Mohamed L. Ashour

Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action

Objectives  Radix Bupleuri represents one of the most successful and widely used herbal drugs in Asia for treatment of many diseases over the past 2000 years. Thorough studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. In this work, we review the chemistry and pharmacology of the genus Bupleurum and explore the relationships between the pharmacological effects and the chemical composition of these drugs.

Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents.

Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion.

Chemical composition and biological activity of the essential oil obtained from Bupleurum marginatum (Apiaceae).

Objectives Bupleurum marginatum is a herb indigenous to the southern and southwestern part of China. It is widely used in many Chinese prescriptions. We aimed to investigate the chemical composition, antioxidant, anti‐inflammatory, antimicrobial and in‐vitro cytotoxic activity of the hydrodistilled and extracted essential oil from B. marginatum to validate some of its ethnopharmacologial uses.

Biological activity of the essential oil of Kadsura longipedunculata (Schisandraceae) and its major components

Objectives  The aim was to determine the chemical composition of the essential oil of Kadsura longipedunculata and the biological activity of the oil and its major components.

Modulation of multidrug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids

Cancer cells often develop multidrug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine and an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects. Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug modifying enzymes CYP3A4 and GST in a dose-dependent manner. The alkaloids induced apoptosis in MDR cells which was accompanied by an activation of caspase-3, -8,-6/9, and phosphatidyl serine (PS) exposure. cDNA arrays were applied to identify differentially expressed genes after treatment with chelidonine and the alkaloid extract. The expression analysis identified a common set of regulated genes related to apoptosis, cell cycle, and drug metabolism. Treatment of Caco-2 cells with 50 μg/ml alkaloid extract and 50 μM chelidonine for up to 48 h resulted in a significant decrease in mRNA levels of P-gp/MDR1, MRP1, BCRP, CYP3A4, GST, and hPXR and in a significant increase in caspase-3 and caspase-8 mRNA. Thus, chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models.

Screening of some Tanzanian medicinal plants for their trypanocidal and cytotoxic activities

The objective of the present study was to evaluate in vitro antitrypanosomal and cytotoxic activities of crude extracts of 20 traditionally used medicinal plants of Tanzania. A total of 40 extracts (dichloromethane and methanol) were screened for antiproliferative activity of bloodstream form of T. b. brucei and human leukaemia HL‐60 cell. Inhibition of cell proliferation was assessed using resazurin as vital stain. Of the 40 extracts tested, the dichloromethane extract from bark of Warburgia salutaris (Canellaceae) exhibited the most potent antitrypanosomal activity with an IC50 value of 10.68 μg/ml. A dichloromethane extract from Lannea stuhlmannii (Anacardiaceae) was found to be the most cytotoxic extract against HL‐60 (IC50 = 27.15 μg/ml). Out of the 20 plants tested, 5 plants exhibited trypanocidal activity with IC50 values below 20 μg/ml. These 5 plants: Entandrophragma bussei (Meliaceae), Securidaca longepedunculata (Polygalaceae), Warburgia salutaris (Canellaceae), Zanha africana (Sapindaceae) and Zanthoxylum chalybeum (Rutaceae) could therefore serve as sources of lead compounds for treatment of trypanosomiasis. Copyright

Chemical composition and anti-inflammatory activity of the essential oils of Psidium guajava fruits and leaves

Psidium guajava L. (Myrtaceae) has been used traditionally against gastrointestinal disturbances and respiratory ailments. The chemical composition of the essential oil of both leaves and fruits were elucidated by gas–liquid chromatography/mass spectrometry (GLC/MS). Forty-five and forty-two compounds, accounting for 93.7% and 89.7% of the fruit and leaf oil, were identified, respectively. The dominant compounds were β-caryophyllene (17.6%) and limonene (11.0%) for the fruit oil and β-caryophyllene (16.9%) and selin-7(11)-en-4α-ol (8.3%) for the leaf oil. The radical scavenging activities of both essential oils were assessed by the diphenyl picrylhydrazyl (DPPH•) and deoxyribose degradation assays. Guava leaf oil reduced DPPH• radicals and prevented the degradation of the deoxyribose with ic50 values of 3.59 and 12.64 μg/mL. The in vitro cytotoxicity of the oils in HepG2 and MCF-7 carcinoma cells was examined using the SRB assay (ic50 32.53 and 49.76 μg/mL for the leaves and fruit oils against HepG2 cells). Inhibition of 5-lipoxygenase (5-LOX) was used to evaluate the anti-inflammatory activity of both oils (ic50 130.69 and 196.45 μg/mL for the leaves and fruit oils). The anti-inflammatory activity was explained via virtual docking of the major identified compounds to the main sites in the 5-LOX crystal structure.

Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor, Induces the Production of Anti-inflammatory Cyclodepsipeptides from Beauveria felina

The addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid to a culture of the filamentous fungus Beauveria felina significantly changed its secondary metabolite profile and led to the isolation of eight compounds, including three new cyclodepsipeptides, desmethylisaridin E (1), desmethylisaridin C2 (2), and isaridin F (3), along with five known cyclodepsipeptide compounds. Isaridin F (3) possesses a cyclodepsipeptide ring with N-methylbutyric acid, which is rare in natural peptides. Absolute configurations of the new cyclodepsipeptides were achieved by Marfeys method. The anti-inflammatory activity of the isolated compounds was investigated through evaluating their effect on superoxide anion production and elastase release by FMLP-induced human neutrophils. Among the tested compounds, desmethylisaridin E (1) inhibited superoxide anion production and desmethylisaridin C2 (2) inhibited elastase release, with IC50 values of 10.00 ± 0.80 and 10.01 ± 0.46 μM, respectively.

Variations of the chemical composition and bioactivity of essential oils from leaves and stems of Liquidambar styraciflua (Altingiaceae).

This study aimed to evaluate the variations of the chemical composition and bioactivity of essential oils of Liquidambar styraciflua L. (Altingiaceae) collected in different seasons.

Medicinal Plants with Potential Antidiabetic Activity and their Assessment

Objective: Diabetes mellitus is a clinical syndrome characterized by a deficiency in insulin production or resistance to insulin action. Consequently, it leads to inappropriate hyperglycemia. Prolonged hyperglycemia can cause severe complications that probably affect every system of the body and every drug taken by the patient. This study highlights the most popular medicinal plants with potential antidiabetic significance, their modes of action together with the method used for their assessment. Key findings: Through antidiabetic evaluation conducted on different medicinal herbs since centuries revealed the presence of potent antidiabetic activity. Moreover, the candidates from natural source with diverse structures of secondary metabolites. This indicates various sites of action within the human body. Conclusions: Further investigations are required, and more attention should be drawn to explore the biological activity of hundreds of traditionally used medicinal plants both in vitro and in vivo to assess the claimed activity with the aim of finding potent antidiabetic candidates from the natural resources.