Prevention of radiotherapy-related oral mucositis with zinc and polyherbal mouthwash: a double-blind, randomized clinical trial.

BACKGROUND: A significant percentage of head and neck cancer (HNCs) patients receiving RT experience oral mucositis (OM). This study aimed to evaluate the effect of the polyherbal (containing chamomile, peppermint oil, Aloe vera, and honey) and zinc mouthwashes in comparison to the control (chlorhexidine) and placebo groups for prevention of radiation-induced OM. METHODS: This study was a double-blinded randomized clinical trial, conducted on 67 patients with HNCs undergoing radiotherapy. The eligible participants were randomized to receive either one of the following; zinc sulfate, polyherbal, chlorhexidine (Vi-one 0.2% CHX), or placebo mouthwash for 6 weeks. Follow-up evaluation of oral hygiene and the checklists of OM and the intensity of pain were filled out according to WHO assessment tool, Oral Mucositis Assessment Scale (OMAS), and Visual Analog Scale (VAS) in all the participants weekly for seven consecutive weeks. RESULTS: The results of present clinical trial demonstrated that the use of either zinc sulfate or polyherbal mouthwash significantly reduced the scores of OM and the severity of pain during weeks 2 to 7 after consumption compared with the CHX or placebo mouthwashes (P < 0.05). According to the post hoc analysis and compared with the placebo, a significantly better result was reported for zinc sulfate and polyherbal mouthwashes at weeks 2 to 7, but not for the CHX mouthwash. CONCLUSION: This study showed that the use of zinc sulfate or polyherbal mouthwashes is effective in prevention of both OM severity scores and pain related to OM intensity at weeks 2 to 7 following consumption in HNCs patients. Trial registration IRCT20190123042475N1 and IRCT20190123042475N2. Registration date: 2019-06-09, 2019-07-26.

Protective effects of 6-gingerol on 6-hydroxydopamine-induced apoptosis in PC12 cells through modulation of SAPK/JNK and survivin activation.

Due to many therapeutic effects, Ginger (Zingiber officinale) is the most widely used spice around the world, including in Iran. Due to its potent anti-inflammatory and antioxidant effects, ginger may protect against neurodegenerative disorders. Here, we investigated the effects of 6-gingerol (the main bioactive compound in ginger) on 6-hydroxydopamine (6-OHDA)-induced cell death in PC12 cells. Cell viability, cell apoptosis, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and survivin expression were measured using resazurin, propidium iodide (PI) and flow cytometry, and western blot analysis. 6-OHDA (100 µM) reduced the cell viability, increased apoptosis, increased the active form of SAPK/JNK, and decreased survivin protein level in PC12 exposed cells in a dose and time-dependent manner. Pretreatment with 6-gingerol significantly increased the viability and reduced apoptosis (2.5 and 5 µM). Also, pretreatment with 6-gingerol at 2.5 and 5 µM increased survivin whereas, 6-gingerol at 2.5 µM reduced (P-SAPK/JNK):(SAPK/JNK) levels to a level near that of the related control. According to the results, 6-gingerol blocks 6-OHDA-induced cell damage by suppressing oxidative stress and anti-apoptotic activity. Thus, 6-gingerol may process beneficial protective effects in slowing the progression of Parkinson's disease.

Antibacterial, Antifungal, and Antioxidant Activity of Cleome coluteoides: An In Vitro Comparative Study Between Leaves, Stems, and Flowers.

OBJECTIVES: Cleome coluteoides, which belongs to the Capparidaceae family, and has been used in folk medicine for a long time. Our research aims to measure the antioxidant, antibacterial, and antifungal activities of C. coluteoides. MATERIALS AND METHODS: Various solvents, such as ethyl acetate, methanol, and dichloromethane, were used to extract different plant parts. Antibacterial and antifungal activities were assayed by disk and well diffusion methods, and the antioxidant activity was screened by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing ability of plasma methods. RESULTS: Results showed that Gram-negative bacteria and fungus were resistant to various plant extracts. Against all Gram-positive bacteria tested, C. coluteoides' flower extract had the highest inhibition effects. Also, the most sensitive bacterium was Bacillus cereus, which had an 18-mm inhibition zone. Due to the solvent's physical and chemical properties, different C. coluteoides extracts exhibited various antioxidant activities in the antioxidant activity assay. To some extent, methanol extract of leaves showed the highest DPPH radical scavenging activity at various concentrations that ranged from 5 to 160 mg.mL-1. The methanol extract of flower was observed to have the highest level of phenolics among all tested extracts. CONCLUSION: This study demonstrates that different extracts from various C. coluteoides parts are different in their properties, therefore, a proper solvent should be used to extract maximum amounts of antioxidant and antibacterial components from a typical plant material.

Tongluojiunao, a traditional Chinese medication with neuroprotective ability: A review of the cellular, molecular and physiological mediators of TLJN's effectiveness.

The pressing need to discover more effective drugs for various CNS disorders has resurrected the idea of investigating the effectiveness of traditional medicines in modern science. Tongluojiunao (TLJN) is an example of revived modern herbal preparation based on traditional Chinese medicine (TCM) with a long history of administration for various types of cerebrovascular injuries and neurodegenerative diseases. TLJN is prepared from the herbal roots of Panax notoginseng (Sanchi) and dried fruits of Gardenia jasminoides (Cape Jasmine), and so far, it has demonstrated promising results in patients with vascular dementia and cerebral ischemic stroke. TLJN has also demonstrated therapeutic ability regarding the slowly-progressed neurodegenerative diseases like Alzheimer's disease. So it tempted us to undertake a thorough review of various features of TLJN therapeutic effects on the mentioned CNS conditions, including the cellular and molecular targets, inflammatory responses, neurogenesis and angiogenesis mediators and cognitive function. For this purpose, multiple global and local databases, including China National Knowledge Infrastructure (CNKI) were checked out and the retrieved information was grouped according to their scope of studies. Among these, TLJN is reported to restore the deregulated cell-cell communication in the neurovascular unit, prevent the stress-related challenges imposed by ischemia/reperfusion insult, help with the cerebral tissue recovery after traumatic brain damage, avoid the epileptic seizure attack and limit the progression of Alzheimer's disease. We hope that the current review provides new insights into TLJN medication as a prospective neuroprotective medication for further more in-depth investigation in the future.

Cytotoxic activity of the genus Ferula (Apiaceae) and its bioactive constituents.

OBJECTIVE: The genus Ferula L. includes perennial flowering plants belonging to the Apiaceae family. This genus is a rich source of biologically active phytochemicals such as sulfur-containing derivatives, coumarins, sesquiterpenes, sesquiterpene lactones, sesquiterpene coumarins, glucuronic acid, galactose, arabinose, rhamnose, and daucane esters. Over the last decade, considerable attention has been paid to biological activities of these compounds; it is assumed that the most prominent biological features of the genus Ferula are their cytotoxic effects. This article discusses cytotoxic activity of the genus Ferula and their important compounds. MATERIALS AND METHODS: In this mini-review article, papers published from 1990 to April 2016 were included and the following information was discussed; cytotoxic activity of the genus Ferula and their important compounds, the type of cell line used in vitro, concentrations of the extracts/active compound that were used, and the underlying mechanisms of action through which Ferula-related chemicals induced cytotoxicity. In addition, we explained different mechanisms of action through which the active constituents isolated from Ferula, could decrease cellular growth. CONCLUSION: It is highly recommended that potent and effective compounds that were isolated from Ferula plants and found to be appropriate as adjuvant therapy for certain diseases, should be identified. Also, the versatile biological activities of sesquiterpene coumarins suggest them as promising agents with a broad range of biological applications to be used in the future.

Biological activities of farnesiferol C: a review.

Farnesiferol C (FC) is a sesquiterpene coumarin, with a unique chemical structure, isolated from Ferula (Apiaceae) species including Ferula assa-foetida and Ferula szowitsiana. The compound is an important natural product with different biological activities. Recently, researchers have been interested in FC and begun to investigate its biological effects. They have shown that FC possesses various biological properties including cytotoxic, apoptotic, MDR reversal, antitumor, antimutagenic, and antiviral activity. In addition, FC has shown moderate neuroprotective activity against oxygen-glucose deprivation in vitro. This review summarizes the biological activities of FC that has been published to date. A complete search performed on relevant databases consists of Pubmed, Scopus, Web of science, Google scholar, Science direct, and Magiran. Selected keywords were sesquiterpene coumarin, farnesiferol C, biological activity, cytotoxicity, pharmacology, anticancer, and anti-angiogenesis. All of the data were checked out and irrelevant articles were discarded.

Sulphur-containing compounds in the essential oil of Ferula alliacea roots and their mass spectral fragmentation patterns.

Context GC-MS analysis is the best way to characterize volatile sulphur-containing compounds. Ferula (Apiaceae) is a genus of perennial herbs. Due to the occurrence of essential oils or oleoresins in the Ferula species, these plants usually possess strong aromatic scent. Terpenoid compounds were the most abundant constituents of Ferula oils, however, in some of Ferula species, the essential oils were dominated by volatile sulphur-containing compounds. Objectives Ferula alliacea Boiss. is considered one of the sources of the oleo-gum-resin asafoetida. In this study, we analyzed the hydrodistilled essential oil from its dried roots and provide new data about retention indices and mass fragmentation patterns of some volatile sulphur-containing compounds that are useful for future studies on this class of compounds. Materials and methods The roots of F. alliacea were collected during the flowering stage of plant, from Bezgh, Kashmar to Neishabour road, Khorasan-Razavi province, Iran, in June 2012. The oil was obtained by hydrodistillation using a Clevenger apparatus and analyzed by GC-MS. Results This is the first report on phytochemical analysis of F. alliacea roots. Seventy-six components, representing 99.5% of the oil, were characterized. The major components were 10-epi-γ-eudesmol (22.3%), valerianol (12.5%), hinesol (8.3%), guaiol (7.3%) and Z-propenyl-sec-butyl trisulphide (6.5%). Predominant mass fragment ions of the identified sulphur-containing compounds are explained in this paper. Conclusion The volatile oil of F. alliacea mostly contains oxygenated sesquiterpenes, however, its odour was dominated by sulphur-containing compounds. The most abundant sulphur-containing compound includes Z-propenyl-sec-butyl trisulphide (6.5%).

Angiotensin II Type 1 Receptor Gene A1166C Polymorphism Was Not Associated With Acute Coronary Syndrome in an Iranian Population.

BACKGROUND: There are very limited data for Iranian populations on the predisposing genetic factors for acute coronary syndrome (ACS). OBJECTIVES: The objective of the present study was to investigate the association of the angiotensin II type 1 receptor (AT1R) gene polymorphism and ACS in an Iranian population. PATIENTS AND METHODS: This cross-sectional study was conducted among 263 subjects (97 men and 166 women). Patients (n = 128) aged 30 - 80 years with chest pain were recruited from the emergency department of Ghaem Hospital (Mashhad, Iran). A 12-lead electrocardiograph plus creatine kinase MB (CK-MB) levels were used as the basis for the diagnosis of myocardial ischemia. The control group was selected from age-matched healthy subjects (n = 135). Non-enzymatic kits were used for extraction of DNA from blood samples. Polymerase chain reaction (PCR) was performed to amplify the DNA fragments. For restriction fragment length polymorphism (RFLP) determination, the DdeI enzyme was used to digest the amplified DNA fragments. Statistical analyses were performed using SPSS version 13.0. RESULTS: There was no statistical difference in the genotype frequency of patients and healthy subjects with regard to age and gender (P > 0.05). CONCLUSIONS: The AT1R A1166C polymorphism appeared not to be associated with the presence of ACS in the population studied.

Modulation of Multidrug Resistance Protein 2 Efflux in the Cisplatin Resistance Human Ovarian Carcinoma Cells A2780/RCIS by Sesquiterpene Coumarins.

Recent in vitro studies showed that sesquiterpene coumarins (SCs) can be used as chemosensitizers. In this study, 14 SCs were isolated and purified from roots of four Ferula species and their structures were elucidated by spectroscopic methods. The purified SCs were evaluated for multidrug resistance (MDR) reversal properties in A2780/RCIS cells (cisplatin-resistant derivatives of the human ovarian carcinoma cell line A2780P). Among the tested compounds, mogoltacin, mogoltadone, farnesiferol A, farnesiferol B, farnesiferol C, lehmferin, conferdione, and samarcandin showed significant MDR reversing effects. The combination of nontoxic concentrations of SCs (20 µM) with cisplatin enhanced cisplatin cytotoxicity on A2780/RCIS cells significantly. Flow cytometric efflux assay confirmed that the intracellular accumulation of 5-carboxyfluorescein diacetate (5-CFDA) was significantly increased in A2780/RCIS cells when treated with SCs. Our findings revealed that conferdione and samarcandin possessed the highest inhibitory effects on multidrug resistance-associated protein 2 pump efflux, and therefore, these compounds could be considered as lead scaffolds for further structure modifications.

Highly Oxygenated Sesquiterpene Lactones from Cousinia aitchisonii and their Cytotoxic Properties: Rhaserolide Induces Apoptosis in Human T Lymphocyte (Jurkat) Cells via the Activation of c-Jun n-terminal Kinase Phosphorylation.

Infrared-guided chromatographic fractionation of sesquiterpene lactones from the extracts of Cousinia aitchisonii and Cousinia concolor led to the isolation of five pure compounds. A new sesquiterpene lactone, namely, aitchisonolide, and two known sesquiterpene lactones (desoxyjanerin and rhaserolide) were isolated from C. aitchisonii and two known lignans (arctiin and arctigenin) from C. concolor. The structures of these compounds were elucidated by one-dimensional and two-dimensional nuclear magnetic resonance techniques, as well as high-resolution mass spectrometry. The purified and characterized compounds were subjected to cytotoxicity assay. The sesquiterpene lactones desoxyjanerin and rhaserolide showed significant cytotoxic activities against five different cancer cell lines and the normal human embryonic kidney cell line. Rhaserolide was chosen to evaluate the possible mechanism of action. Western blot analysis revealed that rhaserolide could induce apoptosis in Jurkat cells via the activation of c-Jun n-terminal kinase phosphorylation.

Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins.

In the present study, fifteen sesquiterpene coumarins were isolated and purified from different Ferula species, and were tested for their MDR reversal properties. Enhancement of doxorubicin cytotoxicity in MCF-7/Adr cells (doxorubicin resistant derivatives of MCF-7 cells overexpressing P-gp), when combined with very non-toxic concentrations of the sesquiterpene coumarins (50 µM) including umbelliprenin, farnesiferol B, farnesiferol C and lehmferin, proved significant MDR reversal activity of these coumarins. Flow cytometric efflux assay confirmed that the intracellular accumulation of Rho123 was significantly increased in MCF-7/Adr cells when treated with sesquiterpene coumarins. A deeper insight into the structure-activity relationship of sesquiterpene coumarins revealed that ring-opened drimane-type sesquiterpene coumarins including farnesiferol B, farnesiferol C and lehmferin possessed the best inhibitory effects on P-gp pump efflux and they could be considered as lead scaffolds for further structure modifications.

Foetithiophenes C-F, thiophene derivatives from the roots of Ferula foetida.

CONTEXT: Ferula foetida Regel (Apiaceae) is an Iranian medicinal plant with various biological activities including antispasmodic and anthelmintic. OBJECTIVE: The sulfur compounds from the roots of F. foetida were isolated and characterized to test their cytotoxic and antimicrobial activities. MATERIALS AND METHODS: The methanolic extract of the roots of F. foetida was fractionated using silica column chromatography. The components of each fraction were further purified using RP-HPLC. Their structures were elucidated by 1- and 2-D NMR spectroscopy as well as HREIMS. Their cytotoxic and antimicrobial activities were evaluated using Alamar Blue assay and broth microdilution method, respectively. RESULTS: Four new thiophene derivatives, namely foetithiophenes C-F (3-6), together with four known compounds, foetithiophenes A (1) and B (2), coniferaldehyde, and sinapic aldehyde, were isolated from the roots of F. foetida. Antimicrobial activities were observed in particular against the Gram-positive bacteria. The best antimicrobial activity was observed for compound 6 against B. cereus with a MIC value 50 µg/mL. The tested compounds did not show cytotoxic properties against MCF-7 and K562 cells. CONCLUSION: Four new thiophene derivatives including foetithiophenes C-F (3-6) were characterized from the roots of F. foetida. Foetithiophene F (6) exhibited the most potent activity against the Gram-positive bacteria B. cereus.

Sesquiterpene lactones from Ferula oopoda and their cytotoxic properties.

Two new sesquiterpene lactones, namely feruhodin A and feruhodin B, together with six known compounds, daucoeudesmanolactone, dehydrooopodin, oopodin, badkhysin, 7-demethylplastochromenol, and scoparone, were isolated from the roots of Ferula oopoda. The structures of these compounds were elucidated by 1D and 2D NMR techniques as well as high-resolution mass spectrometry. Cytotoxic effects of these compounds were evaluated against two human cancer cell lines including MCF7and K562 using the Alamar blue assay. The results showed that dehydrooopodin possessed significant cytotoxic effects with IC50 values of 15 and 5 µM against MCF7 and K562, respectively.

Synthesis, biosynthesis and biological activities of galbanic acid - A review.

Abstract Context: Galbanic acid (GA) is a biologically active sesquiterpene coumarin from Ferula species (Apiaceae). This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral, and antileishmanial activities. Objectives: This article is a review on the synthesis, biosynthesis, and biological activities of GA. In addition, we discussed gaps in our knowledge about GA that deserve future research. In this article, we also evaluated the drug-likeness of GA in silico. Methods: All relevant databases were searched for the terms "galbanic acid", "methyl galbanate", "Ferula" and "sesquiterpene coumarin" without limitation, up to May 2013. Information on GA was collected via electronic search using Pubmed, Scopus, Web of Science, and Sciencedirect. All physicochemical parameters used for the prediction of drug-likeness were calculated using MarvinSketch (version 5.11, academic package, ChemAxon). Results: This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral and antileishmanial activities. GA can inhibit the growth of prostate cancer cells via decreasing androgen receptor abundance. In silico physicochemical studies on GA showed that this compound has drug-like properties, the parameters that are important to predict potential of a compound for being a future drug. Conclusion: GA is a valuable natural product with various biological activities. New discoveries with GA are to be expected.

Association of angiotensin II type 1 receptor gene A1166C polymorphism with the presence of diabetes mellitus and metabolic syndrome in patients with documented coronary artery disease.

BACKGROUND: There are relatively limited data available on the genetic susceptibility to diabetes mellitus and metabolic syndrome in the Iranian population. We have therefore investigated the association between the angiotensin II type I receptor gene polymorphism (AT(1)R/A1166C) and the presence of diabetes mellitus and metabolic syndrome in a well defined group of patients. METHODS: Patients with angiographically defined coronary artery disease (CAD) (n=309) were evaluated for the presence of AT(1)R/A1166C polymorphism. These patients were classified into subgroups with (n=164, M/F: 109/55) and without (n=145, M/F: 84/61) diabetes mellitus. The AT(1)R polymorphism was assessed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based method. RESULTS: There was a higher frequency of polymorphic genotypes (AC+CC) in the diabetic compared with the non-diabetic group (p=0.01). When determined for each gender separately, this difference remained significant in the males (p=0.04) but not in females (p=0.09). With regard to the allele frequencies, the C allele was significantly higher and the A allele frequency was lower in the diabetic group (p=0.01). This remained significant after gender segregation for males (p=0.01) but not females. In the binary logistic regression analysis, only serum fasting glucose was found as the independent predictor for the presence of diabetes in the CAD patients (ß=1.16, p<0.001 for total population and ß=1.29, p<0.001 for male subjects). There was no significant difference in genotype or allele frequencies between subgroups with and without metabolic syndrome, this being unaffected by gender or the definition of metabolic syndrome used apart from a significantly lower frequency of C allele in male subjects with metabolic syndrome defined by the NCEP ATP III criteria (p=0.04). CONCLUSION: The AT(1)R/A1166C polymorphism may be associated with the presence of diabetes mellitus in male subjects with documented CAD.

Association between angiotensin II type 1 receptor gene polymorphism and metabolic syndrome in a young female Iranian population.

BACKGROUND AND AIMS: The overall prevalence of obesity and metabolic syndrome (MetS) is increasing among children and adolescents and can predispose to type II diabetes mellitus and cardiovascular disease. There are reported associations between an angiotensin II type I receptor gene polymorphism (AT(1)R/A1166C) with hypertension, myocardial infarction, insulin resistance and cardiovascular disease risk. In the present study, we aimed to investigate whether the AT(1)R/A1166C polymorphism was associated with MetS among adolescent Iranian girls. METHODS: A total of 350 adolescent girls aged 15-17 years from high schools and different educational zones of Mashhad city participated in this population-based, genetic association study. Of these individuals, 101 patients had MetS (defined by the NCEP-ATP III criteria); the remaining 249 age-matched girls were considered as the control group. All subjects were genotyped for the AT(1)R/A1166C polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Frequencies of the AA, AC and CC genotypes were 164 (65.9%), 80 (32.1%) and 5 (2.0%) in the control group and 79 (78.2%), 20 (19.8%) and 2 (2.0%) in patients, which were not consistent with the Hardy-Weinberg equilibrium (p <0.05 and p <0.001, respectively). Frequency of the AT(1)R C allele was found to be significantly lower in patients compared with controls (p <0.05). CONCLUSIONS: Our findings suggested that the 1166C allele of AT(1)R gene may be associated with a decreased risk of MetS in adolescent Iranian females.