Concentration and non-dietary human health risk assessment of pesticide residues in soil of farms in Golestan province, Iran.

Detection of pesticide residues in soil samples was conducted using UHPLC-MS/MS. Non-dietary health risk assessment was conducted using calculate chronic daily intake (CDI) from ingestion, inhalation and dermal contact pathways and following non-carcinogenic and carcinogenic risks in the adults and adolescent. The rank order of pesticide in soil based on their concentration was malathion (0.082 mg kg-1)> cyproconazole (0.019 mg kg-1)> propargite (0.018 mg kg-1)> butachlor (0.016 mg kg-1) > chlorpyrifos (0.0067 mg kg-1)> diazinon (0.0014 mg kg-1)> imidacloprid (0.0007 mg kg-1). Hazard index (HI) values obtained of exposure to pesticides in soil in adults and adolescent were 0.0012 and 0.0035, respectively. Hence, exposed population are at the acceptable range of non-carcinogenic risk (HI < 1). Cancer risk (CR) values due to propargite in soil via ingestion pathway in adults and adolescent were 2.03E-09 and 2.08E-09, respectively; therefore, carcinogenic risk due to the exposure to pesticide contaminated soil was safe range (CR < 1E-06).

Recent reports in the biggest herbal genus, Astragalus, in Iran; with a special viewpoint on tragacanth gum production.

This comprehensive review was carried out to integrate all the data published in the electronic databases (Scopus, etc.) over the past two decades about the distribution, phytochemistry, ethnopharmacology, and pharmacology of Astragalus L. Although Astragalus is one of the largest genera of flowering plants in Iran, limited phytochemical screening of this genus has been reported. Cycloartane triterpene glycosides, labdane diterpenoids, flavonoids, and polysaccharides are the major identified compounds. Pharmacological studies revealed significant properties such as anti-inflammatory, anticancer, antidiabetic, etc. Moreover, ethnopharmacological studies of Astragalus sp. showed that this genus is used for gastrointestinal, fractures, joint pains, and skin problems in different localities of Iran. Tragacanth gum, as the main product of some Astragalus sp. with economic value, shows proper biological activities and uses as an emulsifier in food industries. This review might be helpful for researchers to find new chemical entities responsible for its claimed traditional uses and food supplements.

Unusual derivatives from Hypericum scabrum.

Three new compounds (1-3) with unusual skeletons were isolated from the n-hexane extract of the air-dried aerial parts of Hypericum scabrum. Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.11,4]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1-3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum, with IC50 values of 3.07 and 2.25 µM, respectively.

Insecticidal activity of the essential oil of Perovskia artemisioides Boiss.

This work reports the phytochemical profile and insecticidal properties of Perovskia artemisioides Boiss essential oil (PAEO) collected in Baluchestan, Iran. Totally, twenty-six substances were identified with 1,8-cineole (25.81%), geranyl acetate (13.00%) and linalool (10.21%) as dominant chemical metabolites by GC-MS analysis. PAEO possessed fumigant toxicity against various growth stages of Phthorimaea operculella. P. operculella adults showed considerable sensitivity (LC50 = 0.58 µL/L air) in comparison to eggs (LC50 = 5.87 µL/L air) and neonate larvae (LC50 = 1.23 µL/L air). Finally, molecular docking of major components of PAEO was performed against detoxification enzymes, including cytochrome P450 and glutathione S-transferase activities. Humulene, ß-caryophyllene, and α-cadinol exhibited the most interactions with the P450 and GST. It can be concluded that PAEO has the potential for development into natural insecticides for the control of storage pests.

New Sesterterpenoids from Salvia mirzayanii Rech.f. and Esfand. Stereochemical Characterization by Computational Electronic Circular Dichroism.

Phytochemical investigation on the acetone extract of Salvia mirzayanii Rech. f. and Esfand. afforded seven new isoprenoids including six new sesterterpenoids salvimirzacolide A-F (1-6), and one new nor-diterpenoid (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS) and DP4+ NMR chemical shift probability calculation technique. Moreover, the absolute configuration of compounds was determined by using electronic circular dichroism spectroscopy. Evaluation of antiproliferative properties of compounds isolated against four human melanoma cancer cells displayed no cytotoxic activity at the concentration range used.

Inhibitory effect of flavonoid xanthomicrol on triple-negative breast tumor via regulation of cancer-associated microRNAs.

Breast cancer is the leading cause of cancer death in women worldwide. Due to the side effects of current chemo-reagents on healthy tissues, it is essential to search for alternative compounds with less toxicity and better efficacy. In the present study, we have investigated the anticancer effects of flavonoid xanthomicrol on the mice breast cancer model using MTT assay, cell cycle and Annexin/PI analysis, colony formation assay, H&E staining, immunohistochemistry, and miRNA analysis. Our results demonstrated that xanthomicrol decreased the cell viability and clonogenic capability, induced G1-arrest and apoptosis in the breast cancer cells in vitro, and caused a significant reduction in the volume and weight of mice tumors in vivo. In addition, xanthomicrol reduced the expression of TNFα, VEGF, MMP9, and Ki67, while upregulating the expression of apoptotic markers such as Bax, caspase3, and caspase9. Finally, the expression of miR21, miR27, and miR125, known as oncomirs, decreased significantly after xanthomicrol administration, while the expression of miR29 and miR34, functioning as tumor suppressors, increased significantly (p < .001). Our data demonstrated that xanthomicrol can induce apoptosis and suppress angiogenesis in breast cancer cells due to its inhibitory effect on oncomirs and its stimulatory effect on tumor suppressor miRNAs.

Integrating Molecular Networking and 1H NMR Spectroscopy for Isolation of Bioactive Metabolites from the Persian Gulf Sponge Axinella sinoxea.

The geographic position, highly fluctuating sea temperatures and hypersalinity make Persian Gulf an extreme environment. Although this unique environment has high biodiversity dominated by invertebrates, its potential in marine biodiscovery has largely remained untapped. Herein, we aimed at a detailed analysis of the metabolome and bioactivity profiles of the marine sponge Axinella sinoxea collected from the northeast coast of the Persian Gulf in Iran. The crude extract and its Kupchan subextracts were tested in multiple in-house bioassays, and the crude extract and its CHCl3-soluble portion showed in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium (Efm). A molecular networking (MN)-based dereplication strategy by UPLC-MS/MS revealed the presence of phospholipids and steroids, while 1H NMR spectroscopy indicated the presence of additional metabolites, such as diketopiperazines (DKPs). Integrated MN and 1H NMR analyses on both the crude and CHCl3 extracts combined with an antibacterial activity-guided isolation approach afforded eight metabolites: a new diketopiperazine, (-)-cyclo(L-trans-Hyp-L-Ile) (8); a known diketopiperazine, cyclo(L-trans-Hyp-L-Phe) (7); two known phospholipids, 1-O-hexadecyl-sn-glycero-3-phosphocholine (1) and 1-O-octadecanoyl-sn-glycero-3-phosphocholine (2); two known steroids, 3ß-hydroxycholest-5-ene-7,24-dione (3) and (22E)-3ß-hydroxycholesta-5,22-diene-7,24-dione (4); two known monoterpenes, loliolide (5) and 5-epi-loliolide (6). The chemical structures of the isolates were elucidated by a combination of NMR spectroscopy, HRMS and [α]D analyses. All compounds were tested against MRSA and Efm, and compound 3 showed moderate antibacterial activity against MRSA (IC50 value 70 µg/mL). This is the first study that has dealt with chemical and bioactivity profiling of A. sinoxea leading to isolation and characterization of pure sponge metabolites.

Flavonoid calycopterin triggers apoptosis in triple-negative and ER-positive human breast cancer cells through activating different patterns of gene expression.

Breast cancer is the most common cause of death related to cancer in women, and several studies proved that flavonoids could induce apoptosis in this cancer through different pathways. Calycopterin is a flavonoid which was shown to induce preferential antiproliferative effects on some cancers; however, no information is available on its effect on breast cancer. Therefore, in this paper, the apoptotic effect of calycopterin and its underlying mechanism in two different breast cancer cells, MDA-MB-231 and MCF7 cell lines were investigated. MTT assay showed that calycopterin reduced the proliferation of both cancer lines with no adverse effect on normal cells. The clonogenic assay showed that calycopterin treatments decreased the colony numbers and sizes, and wound healing assay demonstrated the inhibition of migration in both cancer cells. Cell cycle and annexin/PI analyses indicated that calycopterin augmented sub-G1 population and annexin/PI-positive cells. Gene expression revealed that Bax/Bcl2 increased in the MDA-MB-231 cell line, while no change was observed in that of the MCF7 line. Expression of gene caspase-8 was augmented in both lines, although increased expression of caspase-3 was found just in MDA-MB-231 cells. Our results validated the apoptotic effect of calycopterin on both breast cancer lines with more potency on triple-negative ones.

Terpenoids and phenolics of Micromeria persica.

Phytochemical investigation of the aerial parts of Micromeria persica led to the isolation of a new oleane type triterpenoid ester (1), together with six known compounds 2-7), comprising one phenyl ethanoid ester, one glycosylated flavonoid, two triterpenoids, and two steroids. Their structures were elucidated by interpretation of their one-dimensional and two-dimensional NMR spectra and completed by the analysis of the HRESIMS data. Compounds 1 and 3 were evaluated for their cytotoxic feature against human breast adenocarcinoma cell line (MDA-MB231) and human prostate cancer cell line (DU145). However, they did not show positive effect (IC50 > 75µM).[Figure: see text].

7-epi-Clusianone, a Multi-Targeting Natural Product with Potential Chemotherapeutic, Immune-Modulating, and Anti-Angiogenic Properties.

Targeted therapies have changed the treatment of cancer, giving new hope to many patients in recent years. The shortcomings of targeted therapies including acquired resistance, limited susceptible patients, high cost, and high toxicities, have led to the necessity of combining these therapies with other targeted or chemotherapeutic treatments. Natural products are uniquely capable of synergizing with targeted and non-targeted anticancer regimens due to their ability to affect multiple cellular pathways simultaneously. Compounds which provide an additive effect to the often combined immune therapies and cytotoxic chemotherapies, are exceedingly rare. These compounds would however provide a strengthening bridge between the two treatment modalities, increasing their effectiveness and improving patient prognoses. In this study, 7-epi-clusianone was investigated for its anticancer properties. While previous studies have suggested clusianone and its conformational isomers, including 7-epi-clusianone, are chemotherapeutic, few cancer types have been demonstrated to exhibit sensitivity to these compounds and little is known about the mechanism. In this study, 7-epi-clusianone was shown to inhibit the growth of 60 cancer cell types and induce significant cell death in 25 cancer cell lines, while simultaneously modulating the immune system, inhibiting angiogenesis, and inhibiting cancer cell invasion, making it a promising lead compound for cancer drug discovery.

A multi-targeting natural compound with growth inhibitory and anti-angiogenic properties re-sensitizes chemotherapy resistant cancer.

Targeted therapies have become the focus of much of the cancer therapy research conducted in the United States. While these therapies have made vast improvements in the treatment of cancer, their results have been somewhat disappointing due to acquired resistances, high cost, and limited populations of susceptible patients. As a result, targeted therapeutics are often combined with other targeted therapeutics or chemotherapies. Compounds which target more than one cancer related pathway are rare, but have the potential to synergize multiple components of therapeutic cocktails. Natural products, as opposed to targeted therapies, typically interact with multiple cellular targets simultaneously, making them a potential source of synergistic cancer treatments. In this study, a rare natural product, deacetylnemorone, was shown to inhibit cell growth in a broad spectrum of cancer cell lines, selectively induce cell death in melanoma cells, and inhibit angiogenesis and invasion. Combined, these results demonstrate that deacetylnemorone affects multiple cancer-related targets associated with tumor growth, drug resistance, and metastasis. Thus, the multi-targeting natural product, deacetylnemorone, has the potential to enhance the efficacy of current cancer treatments as well as reduce commonly acquired treatment resistance.

New Diterpenoids from the Aerial Parts of Salvia reuterana.

The genus Salvia is a valuable origin of structurally diverse terpenoids. In a project directed at structurally interesting bioactive metabolites from Iranian Salvia species, we studied Salvia reuterana. Two new labdane diterpene, 6ß, 14α-dihydroxy-15-acetoxysclareol (1), and 14α, 15- dihydroxy sclareol (2), were isolated from the aerial part of the plant. Their structures were established mainly by 1D and 2D NMR spectroscopic techniques, including 1H-1H COSY, HSQC and HMBC methods and HR-ESI-TOFMS spectral data. Compound 1 and 2 were tested for their inhibitory activity toward HeLa and MCF-7 cell lines. Our results showed that S. reuterana is a rich source of labdane diterpenoids. These compounds are rather rare in Salvia species, although they are frequently found in other genera of the Lamiaceae. S. reuterana is a new source of these diterpenoids.

Hypermongone C Accelerates Wound Healing through the Modulation of Inflammatory Factors and Promotion of Fibroblast Migration.

The physiology of wound healing is dependent on the crosstalk between inflammatory mediators and cellular components of skin regeneration including fibroblasts and endothelial cells. Therefore, strategies to promote healing must regulate this crosstalk to achieve maximum efficacy. In light of the remarkable potential of natural compounds to target multiple signaling mechanisms, this study aims to demonstrate the potential of hypermongone C, a polycyclic polyprenylated acylphloroglucinol (PPAP), to accelerate wound closure by concurrently enhancing fibroblast proliferation and migration, promoting angiogenesis, and suppressing pro-inflammatory cytokines. This compound belongs to a family of plants (Hypericum) that traditionally have been used to treat injuries. Nevertheless, the exact biological evidence to support the claims is still missing. The results were obtained using a traditional model of cell scratch assay and endothelial cell tube formation, combined with the analysis of protein and gene expression by macrophages. In summary, the data suggest that hypermongone C is a multi-targeting therapeutic natural compound for the promotion of tissue repair and the regulation of inflammation.

Prevention of recognition memory loss and moderation of mitochondrial dynamic tendency toward fusion by flavone derivatives in Aß-injected rats: a comparison between two flavonoids with different polarity.

Growing evidence sheds light on the use of flavonoids as the promising alternatives for the treatment of chronic conditions, including cancer and neurodegenerative disorders. Accordingly, in the present study, we aimed at evaluating the effects of oral intake of two structurally different flavonoids 5-hydroxy-6,7,4'-trimethoxyflavone (flavone 1) and 5,7,4'-trihydroxyflavone (flavone 2) on recognition memory, hippocampal protein level of immediate early gene cFos and mitochondrial dynamic markers in Amyloid ß (Aß)-injected rats. Recognition aspect of memory and level of proteins were measured using novel object recognition test and Western blot, respectively. Our data indicated that even though flavone 1 was more effective than flavone 2 to prevent memory impairment, feeding with both flavones alleviated memory in Aß-injected rats. Furthermore, in flavones-administered rats, mitochondrial dynamic balancing returned to the control level by the decline in Dynamin-related protein-1 protein level, a known marker for mitochondrial fission, and elevation in protein level of mitochondrial fusion factors Mitofusins 1 and 2. In parallel with behavior results, flavone 1 was more effectual on mitochondrial dynamic moderating. The more neuroprotective effects of flavone 1 could be attributed to its methylated structure leading to crossing of the blood-brain barrier with ease and metabolic stability and bioactivity.

Eupatorin and Salvigenin Potentiate Doxorubicin-Induced Apoptosis and Cell Cycle Arrest in HT-29 and SW948 Human Colon Cancer Cells

Background: Cancer persists as one of the world's most pressing maladies. Notable points about chemotherapy are drug side effects which are almost universally encountered. Emerging knowledge focusing on mechanisms of toxicity due to chemotherapy has led to characterization of novel methods, including the exploitation of natural compounds, in combination therapies. Flavonoids are natural polyphenolic compounds that play protective roles against tumor cell development. The focus of this study was apoptotic effects of two flavonoids, eupatorin and salvigenin, in combination with doxorubicin on a cellular model of colon cancer. Method: Upon establishing a non-effective dose of doxorubicin, and effective doses of eupatorin (100µM) and salvigenin (150µM) via MTT, morphological features of apoptosis were distinguished using DAPI staining and cell cycle blockage in the sub-G1 phase. Apoptosis was determined by annexin/ PI and western blotting. ROS levels and MMP were measured to show any role of mitochondria in apoptosis. Results: Co-administration of flavonoids with doxorubicin induced apoptosis via the mitochondrial pathway as mitochondrial membrane potential and ROS production were changed. Annexin/PI analysis demonstrated that apoptosis frequency was increased with the combination treatments in colon cancer cells. Finally, the combination of these flavonoids with doxorubicin increased the Bax/Bcl-2 ratio, caspase-3 expression and PARP cleavage. Conclusion: Combination of flavonoids with doxorubicin induces apoptosis and enhances effect on cancer cells which might allow amelioration of side effects by dose lowering.

A nor-diterpene from Salvia sahendica leaves.

Phytochemical investigation of n-hexane extract of Salvia sahendica by normal phase column chromatography resulted in the isolation of six compounds. Structures were established by 1D and 2D NMR spectroscopy, and HRMS, as a new norditerpene 1, and known terpenoids, sclareol (2), oleanolic acid (3), ß-sitosterol (4), salvigenin (5) and 3α-hydroxy-11α,12α-epoxyoleanan-28,13ß-olide (6). The absolute configuration of 1 was confirmed by a combination of X-ray single crystal analysis and electronic circular dichroism spectroscopy. In vitro cytotoxic activity on breast cancer cell line (MDA-MB-231) and also the antimicrobial activity of the pure compounds were tested against Staphylococcus aureus, Bacilus cereus and Escherichia coli.

Phytochemical constituents and biological activities of Cleome iberica DC.

Phytochemical investigation of Cleome iberica DC. aerial parts led to the isolation and characterisation of six triterpenoid including glutinol (1), lupeol (2), ß-sitosterol (3), cabraleadiol monoacetate (4), cabraleadiol (6) and daucosterol (8), one flavonoid, calycopterin (5) along with a fatty acid, tricosanoic acid (7). While studied samples showed weak potency in antimicrobial assessment, the acetone extract and some isolated compounds exhibited considerable cytotoxicity against cervical cancer cell line (HeLa) in MTT assay, among them calycopterin with IC50 equals to 5.1 µM was the strongest. The extract showed moderate antioxidant capacity in DPPH assay method (IC50 = 100.2 µg/mL) and total phenolics and total flavonoids contents of the dried extract were also determined as 39.6 and 90.7 mg/g, respectively.

Two new polyhydroxylated triterpenoids from Salvia urmiensis and their cytotoxic activity.

Two new polyhydroxylated triterpenoids were isolated from the acetone extract of the aerial parts of Salvia urmiensis Bunge. Their structures were elucidated by 1D and 2D NMR and HR-ESI-MS analyses as olean-12-ene-1ß,3ß,11α,22α-tetraol (1) and urs-12-ene-1ß,3ß,11ß,22α-tetraol (2). The effect of these compounds on cell viability of MCF-7 cells was investigated by the MTT assay. Compounds 1 and 2 showed weak cytotoxicity with IC50 values of 110.23 ± 0.12 and 88.35 ± 0.09 µM, respectively.

Sesterterpenoids and other constituents from Salvia lachnocalyx Hedge.

Three new sesterterpene lactones, lachnocalyxolide A-C [1, 2, and 3 (as epimeric pair)] together with nine known compounds, including two sesterterpenoids, three flavonoids, two steroidal compounds, one nor diterpenoid and one triterpenoid, were isolated from the acetone extract of the aerial parts of Salvia lachnocalyx Hedge. Their structures were elucidated on the basis of extensive spectroscopic data, including 1D and 2D NMR spectra, as well as HR-ESI-MS. Compounds 1, 2, 4 and 5 were also tested for their inhibitory activity toward MCF-7 and HeLa cell lines.