Crocus sativus L. Extracts and Its Constituents Crocins and Safranal; Potential Candidates for Schizophrenia Treatment?

Schizophrenia is a chronic mental devastating disease. Current therapy suffers from various limitations including low efficacy and serious side effects. Thus, there is an urgent necessity to develop new antipsychotics with higher efficacy and safety. The dried stigma of the plant Crocus sativus L., (CS) commonly known as saffron, are used in traditional medicine for various purposes. It has been demonstrated that saffron and its bioactive components crocins and safranal exert a beneficial action in different pathologies of the central nervous system such as anxiety, depression, epilepsy and memory problems. Recently, their role as potential antipsychotic agents is under investigation. In the present review, I intended to critically assess advances in research of these molecules for the treatment of schizophrenia, comment on their advantages over currently used neuroleptics as well-remaining challenges. Up to our days, few preclinical studies have been conducted to this end. In spite of it, results are encouraging and strongly corroborate that additional research is mandatory aiming to definitively establish a role for saffron and its bioactive components for the treatment of schizophrenia.

Bioactive cyclohexene derivatives from a mangrove-derived fungus Cladosporium sp. JJM22.

Four new cyclohexene derivatives cladoscyclitols A-D (1-4) and one new ribofuranose phenol derivative 4-O-α-D-ribofuranose-2-pentyl-3-phemethylol (5) were obtained from the EtOAC extract of the mangrove-derived endophytic fungus Cladosporium sp. JJM22. The structures were elucidated by extensive NMR and MS analysis, while the absolute configurations of the stereogenic carbons were established based on quantum-chemical electronic circular dichroism calculations or comparison of the optical rotations with those of related compounds. Compounds 2 and 5 displayed potent inhibitory activity against α-glucosidase with the IC50 values of 2.95 and 2.05 µM, respectively.

Protective effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L., against Aß1-42-induced apoptosis in SH-SY5Y cells by reversing Bcl-2/Bax ratio.

BACKGROUND AND PURPOSE: Aß1-42-induced neurotoxicity has been considered as a possible mechanism to aggravate the onset and progression of Alzheimer's disease (AD). In this study, we aim to determine the protective effect of DMDD on the apoptosis of SH-SY5Y cells induced by Aß1-42 and elucidate potential mechanism of DMDD's protective function in apoptosis. EXPERIMENTAL APPROACH: CCK-8, AnnexinV-FITC/PI flow cytometry, and transmission electron microscopy analysis were used to determine the protection of DMDD on Aß1-42-evoked apoptosis of SH-SY5Y cells. Cytochrome c release, JC-1 staining, and measuring the protein of Bcl-2 family by Western blot were applied to elucidate the mechanism of DMDD's protective function in apoptosis. KEY RESULTS: Three concentration of DMDD (5 µmol/L, 10 µmol/L, and 20 µmol/L) rescues the cell viability loss and apoptosis of SH-SY5Y cells cultivated in Aß1-42. The expressions of cleaved Caspase-3, -8, -9, the cytochrome c release, and mitochondrial membrane potential loss were inhibited by DMDD in Aß1-42-insulted SH-SY5Y cells. The Western blot analysis showed that DMDD pretreatment clearly downregulated the protein of Bax and upregulated Bcl-2. Moreover, the Bcl-2/Bax ratio was obviously decreased in cells only exposed to Aß1-42, but, which was suppressed by treated with DMDD. CONCLUSION AND IMPLICATIONS: DMDD attenuated the apoptosis of SH-SY5Y cells induced by Aß1-42 through reversing the Bcl-2/Bax ratio.

Safranal, an active constituent of saffron, ameliorates myocardial ischemia via reduction of oxidative stress and regulation of Ca2+ homeostasis.

Safranal (SFR) is the major constituent of saffron. The purpose of this study was to observe the effect of SFR on myocardial ischemia induced by isoprenaline (ISO) and to explore its possible mechanism. The myocardial ischemia rat model was established by subcutaneous injection of ISO (85 mg/kg/d) on the 8th and 9th day of the experiment. Serum creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured, as were changes in calcium concentration, reactive oxygen species (ROS) and cardiac morphology of the myocardial tissue. The effects of SFR on cell contraction, Ca2+ transient and L-type Ca2+ current (ICa-L) in isolated rat myocardial cells were measured using the Ion Optix detection system and the whole-cell patch-clamp technique. SFR can decrease the activity of serum CK, LDH and MDA, and increase the activity of serum SOD, reduce intracellular calcium concentration and the manufacture of ROS. In addition, SFR can improve changes in heart morphology. SFR can significantly inhibit contraction, Ca2+ transients and ICa-L in isolated ventricular myocytes. SFR has a cardioprotective role in ISO-induced MI rats, and the underling mechanism is related to the inhibition of oxidative stress, myocardial contractility, ICa-L and the regulation of Ca2+ homeostasis.

Four new chemical constituents from Piper pleiocarpum.

Two new polyoxygenated cyclohexenes (1-2), one new benzoate derivative (3), and one new dineolignan (4) together with one known neolignan (5) were isolated from whole plants of Piper pleiocarpum. The structures of these compounds were determined by extensive spectroscopic methods including 1D, 2D NMR, HR-ESI-MS, and by comparison with the literature. The 13C NMR spectra of the known compound 5 were completely assigned for the first time. All isolated compounds (1-5) were evaluated for their cytotoxic activities against five human cancer cell lines (including A-549, SMMC-7721, HL-60, MCF-7, and SW-480), Only compound 4 showed inhibitory activity against MCF-7 cell line with IC50 value of 18.24 ± 0.69 µM.

Potent α-glucosidase inhibitory activity of compounds isolated from the leaf extracts of Uvaria hamiltonii.

The phytochemical investigation of the leaf extracts of Uvaria hamiltonii (Annonaceae) led to the isolation and identification of ten compounds including a new seco-cyclohexene (1) together with nine known compounds (2-10). Their structures were elucidated by intensive analysis by spectroscopic methods and comparisons of their spectroscopic data with those of compounds reported in the literature. Compounds 2, 8, and 9 showed potent α-glucosidase inhibitory activity with the IC50 values ranging from 2.6-7.1 µM.

Uvarialuridols A-C, three new polyoxygenated cyclohexenes from the twig and leaf extracts of Uvaria lurida.

The first phytochemical investigation of Uvaria lurida resulted in the isolation and identification of three new polyoxygenated cyclohexenes, (+)-(1R,2S,3R,6S)-uvarialuridols A-C (1-3), together with 10 known compounds (4-13). All new structures were elucidated by spectroscopic methods and HRESIMS. The absolute configurations of compounds 1 and 5 were confirmed by X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of compounds 2-4 were identified from comparisons of their specific rotations and ECD spectra with those of known compounds. Compound 11 showed α-glucosidase inhibitory activity with an IC50 value of 30 µM which was better than the standard control, acarbose (74 µM) whereas, compound 10 exhibited nitric oxide (NO) production inhibitory activity with an IC50 value of 37 µM.

Cytotoxic polyoxygenated cyclohexene derivatives from the aerial parts of Uvaria cherrevensis.

Three previously undescribed polyoxygenated cyclohexene derivatives named cherrevenol M (1), cherrevenol N (2), and cherrevenone (3), together with nine related known analogues 4-12 were isolated from the ethyl acetate fraction partitioned from the methanol extract of the aerial parts of Uvaria cherrevensis (Annonaceae). The determination of the structures and their relative configurations of the isolated compounds were established by spectroscopic techniques, electronic circular dichroism (ECD) analysis as well as comparison with the literature data. For cherrevenone (3), the relative and absolute configurations were also confirmed by using X-ray diffraction and ECD techniques, respectively. Compounds isolated except for compounds 8 and 10 were evaluated for their cytotoxic activity and cherrevenone (3) showed moderate cytotoxic activity against all cancerous cell lines except for ASK cell line with ED50 values ranging from 1.04 ±â€¯0.13 to 10.09 ±â€¯4.31 µM.

Polyoxygenated Cyclohexenes and Their Chlorinated Derivatives from the Leaves of Uvaria cherrevensis.

The chemical study of leaf extracts from Uvaria cherrevensis resulted in the identification of 11 new polyoxygenated cyclohexenes, cherrevenols A-K (1-11), and a new seco-cyclohexene derivative, cherrevenol L (12). Nine known compounds (13-21) were also isolated. Three of the isolated compounds are chlorinated polyoxygenated cyclohexenes. The structures of these compounds were determined using spectroscopic methods and, in some cases (compounds 2, 6, 8, and 10), single-crystal X-ray crystallographic structural analysis or chemical correlation (compounds 6 and 7). Compounds 6 and 7 were both isolated as scalemic mixtures (ee 23-24%).

Biotoxicological Analyses of Trimeroside from Baccharis trimera Using a Battery of In Vitro Test Systems.

The use in folk medicine of Baccharis trimera and recent studies on DNA damage by oxidative stress mechanisms have motivated this study. We investigated the biotoxicological effects of trimeroside from this plant. Aqueous extract from aerial parts of B. trimera was fractioned by flash chromatography for further isolation by thin-layer chromatography. The novel nor-monoterpene glycoside, trimeroside, and three flavonoids, cirsimaritin, luteolin and quercetin, were isolated. The genotoxic and mutagenic potential of trimeroside was determined by Salmonella/microsome (TA98 and TA100), comet assay, and cytokinesis-block micronucleus cytome assay (CBMN-cyt) in HepG2 cells. We also screened trimeroside into different human tumoral cell lines by sulforhodamine B (SRB) assay. Mutagenicity was detected in TA100 strain with metabolic activation. Genotoxic effects were not observed in HepG2 by comet assay. However, a decrease in the nuclear index division in the 2.0 mg·mL-1 concentration and an increase of nucleoplasmic bridges in the 1.5 mg·mL-1 concentration were detected by CBMN-cyt assay indicating cytotoxic and mutagenic effects. In SRB assay, trimeroside showed weak antiproliferative activity against the cell lines.

Algicidal properties of extracts from Cinnamomum camphora fresh leaves and their main compounds.

Plant allelochemicals are considered as the source of effective, economic and friendly-environmental algaecides. To uncover the anti-algal activities of Cinnamomum camphora fresh leaves and their main algicidal agents, we investigated the inhibitory effects of water and methanol extracts from C. camphora fresh leaves on Microcystis aeruginosa and Chlamydomonas reinhardtii cell growth, analyzed the composition of the water and methanol extracts, and determined the main compounds in extracts on the growth of the two algae and their anti-algal mechanism from photosynthetic abilities. Water and methanol extracts from C. camphora fresh leaves can inhibit M. aeruginosa and C. reinhardtii cell growth, and methanol extracts showed stronger inhibitory effects, due to their more compounds and higher molar concentration. There were 23 compounds in the water extracts, mainly including terpenoids, esters, alcohols, and ketones. Compared to the water extracts, 9 new compounds were detected in the methanol extracts, and the molar concentration of total compounds in methanol extracts increased by 1.3 folds. Camphor, α-terpineol and linalool were 3 main compounds in the water and methanol extracts. Their mixture (1: 3: 6) and individual compound showed remarkable inhibition on M. aeruginosa and C. reinhardtii cell growth. The degradation of photosynthetic pigments and the reduction of maximum quantum yield of photosystem II (PSII) photochemistry, coefficient of photochemical quenching as well as apparent electron transport rate in C. reinhardtii cells aggravated gradually with increasing the concentration of the mixture and individual compound, while the non-photochemical dissipation of absorbed light energy increased gradually, which led to the decline of photosynthetic abilities. This indicated that camphor, α-terpineol and linalool were 3 main algicidal agents in C. camphora fresh leaf extracts, and they inhibited algal growth by inducing photosynthetic pigment degradation and declining PSII efficiency. Therefore, C. camphora fresh leaf extracts and their main components have potential utilization values as algaecides.

Antibacterial Activity of Emulsified Pomelo (Citrus grandis Osbeck) Peel Oil and Water-Soluble Chitosan on Staphylococcus aureus and Escherichia coli.

This study utilized pomelo steam distillation to isolate pomelo peel essential oil. The constituents were then analyzed through gas chromatography-mass spectrometry (GC-MS), and the antibacterial activity of the essential oil emulsions at different homogenizer speed conditions and concentrations of water-soluble chitosan (degree of acetylation, DA = 54.8%) against S. aureus and E. coli was examined. Analysis of the essential oil composition identified a total of 33 compounds with the main constituent, limonene accounting for 87.5% (940.07 mg/g) of the total. The pomelo peel oil was emulsified through homogenization at 24,000 rpm, resulting in a minimal inhibitory concentration (MIC) for E. coli that was 1.9 times lower than that of the essential oil without homogenization. In addition, a mixture of 0.4% essential oil emulsion and 0.03% water-soluble chitosan had the strongest synergetic antibacterial effect on S. aureus and E. coli at pH 7.4. In comparison with chitosan alone, the MIC value of this mixture was significantly 2.4 and 2.5 times lower. Hence, this study suggests using a mixture of emulsified pomelo peel oil and water-soluble chitosan to develop a novel natural food preservative, and that the processability of food, as well as the economic value of the byproducts of the Taiwan Matou pomelo and chitosan, could be increased.

Quality assessment of saffron (Crocus sativus L.) extracts via UHPLC-DAD-MS analysis and detection of adulteration using gardenia fruit extract (Gardenia jasminoides Ellis).

A new UHPLC-DAD-MS method based on a Core-Shell particles column was developed to realize the rapid separation of saffron stigma metabolites (Crocus sativus L.). A single separation of 35 compounds included cis and trans-crocetin esters (crocins), cis-crocetin, trans-crocetin, kaempferol derivatives, safranal, and picrocrocin from pure saffron stigmas. This method permitted the detection of 11 picrocrocin derivatives as the typical group of compounds from saffron as well as the detection of gardenia-specific compounds as typical adulterant markers. The metabolite concentration in a Standardized Saffron Extract (SSE) was determined using the method described herein and by comparison to the ISO3632 conventional method. The safranal content was 5-150 times lower than the value of 2% that was expected via ISO3632 analyses. Using the same Core-Shell separation, geniposide detection appeared to be a relevant approach for detecting the adulteration of saffron by using gardenia.

Protective effects of saffron and its active components against oxidative stress and apoptosis in endothelial cells.

In this study, we investigated the role of mitogen-activated protein kinase (MAPK) signaling pathways in mediation of the protective effects of saffron extract, saffron essential oil, safranal and crocin on bovine aortic endothelial cells against oxidative injury. The viability of cells in response to H2O2-induced toxicity (0.4, 2 and 10 mM) was measured using resazurin assay in the presence or absence of saffron extract (2-40 µg/ml), saffron oil (2-40 µg/ml), safranal (2-40 µM) and crocin (2-40 µM). Dichlorodihydrofluorescin diacetate was used as an indicator for the amount of reactive oxygen species (ROS) in cells at the same concentrations of samples as the former test. In addition, propidium iodide staining of the fragmented DNA was performed to measure the level of apoptotic cells by the application of 2-10 µM of crocin and safranal. Finally, the proteins involved in apoptosis were detected using western blotting at the concentration of 0, 2, 10 µM for crocin and safranal. The results indicated that all tested moieties improved viability and reduced ROS production in H2O2-treated cells (p < 0.001 compared to H2O2). In addition, a significant decrease in apoptosis (3-35%) was observed in the cells that were treated with crocin and safranal. The observed protective effects of crocin and safranal were associated with the activation of SAPK/JNK and inhibition of ERK ½ that are related to MAPK pathways. The antioxidant and anti-apoptotic activities of saffron and its ingredients in endothelial cells are mediated via MAPK signaling pathways and might be of therapeutic potential for endothelial dysfunctionalities.

Antimalarial polyoxygenated cyclohexene derivatives from the roots of Uvaria cherrevensis.

Three new polyoxygenated cyclohexene derivatives named cherrevenisyls A and B (1 and 2), and ellipeiopsol E (3), along with fifteen known compounds, were isolated from the roots of Uvaria cherrevensis. Their structures were determined by spectroscopic methods including 2D NMR techniques and mass spectrometry. The absolute configurations of 1 and 2 were assigned. Compounds 1, 2 and 5 showed antimalarial activity against Plasmodium falciparum with IC50 ranging from 3.34-7.34µg/mL. Compounds 5-18 exhibited cytotoxicity against three cancer cell lines (KB, MCF-7 and NCI-H187) with IC50 values in ranging from 1.26-49.03µg/mL.

Saffron and its derivatives, crocin, crocetin and safranal: a patent review.

INTRODUCTION: Saffron and its main components have traditionally been used as pharmaceutical agents. Current experimental research projects have also exhibited their applications in a wide spectrum of disorder treatments. AREAS COVERED: This review covers the demonstrated findings and patents on therapeutic/pharmaceutical properties of saffron and related derivatives, since 2000 to bold their outstanding merit on human health. An extensive literature review was performed in USP Patent, Patentscope, Espacenet and Google Patent in the field of CNS, cardiovascular, urogenital, dermatological and inflammatory disorders. EXPERT OPINION: The growing body of patents showed the value of saffron and the respective crucial components alone or in combination with the other raw materials, herbal extracts, to apply in various therapeutic/pharmaceutical areas. They could be engaged as an adjuvant treatment in phototherapy, cancer, cardiovascular and neurodegenerative diseases and hypoxia-induced dangerous conditions. However, the application of these components in the clinic has been limited to very few drugs yet. This might be due poor clinical trials data. According the human trend toward the use of plant-derived compounds instead of medicines derived from chemical substances, special attention must be focused to link the worth of saffron, herbal medicine of third millennium, from basic sciences to patients' bed.

Antioxidant activity of rosemary essential oil fractions obtained by molecular distillation and their effect on oxidative stability of sunflower oil.

The objective of this study was to evaluate the antioxidant activity of rosemary essential oil fractions obtained by molecular distillation (MD) and investigate their effect on the oxidative stability of sunflower oil. MD fractions were prepared in a series of low-pressure stages where rosemary essential oil was the first feed. Subsequently, a distillate (D1) and residue (R1) were obtained and the residue fraction from the previous stage used as the feed for the next. The residue fractions had the largest capacity to capture free radicals, and the lowest peroxide values, conjugated dienes and conjugated trienes. The antioxidant activity of the fractions was due to oxygenated monoterpenes, specifically α-terpineol and cis-sabinene hydrate. Oxidative stability results showed the residues (R1 and R4) and butylated hydroxytoluene had greater antioxidant activity than either the distillate fractions or original rosemary essential oil. The residue fractions obtained by short path MD of rosemary essential oil could be used as a natural antioxidants by the food industry.

Strong antimicrobial activity of xanthohumol and other derivatives from hops (Humulus lupulus L.) on gut anaerobic bacteria.

Anaerobic bacteria, such as Bacteroides fragilis or Clostridium perfringens, are part of indigenous human flora. However, Clostridium difficile represents also an important causative agent of nosocomial infectious antibiotic-associated diarrhoea. Treatment of C. difficile infection is problematic, making it imperative to search for new compounds with antimicrobial properties. Hops (Humulus lupulus L.) contain substances with antibacterial properties. We tested antimicrobial activity of purified hop constituents humulone, lupulone and xanthohumol against anaerobic bacteria. The antimicrobial activity was established against B. fragilis, C. perfringens and C. difficile strains according to standard testing protocols (CLSI, EUCAST), and the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBC) were calculated. All C. difficile strains were toxigenic and clinically relevant, as they were isolated from patients with diarrhoea. Strongest antimicrobial effects were observed with xanthohumol showing MIC and MBC values of 15-107 µg/mL, which are close to those of conventional antibiotics in the strains of bacteria with increased resistance. Slightly higher MIC and MBC values were obtained with lupulone followed by higher values of humulone. Our study, thus, shows a potential of purified hop compounds, especially xanthohumol, as alternatives for treatment of infections caused by select anaerobic bacteria, namely nosocomial diarrhoea caused by resistant strains.

Rapid prediction and identification of lipase inhibitors in volatile oil from Pinus massoniana L. needles.

A facile method based on gas chromatography-mass spectrometry (GC-MS) and molecular docking was established to analyze, identify, and predict lipase inhibitors in volatile oil from Pinus massoniana L. needles (PMLN). The volatile oil, with an IC50 value of 15.25 ± 0.06 µg/mL, exhibited potential inhibitory activity against lipase in vitro. In total, 33 compounds were identified from the volatile oil through GC-MS analysis. The major compounds in the volatile oil were ß-pinene (39.24%), α-pinene (14.68%), germacrene D (9.08%), caryophyllene (6.94%), α-terpineol (5.39%), ß-phellandrene (4.82%), and D-limonene (3.93%). The identified compounds were individually docked with lipase as the target through molecular docking. Among the compounds, longifolene characterized by preferable binding energy and the good inhibition constant exhibited potential lipase inhibitory activity. The IC50 value of longifolene was 25.10 ± 0.49 µM, indicating that this compound is the active ingredient responsible for the lipase inhibitory activity of PMLN volatile oil.

Identification and biological activity of the volatile compounds of Glycyrrhiza triphylla Fisch. & C.A.Mey.

Chemical composition and biological (antimicrobial, antioxidant and cytotoxic) activities of essential oils (EO) obtained from the aerial parts of Glycyrrhiza triphylla Fisch. & C.A.Mey (G. triphylla) were evaluated in the present study. The EO was isolated and analyzed using gas chromatography-mass spectrometry (GC-MS). Fifty-five compounds representing 99.3% of the total oil composition were identified. Major components of the oil were ß-caryophyllene (25.4%), limonene (16.7%), ß-myrcene (16.0%) and α-humulene (4.4%). The oil composition was dominated by the presence of sesquiterpene hydrocarbons comprising 43.6% of the total oil. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the oil were determined against eight bacterial strains and one fungus. The EO showed a good antibacterial activity against both Gram-positive and Gram-negative bacteria. The most susceptible strain was Micrococcus luteus (MIC = 2.7 µg/mL, MBC = 43.6 µg/mL). The antioxidant potential of the EO was examined using DPPH and ß-carotene/linoleic acid (BCB) assays. The oil was considerably active in the DPPH assay (IC50 = 100.40 ± 0.03 µg/mL). Moreover, in vitro cytotoxic activity was assessed against six cancer cell lines using MTT assay. The EO showed no significant cytotoxic activity. In light of the present findings, G. triphylla oil may deserves to be further investigated for its potential therapeutic effects and also as a natural preservative in food industry.