavonoids. In some cases, flavonoids (especially chalcones) showed up to sixfold stronger antibacterial activities than standard drugs in the market. Some synthetic derivatives of flavonoids also exhibited remarkable antibacterial activities with 20- to 80-fold more potent activity than the standard drug against multidrug-resistant Gram-negative and Gram-positive bacteria (including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). This review summarizes the ever changing information on antibacterial activity of flavonoids since 2005, with a special focus on the structure-activity relationship and mechanisms of actions of this broad class of natural compounds.

An overview of analytical methods employed for quality assessment of Crocus sativus (saffron).

This paper reviews qualitative and quantitative analytical methodologies used for the appraisal of saffron quality, as the most expensive spice. Due to the chemical diversity of biologically active compounds of the Crocus genus, analytical methods with different features are required for their complete analysis. However, screening of the main components, such as carotenoids and flavonoids, appears to be sufficient for quality control, a more precise examination needs evaluation of minor compounds, including anthocyanins and fatty acids. High-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), ultraviolet-visible spectroscopy (UV), nuclear magnetic resonance spectroscopy (NMR), and thin-layer chromatography (TLC), are elementary and applicable methods in quality control analysis, whereas HPLC provides metabolite fingerprint and monitoring multi-compound instances at preparative and analytical levels. Combination approaches like metabolomics using different methods could classify saffron types, identify its adulterations, contaminants and provide a comprehensive metabolite map for quality control of selected compounds.

Effects of rosmarinic acid, carnosic acid, rosmanol, carnosol, and ursolic acid on the pathogenesis of respiratory diseases.

This review aimed to identify preclinical and clinical studies examining the effects of rosmarinic acid (RA), carnosic acid (CaA), rosmanol (RO), carnosol (CA), and ursolic acid (UA) against allergic and immunologic disorders. Various online databases, including PubMed, Science Direct, EMBASE, Web of Sciences, Cochrane trials, and Scopus, were searched from inception until October 2022. Due to the suppression of the nuclear factor-κB (NF-κB) pathway, the main factor in allergic asthma, RA may be a promising candidate for the treatment of asthma. The other ingredients comprising CA and UA reduce the expression of interleukin (IL)-4, IL-5, and IL-13 and improve airway inflammation. Rosemary's anti-cancer effect is mediated by several mechanisms, including DNA fragmentation, apoptosis induction, inhibition of astrocyte-upregulated gene-1 expression, and obstruction of cell cycle progression in the G1 phase. The compounds, essentially found in Rosemary essential oil, prevent smooth muscle contraction through its calcium antagonistic effects, inhibiting acetylcholine (ACH), histamine, and norepinephrine stimulation. Additionally, CA exhibits a substantially greater interaction with the nicotinic ACH receptor than a family of medications that relax the smooth muscles, making it a potent antispasmodic treatment. The components have demonstrated therapeutic effects on the immune, allergy, and respiratory disorders.

Polyphenolic Nano-formulations: A New Avenue against Bacterial Infection.

The gradual emergence of new bacterial strains impervious to one or more antibiotics necessitates discovering and applying natural alternatives. Among natural products, various polyphenols exhibit antibacterial activity. However, polyphenols with biocompatible and potent antibacterial characteristics are limited due to low aqueous solubility and bioavailability; therefore, recent studies are considering new polyphenol formulations. Nanoformulations of polyphenols, especially metal nanoparticles, are currently being investigated for their potential antibacterial activity. Nanonization of such products increases their solubility and helps attain a high surface-to-volume ratio and, therefore, a higher reactivity of the nanonized products with better remedial potential than non-nanonized products. Polyphenolic compounds with catechol and pyrogallol moieties efficiently bond with many metal ions, especially Au and Ag. These synergistic effects exhibit antibacterial pro-oxidant ROS generation, membrane damage, and biofilm eradication. This review discusses various nano-delivery systems for considering polyphenols as antibacterial agents.

Anti-quorum sensing and antibiofilm activity of coumarin derivatives against Pseudomonas aeruginosa PAO1: Insights from in vitro and in silico studies.

Objectives: Biofilm-associated infections are challenging to manage or treat since the biofilm matrix is impenetrable to most antibiotics. Therefore, the best approach to deal with biofilm infections is to interrupt the construction during the initial levels. Biofilm formation has been regulated through the quorum sensing (QS) network, making it an attractive target for any antibacterial therapy. Materials and Methods: Here, some coumarin members, including umbelliprenin, 4-farnesyloxycoumarin, gummosin, samarcandin, farnesifrol A, B, C, and auraptan, have been assessed as QS inhibitors in silico and in vitro. Their potential inhibitory effects on biofilm formation and virulence factor production of Pseudomonas aeruginosa PAO1 were evaluated. Results: First, the interaction of these compounds was investigated against one of the major transcriptional regulator proteins, PqsR, using molecular docking and structural analysis methodology. After that, in vitro evaluations indicated that 4-farnesyloxycoumarin and farnesifrol B showed considerable reduction in biofilm formation (62% and 56%, respectively), virulence factor production, and synergistic effects with tobramycin. Moreover, 4-farnesyloxycoumarin significantly (99.5%) reduced PqsR gene expression. Conclusion: The biofilm formation test, virulence factors production assays, gene expression analysis, and molecular dynamic simulations data demonstrated that coumarin derivatives are a potential anti-QS family through PqsR inhibition.

An evaluation of qH NMR: A complementary approach to GC-FID for quantification of Thymol and trans-Anethole in essential oils and supplements.

Sweet fennel (Foeniculum vulgare Mill. var. dulce) and thyme (Zataria multiflora Boiss.) are regarded as the important supplies for pharmaceutical, food, cosmetic, and perfume industries. The major components trans-anethole and thymol are represented in fennel and thyme, respectively. The essential oils (EOs) content and the value of their related constituents should be given in strict quality control due to the storage conditions, source, and adulterations. In this study, we compared the validation of quantitative 1H NMR (qH NMR) method with the gas chromatography with flame ionization detection (GC-FID) to quantify the trans-anethole and thymol in fennel and thyme EOs and their related supplements. The current results showed that the quantification of trans-anethole and thymol by qH NMR method was successfully achieved from their EOs and supplements. All the validation parameters including linearity, robustness, repeatability, and stability were authenticated for thymol and trans-anethole quantification. Similar results were obtained in both qH NMR and conventional GC-FID methods. Therefore, according to the measured values, the qH NMR method was adequate to determine the constituents of the EOs, with the results being roughly comparable to those obtained by GC-FID, with the advantage of being simple, repeatable, rapid (8-10 min, while for GC-FID 55 min) and essential for quality control of commercial samples.

A validated 1H-NMR method for quantitative analysis of DOTAP lipid in nanoliposomes containing soluble Leishmania antigen.

Leishmaniasis is a serious health problem that needs a suitable vaccine delivery system to control the disease. Cationic lipids such as 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) have been widely used in nanoliposomes' formulation to deliver antigen and adjuvant at the same time to induce protection against Leishmaniasis. Therefore, it is necessary to accurately quantify DOTAP concentration in the formulation and biological materials. Due to the poor UV absorbance of DOTAP, the use of the conventional HPLC-UV method was impossible. Currently, an evaporative light scattering detector (ELSD) or MS/MS detector in conjunction with HPLC is used to quantify DOTAP. These methods have several disadvantages, including time- consuming during extraction procedure and decrease or/and even remove some components of the formulation. According to the advantages of the quantitative 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopic method, a free extraction approach was developed to the assay of DOTAP in nanoliposomes containing Leishmania antigens. This method was carried out based on the relative ratio of signal integration of DOTAP [CH2 (CH2-CH = CH-CH2)] in δ 2 ppm to a definite amount of an internal standard called dimethyl sulfone (DMSO2). The q1H-NMR method showed good precision (intra-day RSD = 1.8 % and inter-day RSD = 2.5 %), linearity (in the ranges of 1.3-7.8 mg. mL-1 with correlation coefficients at 1), repeatability (RSD ≤ 2.39 %), and stability (RSD ≤ 2.32 %) for the quantification of the DOTAP without any extraction method. Considering all the experiments conducted in this study, NMR can be a feasible alternative to other traditional techniques for the simultaneous quantification of lipids in liposome formulations.

Effects of curcumin on neurological diseases: focus on astrocytes.

Astrocytes are the most abundant glial cells in the central nervous system, and are important players in both brain injury and neurodegenerative disease. Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione), the major active component of turmeric, belongs to the curcuminoid family that was originally isolated from the plant Curcuma longa. Several studies suggest that curcumin may have a beneficial impact on the brain pathology and aging. These effects are due to curcumin's antioxidant, free-radical scavenging, and anti-inflammatory activity. In light of this, our current review aims to discuss the role of astrocytes as essential players in neurodegenerative diseases and suggest that curcumin is capable of direct inhibition of astrocyte activity with a particular focus on its effects in Alexander disease, Alzheimer's disease, ischemia stroke, spinal cord injury, Multiple sclerosis, and Parkinson's disease.

Selective isolation of sesquiterpene coumarins from asafoetida using dummy molecularly imprinted solid phase extraction method.

Due to the biological features of sesquiterpene coumarins and incomparable interest in therapeutics application of natural products, extraction of sesquiterpene coumarins from asafoetida have gained highly attention. One of the most important problems is removal of sulfur containing compounds which are co-existed with sesquiterpene coumarins. So employment of new methods for selective extraction and cleanup of sesquiterpene coumarins is very substantial. In this study using dummy molecularly imprinting technique, 7-hydroxycoumarin-imprited polymer was synthesized and after evaluation of binding properties of polymers, the optimum one was used as sorbent in solid phase extraction. Afterwards dummy molecularly imprinting solid phase extraction (DMISPE) method was calibrated for simultaneous extraction of galbanic acid, 7-isopentenyloxy coumarin and auraptene from aqueous media before high performance liquid chromatography with UV detector (HPLC-UV) analysis. The recovery was in the range of 68.32%-84.69%, which were in the acceptable range compared to previous works. Finally, the calibrated DMISPE method was used for extraction and cleanup of sesquiterpene coumarins from asafetida plant. The concentration of isosamarcandin, kellerin and farnesiferol in asafoetida extract was obtained 0.8, 2.7, and 5 µg/mL, respectively, using standard addition method.

A qHNMR method for simultaneous quantification of terpenoids from Ferula ovina (Boiss.) Boiss roots.

Ferula ovina (Boiss.) Boiss is one of the most important endemic medicinal plants in Iran, which has three main terpenoid compounds including ferutinin, stylosin and tschimgine. Ferutinin is the strongest natural phytoestrogen that has agonistic activity on estrogen receptors, particularly α-receptors. To determine the amount of ferutinin in F. ovina roots, we firstly used HPLC-UV method. In the HPLC method, the resolution of ferutinin from the two other compounds, stylosin and tshimgine, was poor. Therefore, we decided to use qHNMR method for simultaneous quantification of ferutinin, stylosin and tshimgine in the plant roots. Quantitative 1H-NMR (qHNMR) was carried out based on the relative ratio of signal integration of each compound [(H-1 for tschimgine (δH 4.94-5.03), OCH3 for stylosin (δH 3.8), and H-9 for ferutinin (δH 5.58)] to certain amount of the internal standard dimethyl sulfone (DMSO2). The qHNMR method showed good precision (intra-day RSD ≤ 2.31%, inter-day RSD ≤ 2.72%), linearity (in the ranges of 1.3-10.41, 1.2-9.7 and 1.1-9.02 mg/mL with correlation coefficients at 0.9991), repeatability (RSD ≤ 2.99%) and stability (RSD ≤ 2.4%) for the quantification of the compounds. This work confirmed that qHNMR represents a feasible alternative to high-performance liquid chromatography based methods for simultaneous quantification of ingredients in plant extracts.

NMR-based metabolomic study of asafoetida.

Asafoetida, an oleo-gum-resin obtained from the exudates of Ferula assa-foetida L. roots, is traditionally used to treat various diseases including asthma, gastrointestinal disorders, and intestinal parasites. On the basis of Iranian traditional medicine, the main source of asafetida is F. assa-foetida roots. In folk medicine, however, different Ferula species have been used as sources of asafoetida. To identify the original asafoetida that possesses medicinal properties, we should compare metabolic profiles of different asafoetida sources which are commonly used for the oleo-gum-resin preparation.1H-NMR based metabolomics was used to obtain metabolic profiles of eight asafoetida oleo-gum-resin samples and forty-six samples of Ferula species roots from two main regions of Iran. The acquired data were analyzed using multivariate principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal projection to latent structures discriminant analysis (OPLS-DA) to identify the metabolic differences and similarities between the samples. Asafoetida is usually produced from Ferula species of southern and eastern regions of Iran. A clear metabolic differentiation was evident between asafoetida oleo-gum- resin samples from the southern and those of the eastern Iran. The distinguished metabolites, umbelliprenin, farnesiferol B, farnesiferol C, samarcandin and galbanic acid are significantly found in southern samples. Only southern asafoetida is obtained from F. assa-foetida. Asafoetida from eastern region of Iran is obtained from other species of Ferula such as F. alliacea and its metabolic profile is far different from that of southern asafoetida.

Gummosin, a sesquiterpene coumarin from Ferula assa-foetida is preferentially cytotoxic to human breast and prostate cancer cell lines.

OBJECTIVE: The present study was conducted to find cytotoxic compounds from oleo-gum-resin of Ferula assa-foetida (asafoetida). MATERIALS AND METHODS: A dichloromethane extract of asafoetida was subjected to different chromatography analyses (including column chromatography, preparative thin layer chromatography and high performance liquid chromatography) to isolate its bioactive sesquiterpene coumarins. The structures of isolated compounds were elucidated through 1H-NMR spectra interpretation and comparison with those reported in the literature. To measure the cytotoxic activity of pure compounds, a non-fluorescent substrate called resazurin (alamarBlue®) was used in this study. Human breast and prostate cancer cell lines (MCF-7 and PC-3, respectively) and a normal human embryonic stem cell (NIH) were treated with different concentrations (50, 25, 12.5 and 6.25 µg/mL) of pure compounds. RESULTS: In this study, 10 sesquiterpene coumarins were isolated from oleo-gum-resin of F. assa-foetida and cytotoxic activity of 6 compounds was tested against MCF-7 and PC-3 cell lines and NIH cells. Badrakemin acetate (7), ferukrinone (8) and deacetyl kellerin (10) were found for the first time in the oleo-gum-resin of F. assa-foetida. Gummosin (4) showed moderate cytotoxic activity with IC50 values of 30 and 32.1 µg/mL against PC-3 and MCF-7 cell lines, respectively. None of the isolated compounds showed toxicity against NIH as a normal human cell line. CONCLUSION: The preferential cytotoxic activity of gummosin against cancer cell lines is reported for the first time in this study.