Evaluation of the Antihyperglycemic efficacy of the roots of Ferula orientalis L.: An in vitro to in vivo assessment.

Decoctions of Ferula orientalis L. (Apiaceae), have been traditionally used to lower blood glucose levels (BGLs). After in vitro enzyme inhibition tests on the dichloromethane extracts of the roots (FOD) and the methanol extract of the roots (FOM), isolation studies were carried out on the FOD extract. The anti-hyperglycemic effects of the FOD extract and the pure compounds were studied in mice using the Oral Glucose Tolerance Test (OGTT) and streptozotocin (STZ)-induced diabetes mellitus (DM) models. Molecular docking studies were performed on potent compounds in the binding pockets of enzymes α-glucosidase and α-amylase. The isolations of 11 compounds were isolated from the FOD extract, which comprised teferidine (1), ferutinin (FT) (2), teferin (3), epoxy-jaeschkeanadiol-p-hydroxybenzoate (4), epoxy-jaeschkeanadiol-6-vanillate (5), tovarol-8-angelate (6), leucoferin (7), tovarol-8-p-hydroxybenzoate (8), tovarol-8-vanillate (9), 6-ß-p-hydroxybenzoyloxy-germacra-1(10),4-diene (10), and chimgin (11). Compounds 2 and 8-11 exhibited a higher inhibitory activity on α-glucosidase. In the OGTT, pretreatment with the FOD extract or compound 2 did not alter the BGLs after administration of the glucose solution compared to the control. In the STZ-induced diabetic mice model, no significant difference in the BGLs was observed with the FOD extract (200 mg/kg) or compound 2 (100 mg/kg)-treated diabetic mice compared to the diabetic control mice. The experimental studies all showed that the F. orientalis extract had significant effects on the enzyme systems involved in DM, and it would be appropriate to plan further studies on possible problems of bioavailability of the compound FT and the FOD extract, inadequate dose, and duration of administration.

Evaluation of the Potential Beneficial Effects of Ferula communis L. Extract Supplementation in Postmenopausal Discomfort.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Ferula latisecta gels for synthesis of zinc/silver binary nanoparticles: antibacterial effects against gram-negative and gram-positive bacteria and physicochemical characteristics.

This study explores the potential antibacterial applications of zinc oxide nanoparticles (ZnO NPs) enhanced with silver (Ag) using plant gel (ZnO-AgO NPs). The problem addressed is the increasing prevalence of pathogenic bacteria and the need for new, effective antimicrobial agents. ZnO NPs possess distinctive physicochemical properties that enable them to selectively target bacterial cells. Their small size and high surface area-to-volume ratio allow efficient cellular uptake and interaction with bacterial cells. In this study, the average size of the synthesized ZnO-Ag nanoparticles was 77.1 nm, with a significant standard deviation of 33.7 nm, indicating a wide size distribution. The nanoparticles demonstrated remarkable antibacterial efficacy against gram-negative and gram-positive bacteria, with inhibition zones of 14.33 mm for E. coli and 15.66 mm for B. subtilis at a concentration of 300 µg/ml. Minimum inhibitory concentrations (MIC) were determined to be 100 µg/ml for E. coli and 75 µg/ml for S. saprophyticus. Additionally, ZnO-Ag NPs exhibited excellent biocompatibility, making them appropriate for various pharmacological uses. This study utilizes Ferula latisecta gels, offering a sustainable and eco-friendly approach to nanoparticle synthesis. Incorporating of Ag into ZnO NPs significantly enhances their antimicrobial properties, with the combined results showing great inhibition effects on pathogenic microbes. The findings suggest that ZnO-Ag NPs could be a promising candidate for addressing the challenges posed by drug-resistant bacterial infections and enhancing antimicrobial treatments.

Antiviral Effect of Ferula Plants and their Potential for Treatment of COVID-19: A Comprehensive Review.

Viral diseases have always been a threat to mankind throughout history, and many people have lost their lives due to the epidemic of these diseases. In recent years, despite the progress of science, we are still witnessing a pandemic of dangerous diseases such as COVID-19 all over the world, which can be a warning for humanity. Ferula is a genus of flowering plants commonly found in Central Asia, and its species have shown antiviral activity against a variety of viruses, including respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, hepatitis B, and coronaviruses. In this study, we intend to review the antiviral effects of Ferula plants, emphasizing the therapeutic potential of these plants in the treatment of COVID-19. Google, PubMed, Web of Science, and Scopus databases were searched to review the relevant literature on the antiviral effect of Ferula or its isolated compounds. The search was performed using the keywords Ferula, antiviral, Coronaviruses, respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, and hepatitis B. According to the reviewed articles and available scientific evidence, it was determined that the plants of this genus have strong antiviral effects. Also, clinical studies have shown that some species, such as Ferula assa-foetida, can be used effectively in the treatment of COVID-19. Ferula plants have inhibitory effects on various viruses, making them an attractive alternative to conventional antiviral agents. Therefore, these plants are a natural source of valuable compounds that can help us fight infectious diseases.

A Comprehensive Review of the Pharmacological Effects of Genus Ferula on Central Nervous System Disorders.

BACKGROUND: Plants of the genus Ferula have long been used to treat neurological diseases such as Alzheimer's disease (AD), pain, depression, and seizures. The main compounds include coumarins, monoterpenes, sulfide compounds, and polyphenol compounds, which can improve the functioning of the nervous system. OBJECTIVE: This article has been compiled with the aim of collecting evidence and articles related to the Ferula effects on central nervous system disease. METHODS: This review article was prepared by searching the terms Ferula and analgesic, anticonvulsant, antidepressant, anti-multiple sclerosis, anti-dementia, and neuroprotective effects.The relevant information was collected through searching electronic databases such as ISI Web of Knowledge, PubMed, and Google Scholar. RESULTS: Genus Ferula has a protective effect on nerve cells by reducing cytokines such as IL-6, IL- 1b, and TNF-α. Therefore, the effects of Ferula plants and their effective ingredients can be used to prevent or improve diseases that destroy the nervous system. The members of this genus play a role in strengthening and improving the antioxidant system, reducing the level of oxidative stress, and inhibiting or reducing inflammatory factors in the nervous system. CONCLUSION: Although the effects of several species of Ferula on the nervous system have been investigated, most studies have not clearly identified the molecular mechanisms as well as the specific functional regions of the brain. The present study was compiled in order to investigate different aspects of the effects of Ferula plants on the central nervous system.

Structure-guided isolation of anti-neuroinflammatory sesquiterpene coumarins from Ferula sinkiangensis.

The resin of Ferula sinkiangensis has been traditionally utilized for treating gastrointestinal disorders, inflammation, tumors, various cancers, and alopecia areata. The primary bioactive constituents, sesquiterpene coumarins, have demonstrated notable therapeutic potential against neuroinflammation. In this study, a structure-guided fractionation method was used to isolate nine novel sesquiterpene coumarins from the resin of F. sinkiangensis. These compounds were characterized and structurally elucidated using comprehensive physicochemical and spectroscopic techniques, including calculated electronic circular dichroism (ECD). Anti-neuroinflammatory assays revealed that compounds 2, 3, and 6 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values ranging from 1.63 to 12.25 µmol·L-1.

Culture-based diversity of endophytic fungi of three species of Ferula grown in Iran.

A total of 1,348 endophytic fungal strains were isolated from Ferula ovina, F. galbaniflua, and F. persica. They included Eurotiales (16 species), Pleosporales (11 species), Botryosphaeriales (1 species), Cladosporiales (2 species), Helotiales (6 species), Hypocreales (31 species), Sordariales (7 species), Glomerellales (2 species), and Polyporales (1 species). F. ovina had the richest species composition of endophytic fungi, and the endophytic fungi were most abundant in their roots compared to shoots. Chao, Margalef, Shannon, Simpson, Berger-Parker, Menhinick, and Camargo indices showed that F. ovina roots had the most endophytic fungal species. The frequency distribution of fungal species isolated from Ferula spp. fell into the log-series model, and F. ovina roots had the highest Fisher alpha. The dominance indices showed that there are no dominant species in the endophytic fungal community isolated from Ferula spp., indicating community stability. Evenness values were 0.69, 0.90, 0.94, and 0.57 for endophytic fungi isolated from F. ovina roots, F. ovina shoots, F. galbaniflua roots, and F. persica roots, respectively, indicating a species distribution that tends toward evenness. The fungal species community isolated from each of F. ovina roots, F. ovina shoots, F. galbaniflua roots, and F. persica roots was a diverse species group originating from a homogeneous habitat. Their distribution followed a log-normal distribution, suggesting that the interactions of numerous independent environmental factors multiplicatively control species abundances. Principal component analysis showed that the highest species diversity and dominance were observed in the endophytic fungal community isolated from F. ovina and F. persica roots, respectively.

New Phenylpropanoids and Disulphides Dimers from Ferula Kuhistanica.

Five undescribed compounds, including three phenylpropanoid derivatives, 4'-methoxycinnamyl isobutyrate (1), 4'-methoxycinnamyl-2"-methyl butyrate (2) and (2Z)-3',4'-dimethoxycinnamyl isovalerate (3) and two disulphides dimers, kuhistanicasulphide A (7) and kuhistanicasulphide B (8) together with five known ones, including three phenylpropanoids (4-6) and two disulphides (9-10), were isolated from the roots of Ferula kuhistanica Korovin. Their structures were elucidated on the basis of spectroscopic analysis, including IR, UV, HRESIMS, NMR and quantum 13C NMR DP4+ probability. Anti-inflammatory and cytotoxic (Hela, A549 and HT-29 cell lines) activities of the obtained compounds was tested, which compounds 4 and 5 demonstrated good anti-inflammatory with IC50 values of 25.41±2.30 µM and 31.70±3.82 µM, respectively.

Characteristic terpenylated coumarins from Ferula ferulaeoides as potential inhibitors on overactivation of microglia.

A total of 37 characteristic terpenylated coumarins (1-25), including 17 undescribed compounds (1-5, 6a/6b, 7-10, 11a/11b-13a/13b), have been isolated from the root of Ferula ferulaeoides. Meanwhile, twelve pairs of enantiomers (6a/6b, 11a/11b-15a/15b, 17a/17b, 18a/18b, 20a/20b-22a/22b, and 25a/25b) were chirally purified. The structures of these new compounds were elucidated using HRESIMS, UV, NMR, and calculated 13C NMR with a custom DP4 + analysis. The absolute configurations of all the compounds were determined for the first time using electronic circular dichroism (ECD). Then, their inhibitory effects on nitric oxide (NO) production were evaluated with LPS-induced BV-2 microglia. Compared with the positive control minocycline (IC50 = 59.3 µM), ferulaferone B (2) exhibited stronger inhibitory potency with an IC50 value of 12.4 µM. The immunofluorescence investigation indicated that ferulaferone B (2) could inhibit Iba-1 expression in LPS-stimulated BV-2 microglia.

A comprehensive review of the molecular and genetic mechanisms underlying gum and resin synthesis in Ferula species.

Ferula spp. are plants that produce oleo-gum-resins (OGRs), which are plant exudates with various colors. These OGRs have various industrial applications in pharmacology, perfumery, and food. The main constituents of these OGRs are terpenoids, a diverse group of organic compounds with different structures and functions. The biosynthesis of OGRs in Ferula spp., particularly galbanum, holds considerable economic and ecological importance. However, the molecular and genetic underpinnings of this biosynthetic pathway remain largely enigmatic. This review provides an overview of the current state of knowledge on the biosynthesis of OGRs in Ferula spp., highlighting the major enzymes, genes, and pathways involved in the synthesis of different terpenoid classes, such as monoterpenes, sesquiterpenes, and triterpenes. It also examines the potential of using omics techniques, such as transcriptomics and metabolomics, and genome editing tools, such as CRISPR/Cas, to increase the yield and quality of Ferula OGRs, as well as to create novel bioactive compounds with enhanced properties. Moreover, this review addresses the current challenges and opportunities of applying gene editing in Ferula spp., and suggests some directions for future research and development.

Unveiling the anti-vitiligo, anti-inflammatory, and antitumor activities of sesquiterpene coumarins isolated from Ferula kuhistanica.

Six undescribed bicyclic sesquiterpene coumarins, kuhistanin A, ferukrin isovalerate, 9'ß,12'α - ferukrin isovalerate, (17'E)- 9'α, 12'ß - isomarcandin, (17'Z)- 9'α, 12'ß - isomarcandin and (17'E) - isomarcandin, together with nine known ones were isolated from the roots of Ferula kuhistanica Korovin. The structures of them were elucidated using NMR and HRESIMS data analysis. The relative configurations of the isolates were confirmed by NOE correlations and NMR calculation. The absolute configurations of them were confirmed by X-ray diffraction analysis and ECD calculation. Anti-vitiligo, anti-inflammatory and cytotoxicity of the isolates were tested. Acetyl feselol, feselol, ferusingensine I and farnesiferol A significantly increased the melanin content at the concentration of 10 µM. (17'E) - 9'α, 12'ß - isomarcandin exhibited strong cytotoxicity against HT-29 cell line with IC50 values of 8.94 ± 0.47 µM, and (17'E) - isomarcandin demonstrated strong cytotoxicity against Hela, A549 and HT-29 cell lines with IC50 values of 5.29 ± 0.25, 4.01 ± 0.20, and 4.16 ± 0.21 µM, respectively. This study concluded that, isolated compounds from F. kuhistanica demonstrated strong bioactivity towards anti-vitiligo and cytotoxicity and active compounds are suggested as anti-vitiligo and cytotoxicity agent for future drug development.

Gone with the waves: the role of sea currents as key dispersal mechanism for Mediterranean coastal and inland plant species.

Thalassochory, the dispersal of propagules through marine currents, is a key long-distance dispersal (LDD) mechanism with implications for global biogeography and particularly for island colonization. The propagules of coastal plant species are generally assumed to be better adapted for sea dispersal than those of inland plants, but this hypothesis remains largely untested. We conducted experiments on four genera (Juniperus, Daucus, Ferula, and Pancratium) and compared traits among nine species with different habitats and distributions. Our results showed that Juniperus spp. and P. maritimum have strong thalassochorous potential within the Mediterranean Basin. Interestingly, we did not find a clear association on the thalassochorous potential of coastal versus inland species within all the tested genera, apart from P. maritimum compared with the endemic inland P. illyricum. These findings suggest that thalassochory may be a more common dispersal mechanism than previously assumed. The apparently weak link of dispersal syndrome with species ecology broadens the possibility of dispersal by the sea also for inland plants, although considered to be poorly salt-tolerant. Moreover, our results reveal significant differences in sea dispersal between endemic and widespread species, but do not rule out an important role of thalassochory in shaping the distribution patterns of archipelago endemic flora. The presented method is largely replicable and could be used for further studies with a larger set of species to better delineate trends of sea dispersal syndrome among species with different ecology or dispersal traits.

Cytotoxic and apoptotic effects of Ferula gummosa Boiss: extract on human breast adenocarcinoma cell line.

PURPOSE: Ferula gummosa Boiss. is a well-known and valuable medicinal plant in Iran. Research has shown that this plant has several pharmacological properties, including anti-bacterial, anti-cancer and etc. In the present study, we investigated the cytotoxic properties of F. gummosa Boiss. extract in MCF-7 breast adenocarcinoma cells. METHODS: The cytotoxicity and pro-apoptotic properties of the extract were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and propidium iodide (PI) stained cells, respectively. Apoptosis and necrosis were evaluated by annexin V-PI staining. The levels of reactive oxygen species (ROS),malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) was determined to evaluate oxidative stress. The cell migration and the gene expression were assessed by scratch assay and quantitative real-time polymerase chain reaction (q-RT-PCR), respectively. RESULTS: The extract of F. gummosa decreased the viability and cell cycle progression of MCF-7 cells by inducing apoptosis and necrosis, increasing ROS and MDA levels, and decreasing GSH levels and SOD activity. It also lowered the cells' migration capability by enhancing p53 mRNA levels and reducing MMP-9 mRNA expression. CONCLUSION: F. gummosa exhibited pro-apoptotic, anti-proliferative, and anti-metastatic effects on MCF-7 cells. It is therefore recommended that detailed future research be done on different parts of the plant or its secondary metabolites to find anti-cancer lead compounds.

A histological examination of the effects of Ferula elaeochytris extract on kidney and liver tissues in myoglobinuric acute renal failure.

Myoglobinuric acute renal failure (MARF) is a structural and functional disorder that occurs in the kidney following the release of muscle cell contents into the circulation. In this present study, possible protective and curative effects of Ferula elaeochytris extract against kidney and liver damage in experimentally induced MARF in a rat model were investigated. 3-4 Month-old, 200-250 g Sprague Dawley rats were divided into 8 equal groups with 7 rats per group. Group I was a no-intervention Control group. All groups except for the Group I were dehydrated for 16 hours. Following this dehydration, 50% v/v aqueous glycerol solution was injected into both hind leg muscles of the animals, at a dose of 8 ml/kg. The rats were given physiological saline (SF) once orally before the model was administered (Group II) and after the model was administered (Group V). Similarly, two different doses of Ferula elaeochytris root extract (40 mg/kg and 80 mg/kg) were dissolved in 2 ml of SF and administered orally before (Groups III and IV) and after (Group VI, VII) the model was created. Following the experimental period, kidney and liver tissues were removed from all groups, and fixed in 10% neutral formaldehyde solution for light microscopic examinations. Intracellular vacuolization, enlargement in the Bowman's space, widespread atrophy in the tubular structures, luminal enlargement, and desquamation were detected in the kidney tissue sections of all the experimental model groups. In the liver tissue sections, was detected hepatocyte degeneration, intracellular vacuolization, irregularity in cell membrane borders, and apoptotic bodies. These histopathological consequences of MARF were evaluated for all groups, and whereas a curative effect of Ferula elaeochytris could be seen, its protective effect was higher than its curative effect.

Investigation of physio-mechanical, antioxidant and antimicrobial properties of starch-zinc oxide nanoparticles active films reinforced with Ferula gummosa Boiss essential oil.

The production of surface compounds coated with active substances has gained significant attention in recent years. This study investigated the physical, mechanical, antioxidant, and antimicrobial properties of a composite made of starch and zinc oxide nanoparticles (ZnO NPs) containing various concentrations of Ferula gummosa essential oil (0.5%, 1%, and 1.5%). The addition of ZnO NPs improved the thickness, mechanical and microbial properties, and reduced the water vapor permeability of the starch active film. The addition of F. gummosa essential oil to the starch nanocomposite decreased the water vapor permeability from 6.25 to 5.63 g mm-2 d-1 kPa-1, but this decrease was significant only at the concentration of 1.5% of essential oils (p < 0.05). Adding 1.5% of F. gummosa essential oil to starch nanocomposite led to a decrease in Tensile Strength value, while an increase in Elongation at Break values was observed. The results of the antimicrobial activity of the nanocomposite revealed that the pure starch film did not show any lack of growth zone. The addition of ZnO NPs to the starch matrix resulted in antimicrobial activity on both studied bacteria (Staphylococcus aureus and Escherichia coli). The highest antimicrobial activity was observed in the starch/ZnO NPs film containing 1.5% essential oil with an inhibition zone of 340 mm2 on S. aureus. Antioxidant activity increased significantly with increasing concentration of F. gummosa essential oil (P < 0.05). The film containing 1.5% essential oil had the highest (50.5%) antioxidant activity. Coating also improved the chemical characteristics of fish fillet. In conclusion, the starch nanocomposite containing ZnO NPs and F. gummosa essential oil has the potential to be used in the aquatic packaging industry.

A new sesquiterpene coumarins from Ferula bungeana Kitagawa.

A new sesquiterpene coumarin, bungeanin A (1), together with four known sesquiterpene coumarins, were isolated from the whole plants of Ferula bungeana Kitagawa. The structure of bungeanin A was elucidated by analysis of its spectroscopic data, including UV, IR, HR-ESI-MS, and extensive 1D and 2D NMR spectroscopy.

Characterization and investigation of cytotoxicity and antimicrobial properties of coencapsulated limonene and thymol into the Ferula assafoetida gum microparticles.

Thymol (Th) and d-limonene (L) exhibit low stability and are prone to oxidation when exposed to air, light, humidity, and high temperatures. This study examined the coencapsulation of Th and L into Ferula assafoetida gum (AFG) microparticles. Scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analyzer (TGA) were done to characterize the obtained complexes. Furthermore, the encapsulation efficiency, antibacterial properties, cytotoxicity, and anticancer properties of both the free and encapsulated forms of L and Th were measured. For all samples, by increasing the percentage of bioactive compound (L, Th, and L-Th) from 2.5 to 5 % w/w, the EE was increased. FTIR and XRD analysis results demonstrated that Th and L were successfully incorporated into the AFG. Additionally, thermogravimetric analysis showed that in the thermal graphs of all samples, the first weight loss occurred between 30 °C and 160 °C, which was due to the evaporation of water. In the free L and Th graph, a sharp reduction peak was observed in which 80 % of compounds were lost. These reduction peaks disappeared in the thermal graphs of L: AFG and Th: AFG revealing that the thermal stability of Th and L was significantly increased upon their incorporation into the AFG. The inclusion of Th into the AFG also led to an increase in its antibacterial activity, while L exhibited acceptable antibacterial activity, albeit not as high as Th. Additionally, according to the MIC results, Th: AFG had the best antibacterial activity among all compounds, especially on gram-positive bacteria. According to the result of the MTT assay, there was a significant difference between the IC50 of free Th (123.4 µg/ml) and Th: AFG (2312 µg/ml), and free L (1762 µg/ml) and L: AFG (2480 µg/ml) showing that encapsulated Th and L into the AFG has decreased the cytotoxicity of free compounds against L929 cell line. Also, Th: AFG had the best anticancer activity against Hella and CT26 cell lines among all compounds. Finally, the flow cytometry analysis demonstrated that the encapsulated particles effectively eliminated cancer cells. The outcomes imply that AFG can be employed as a suitable delivery system to enhance the use of Th and L into the food and pharmaceutical industries.

Dauferulins A-L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities.

Phytochemical study on the roots of a medicinal plant Ferula communis L. (Apiaceae) resulted in the isolation of 20 sesquiterpenes including 12 previously undescribed compounds, dauferulins A-L (1-12). The detailed spectroscopic analysis revealed 1-12 to be daucane-type sesquiterpenes with a p-methoxybenzoyloxy group at C-6. The absolute configurations of 1-12 were deduced by analysis of the ECD spectra. Dauferulins A-L (1-12), known sesquiterpenes (13-20), and analogues (14a-14l) derived from 6-O-p-methoxybenzoyl-10α-angeloyloxy-jeaschkeanadiol (14) were evaluated for their effects on AMPK phosphorylation in human hepatoma HepG2 cells as well as inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and IL-1ß production from LPS-treated murine microglial cells.

Exploring the anticancer properties of the gum of Ferula gummosa: impact on cytotoxicity, caspase 3/7 activity and apoptosis, and gene expression in SW-480 cells.

Ferula gummosa Boiss. is a well-known Iranian endemic plant that grows in the north and northeast regions of Iran. In Iranian traditional medicine, its gum is utilized to treat inflammation, pain, and infections of the gastrointestinal system. However, no studies have been conducted to investigate the anticancer potential of its gum against colorectal cancer cells. This study aimed to identify the chemical components of the gum of F. gummosa and investigate its effects on SW-480 cells. The experiments included MTT, clonogenic, micronucleus formation, acridine orange/ethidium bromide stain, DNA degradation, caspase 3/7 activity assay, and in vitro wound-healing experiment and investigating the expression of BAX, BCL2, MTOR, and PTEN genes. Chemical analysis using GC/MS identified 102 compounds. The gum had a significant cytotoxic effect on SW-480 cells, with an IC50 value of 1.8 µg/ml for 48 hours. The gum induced apoptosis. Microscopic observations revealed a decrease in cell proliferation, as evidenced by nuclear condensation, increased micronucleus formation, and inhibition of colony formation. Additionally, the gum suppressed cell migration, induced the expression of PTEN and BAX, and down-regulated MTOR and BCL2 genes. These findings suggest that Ferula gummosa has strong cytotoxic properties and warrants further investigation.

In vitro Evaluation of the Potent Antileishmanial Activity of Ferula tabasensis Alone or in Combination with Shark Cartilage Extract Against the Standard Iranian Strain of Leishmania major (MRHO/IR/75/ER).

Background: The available drugs for the treatment of leishmaniasis are highly toxic and extremely expensive, with low efficiency; therefore, the development of effective therapeutic compounds is essential. Objectives: The present study aimed to explore the antileishmanial effects of ethyl acetate extract, methanol extract, and fractions 1-4 (F1-F4) of Ferula tabasensis, alone or in combination with shark cartilage extract (ShCE), on L. major in vitro. Methods: In this study, ethyl acetate, methanol, and n-hexane extracts were extracted from the aerial roots of F. tabasensis by the maceration method. The silica gel column chromatography was used to separate n-hexane extracts at varying polarities (F1-F4 fractions). Subsequently, the effects of extracts and fractions against promastigotes were assessed by the parasite counting method microscopic inhibition test and MTT assay. Besides, their effects on the infected macrophage cells and the number of amastigotes were investigated. Cytotoxicity was evaluated in non-infected J774A.1 macrophage cells. Finally, apoptosis induction of promastigotes, including infected and non-infected macrophages, was evaluated. Results: The results indicated the highly potent activity of F. tabasensis extracts and F1-F4 fractions, alone or in combination with ShCE, against L. major promastigotes and amastigotes in a dose-dependent manner (P < 0.05). The F1 fraction and methanol extract showed markedly higher toxicity compared to the other extracts and fractions, with 50% inhibitory concentrations (IC50/72h) of 2.4 ± 0.29 and 2.9 ± 0.55 µg/mL against promastigotes and 1.79 ± 0.27 µg/mL and 1.39 ± 0.27 µg/mL against amastigotes (P < 0.001). Moreover, they had a high selectivity index (SI) due to the low toxicity of macrophages (P < 0.0001). The results of flow cytometry indicated that the percentages of apoptotic promastigote cells in contact with IC50 concentrations of F1 and methanol extract alone after 72 h were 43.83 and 43.93%, as well as 78.4%, and 65.45% for their combination with ShCE, respectively.Also, apoptosis of infected macrophages induced by F1 and methanol extracts was estimated at 68.5% and 83.7%, respectively. Conclusions: In this study, the F1 fraction and methanol extract of F. tabasensis showed potent efficacy against L. major, associated with low toxicity and apoptosis induction. Therefore, they can be promising therapeutic candidates in future animal and even human studies.