Evaluation of curcuminoids, physiological adaptation, and growth of Curcuma longa under water deficit and controlled temperature.

Turmeric (Curcuma longa L.; Zingiberaceae), an economically important crop and a major spice in Indian cuisine, produces natural yellow color (curcumin) as well as curcuminoids which are widely utilized in traditional and modern medicinal practices. During the turmeric culture, the fluctuations of precipitation and seasonal changes in the whole life cycle play a major role, especially water shortage and decreasing temperature (in winter season), leading to rhizome dormancy under extreme weather conditions. The objective of this investigation was to understand how the water deficit and reduced temperature affect turmeric growth, physiological adaptation, quantity, and quality of turmeric rhizomes. Four-month-old turmeric plants were subjected to four treatments, namely normal temperature and well-watered (RT-WW), or water-deficit (RT-WD) conditions in the greenhouse, 25 °C controlled temperature and well-watered (CT-WW), or water-deficit (CT-WD) conditions in glasshouse. Leaf osmotic potential considerably declined in 30 days CT-WD treatment, leading to chlorophyll degradation by 26.04%, diminution of maximum quantum yield of PSII (Fv/Fm) by 23.50%, photon yield of PSII (ΦPSII) by 29.01%, and reduction of net photosynthetic rate (Pn) by 89.39% over CT-WW (control). After 30 days water withholding, fresh- and dry-weights of rhizomes of turmeric plants grown under CT-WD declined by 30-50% when compared with RT-WW conditions. Subsequently, curcuminoid content was reduced by 40% over RT-WW plants (control), whereas transcriptional expression levels of curcuminoids-related genes (CURS1, CURS2, CURS3, and DCS) were upregulated in CT-WD conditions. In summary, the water withholding and controlled temperature (constant at 25 °C day/night) negatively affected turmeric plants as abiotic stresses tend to limit overall plant growth performances and curcuminoid yield.

Anti-Herbivore Activity of Oregonin, a Diarylheptanoid Found in Leaves and Bark of Red Alder (Alnus rubra).

Plants synthesize a wide range of bioactive secondary metabolites to defend against pests and pathogens. Red alder (Alnus rubra) bark, root, and leaf extract have a long history of use in traditional medicine and hygiene. Diarylheptanoids, especially oregonin ((5S)-1,7-bis(3,4-dihydroxyphenyl)-5-(ß-D-xylopyranosyloxy)-heptan-3-one), have been identified as major bioactive constituents. Diarylheptanoids have become a focus of research following reports of their antioxidant, antifungal, and anti-cancer activities. Recent data suggest that high oregonin concentration is associated with resistance of red alder leaves to western tent caterpillar (Malacosoma californicum) defoliation. Here we test effects of this compound directly on leaf-eating insects. Purified oregonin was examined in insect choice and toxicity tests using lepidopteran caterpillars. The compound exhibited significant anti-feedant activity against cabbage looper (Trichoplusia ni), white-marked tussock moth (Orgyia leucostigma), fall webworm (Hyphantria cunea), and M. californicum at concentrations corresponding to oregonin content of the most resistant alder clones in previous experiments. Toxicity tests were carried out with cabbage looper larvae only, but no contact or ingested toxicity was detected. Our results suggest that oregonin at levels found in red alder leaves early in the growing season may contribute to protecting red alder from leaf-eating insects.

The role of curcumin/curcuminoids during gastric cancer chemotherapy: A systematic review of non-clinical study.

AIMS: Chemotherapy is an effective therapeutic modality which is commonly used for battling various cancers. However, several side effects induced by chemotherapeutic drugs would limit their clinical use. The present systematic review aims to evaluate the role of curcumin/curcuminoids co-administration during gastric cancer chemotherapy. METHODS: This systematic review was done according to PRISMA guidelines and a full systematic search in the electronic databases up to May 2020 using search terms in the titles and abstracts for the identification of relevant literature. 279 articles were found in electronic databases and 175 articles screened by title and abstract. Finally, 13 articles were included in this systematic review according to our inclusion and exclusion criteria. KEY FINDINGS: The findings indicated that gastric cancer chemotherapy induces cytotoxicity effects in various ways including a decrease of cell viability, colony formation, metastasis, tumor growth, and weight, as well as elevation of apoptosis pathway, oxidative stress pathway compared to the control group. Co-administration of curcumin/curcuminoids with chemotherapy synergistically increased the effects of anti-cancer chemotherapy compared to the group solo treated with chemotherapeutic agents. Also, in chemoresistance gastric cancer cells, co-administration of curcumin reduced chemoresistance mainly through the reduction of NF-κB activation and elevation of apoptosis. SIGNIFICANCE: According to the findings, the use of curcumin/curcuminoids during gastric cancer chemotherapy has chemosensitizing effects, and also it can reduce chemoresistance in gastric cancer.

A novel predict-verify strategy for targeted metabolomics: Comparison of the curcuminoids between crude and fermented turmeric.

Curcuminoids are the major bioactive constituents of turmeric, the application of which are limited by the poor bioavailability. In this study, turmeric was fermented by the Monascus purpureus and Eurotium cristatum fungi to enhance its bioavailability. To explore the variations in the curcuminoids contents in fermented turmeric, a targeted predict-verify strategy was established. For targeted analysis of curcuminoids, a compound library containing all possible curcuminoids based on their structural skeleton was predicted and built for targeted scanning. Then, the MS data were automatically matched with the predicted library to verify the corresponding curcuminoids. As a result, 115 curcuminoids (48 novel compounds and 14 compounds reported in turmeric for the first time) were fully characterized in crude and fermented turmeric. Among these curcuminoids, 31 were newly generated in fermented turmeric. The established predict-verify strategy allows for an efficient and automatic metabolomic analysis to screen for curcuminoids with potentially better bioavailability.

Chemical markers' knockout coupled with UHPLC-HRMS-based metabolomics reveals anti-cancer integration effects of the curcuminoids of turmeric (Curcuma longa L.) on lung cancer cell line.

Turmeric (Curcuma longa L, Zingiberaceae) rhizomes exhibit versatile biological activities including the significant anti-cancer property. As an herbal medicine, the therapeutic effects of turmeric may be expressed by multi-components which have complicated integration effects on multi-targets. Therefore, having previously found three A549 cell-binding curcuminoids (curcumin, Cur; demethoxycurcumin, DMcur; bisdemethoxycurcumin, BMcur) from turmeric, studies were undertaken in this paper to determine the anti-cancer mechanism and integration effects of these curcuminoids by using chemical markers' knockout and UHPLC-LTQ Orbitrap MS-based metabolomics. Four curcuminoid-containing fractions including a mixture of 3 cell-binding curcuminoids (CE), and three individual curcuminoids with natural proportion in turmeric were prepared by chemical markers' knockout method. CE, Cur, DMcur and BMcur fractions showed significant anti-cancer activity on A549 cells. The activities of CE, Cur and BMcur fractions were comparative with the turmeric crude extract (TcE). In the metabolomics study, CE and three individual curcuminoid fractions changed the expression of 25 metabolites in A549 cells, which were involved in glycerophospholipid catabolism, sphingolipid metabolism and fatty acid metabolism, etc. Among them, glycerophospholipid catabolism was disordered greatly in CE group, while sphingolipid metabolism was suggested to be closely related to DMcur and BMcur activity. Furthermore, the metabolomics data showed that three curcuminoids existed synergistic and antagonistic actions and the use of multi-curcuminoids is more powerful than use of single curcuminoid on the metabolic alterations of A549 cells.

Diarylheptanoids from Alnus viridis ssp. viridis and Alnus glutinosa: Modulation of Quorum Sensing Activity in Pseudomonas aeruginosa.

Diarylheptanoids from the barks of Alnus viridis ssp. viridis (green alder) and Alnus glutinosa (black alder) were explored for anti-quorum sensing activity. Chemicals with anti-quorum sensing activity have recently been examined for antimicrobial applications. The anti-quorum sensing activity of the selected diarylheptanoids was determined using two biosensors, namely Pseudomonas aeruginosa PAO1 and Chromobacterium violaceum CV026. Although all of the investigated compounds negatively influenced the motility of P. aeruginosa PAO1, four were able to inhibit biofilm formation of this human opportunistic pathogen for 40-70 %. Three of the diarylheptanoids (3, 4, and 5) negatively influenced the biosynthesis of pyocyanin, which is under the control of quorum sensing. Platyphyllenone (7) and hirsutenone (5) were able to inhibit the biosynthesis of violacein in C. violaceum CV026, with 5 being able to inhibit the synthesis of both biopigments. Only one of the tested diarylheptanoids (1) was shown to significantly decrease the production of acyl homoserine lactones (AHL) in P. aeruginosa PAO1, more specifically, production of the long chain N-(3-oxododecanoyl)-l-HSL. On the other side, four diarylheptanoids (2-5) significantly reduced the synthesis of 2-alkyl-4-quinolones, part of the P. aeruginosa quinolone-mediated signaling system. To properly assess therapeutic potential of these compounds, their in vitro antiproliferative effect on normal human lung fibroblasts was determined, with doses affecting cell proliferation between 10 and 100 µg/mL. This study confirms that the barks of green and black alders are rich source of phytochemicals with a wide range of biological activities that could further be exploited as natural agents against bacterial contaminations and infections.

Effects of Vehicles and Enhancers on the Skin Permeation of Phytoestrogenic Diarylheptanoids from Curcuma comosa.

Curcuma comosa (C. comosa) is widely used in traditional medicine as a dietary supplement for health promotion in postmenopausal women in Thailand. It contains several diarylheptanoids, which are considered to be a novel class of phytoestrogens. However, the diarylheptanoids isolated from the plant rhizome are shown to have low oral bioavailability and faster elimination characteristics. The aim of this study was to investigate the permeation behavior of the active compounds of diarylheptanoids. The effects of binary vehicle systems and permeation enhancers on diarylheptanoids permeation and accumulation within the skin were studied using side-by-side diffusion cells through the porcine ear skin. Among the tested binary vehicle systems, the ethanol/water vehicle appeared to be the most effective system for diarylheptanoids permeation with the highest flux and shortest lag time. The presence of transcutol in the vehicle system significantly increased diarylheptanoid's permeation and accumulation within the skin in a concentration-dependent manner. Although the presence of terpenes in formulation decreased the flux of diarylheptanoids, it raised the amount of diarylheptanoids retained within the skin substantially. Based on the feasibility of diarylheptanoid permeation, C. comosa extract should be further developed into an effective transdermal product for health benefits and hormone replacement therapy.

Diarylheptanoid-myricanone isolated from ethanolic extract of Myrica cerifera shows anticancer effects on HeLa and PC3 cell lines: signalling pathway and drug-DNA interaction.

OBJECTIVE: To test if myricanone (C21H24O5), a cyclic diarylheptanoid, has anticancer effects on two different cancer cell lines HeLa and PC3. The present study was conducted with a note on the drug-DNA interaction and apoptotic signalling pathway. METHODS: Several studies like cytotoxicity, nuclear damage, annexin-V-fluorescein isothiocyanate (FITC)/propidium iodide (PI)-labelled apoptotic assay and cell cycle arrest, immunoblot and reverse transcriptase-polymerase chain reaction (RT-PCR) were used following standard protocols. Circular dichroism (CD) spectroscopy was also done to evaluate whether myricanone effectively interacted with DNA to bring about conformational changes that could strongly inhibit the cancer cell proliferation. RESULTS: Myricanone showed a greater cytotoxic effect on PC3 cells than on HeLa cells. Myricanone promoted G0/G1 arrest in HeLa cells and S phase arrest in PC3 cells. Nuclear condensation and annexin V-FITC/PI studies revealed that myricanone promoted apoptotic cell death. CD spectroscopic data indicated that myricanone had an interaction with calf thymus DNA that changed DNA structural conformation. RT-PCR and immunoblot studies revealed that myricanone activated the apoptotic signalling cascades through down-regulation of transcription factors like nuclear factor-κB (NF-κB) (p65), and signal transducers and activators of transcription 3 (STAT3); cell cycle regulators like cyclin D1, and survivin and other signal proteins like Bcl-2 and up-regulation of Bax, caspase-9 and caspase-3. CONCLUSION: Myricanone induced apoptosis in both types of cancer cells by triggering caspase activation, and suppression of cell proliferation by down-regulation of NF-κB and STAT3 signalling cascades, which makes it a suitable candidate for possible use in the formulation of therapeutic agent for combating cancer.

A diarylheptanoid phytoestrogen from Curcuma comosa, 1,7-diphenyl-4,6-heptadien-3-ol, accelerates human osteoblast proliferation and differentiation.

Curcuma comosa Roxb. is ginger-family plant used to relieve menopausal symptoms. Previous work showed that C. comosa extracts protect mice from ovariectomy-induced osteopenia with minimal effects on reproductive organs, and identified the diarylheptanoid (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (DPHD) as the major active component of C. comosa rhizomes. At 1-10µM, DPHD increased differentiation in transformed mouse osteoblasts, but the effect of DPHD on normal bone cells was unknown. We examined the concentration dependency and mechanism of action of DPHD relative to 17ß-estradiol in nontransformed human osteoblasts (h-OB). The h-OB were 10-100 fold more sensitive to DPHD than transformed osteoblasts: DPHD increased h-OB proliferation at 10nM and, at 100nM, activated MAP kinase signaling within 30 min. In long-term differentiation assays, responses of h-OB to DPHD were significant at 10nM, and optimal response in most cases was at 100 nM. At 7-21 days, DPHD accelerated osteoblast differentiation, indicated by alkaline phosphatase activity and osteoblast-specific mRNA production. Effects of DPHD were eliminated by the estrogen receptor antagonist ICI182780. During differentiation, DPHD promoted early expression of osteoblast transcription factors, RUNX2 and osterix. Subsequently, DPHD accelerated production of bone structural genes, including COL1A1 and osteocalcin comparably to 17ß-estradiol. In h-OB, DPHD increased the osteoprotegerin to RANKL ratio and supported mineralization more efficiently than 10nM 17ß-estradiol. We conclude that DPHD promotes human osteoblast function in vitro effectively at nanomolar concentrations, making it a promising compound to protect bone in menopausal women.

The natural estrogenic compound diarylheptanoid (D3): in vitro mechanisms of action and in vivo uterine responses via estrogen receptor α.

BACKGROUND: Diarylheptanoid (D3) isolated from the medicinal plant, Curcuma comosa, has estrogenic activity. OBJECTIVE: We aimed to elucidate the mechanism(s) of D3 action and compare it with that of 17ß-estradiol (E2) using both in vitro and in vivo uterine models. METHODS: We used human uterine (Ishikawa) cells to determine the estrogenic action of D3 on the activation and nuclear translocation of estrogen receptor α (ERα). In addition, we further characterized the uterine response to D3 treatment in vivo. RESULTS: D3 activated an estrogen responsive element (ERE) luciferase reporter through ERα, and molecular modeling suggested that D3 could be accommodated in the ERα binding pocket. Using modified ERα to assay ligand-dependent nuclear translocation, we observed D3-dependent ERα interaction and translocation. In mouse uteri, early- and late-phase estrogen-regulated gene responses were increased in D3-treated ovariectomized wild-type animals, in a manner similar to that of E2; no response was seen in ERα knockout animals. We observed a divergence in estrogen responses after D3 treatment: D3 induced robust DNA synthesis in uterine epithelial cells, linked to an increase in cell-cycle-related genes; however, no increase in uterine weight was observed 24 hr after treatment. D3 also affected uterine progesterone receptor expression patterns similar to E2. When D3 and E2 were administered together, we observed no additive or antagonistic effects of D3 on E2. Our findings suggest that D3 is a weak estrogenic agonist compound. CONCLUSION: D3 is a weakly acting phytoestrogen that mimics the mitogenic responses produced by E2 in an ERα-dependent manner, but it is unable to increase uterine weight or enhance or antagonize the effects of estrogen.

[Antioxidative and cytotoxic properties of diarylheptanoids isolated from Zingiber officinale].

OBJECTIVE: To investigate the antioxidant and cytotoxic properties of five diarylheptanoids (1-5) isolated from the rhizomes of Zingiber officinale. METHOD: Various models such as scavenging superoxide anions and 1,1-diphenyl-2- picrylhydrazyl (DPPH) radicals, inhibiting lipid peroxidation, as well as protecting of rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H2O2) were employed to assay the antioxidative effects of the diarylheptanoids. The cytotoxicities of compounds 1-5 were measured with MTT assays. RESULT: The test compounds (1-5) showed promising DPPH inhibitory activities, and compound 5 exhibited the strongest DPPH scavenging activity with an IC50 value of (22.6+/-2.4) micromol x L(-1). Compounds 1, 3 and 4 showed potential anti-peroxidative effects with inhibitory rates of (66.3+/-15.4)%, (68.7+/-15.8)% and (72.2+/-10.6)%, respectively, at 100 microg x mL(-1). It could be observed that compounds 1, 3 and 4 demonstrated significant neuroprotective activities in a dose-dependent manner. Moreover, compound 3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR) with IC50 values of (34.9+/-0.6), (50.6+/-23.5) micromol x L(-1), respectively. CONCLUSION: In vitro results demonstrated that five diarylheptanoids (1-5) isolated from the roots of Z. officinale were capable of scavenging radicals, inhibiting lipid peroxidation and protecting PC12 cells against the insult by H2O2. Additionally, compound 3 could inhibit the growth of K562 and K562/ADR cells.

NMR-based metabolic profiling of Anigozanthos floral nectar.

Nuclear magnetic resonance spectroscopic methods have been used to characterize the chemical composition of floral nectar of Anigozanthos species with a minimum of sample preparation and without derivatization. The nectar of this passerine-pollinated plant is largely dominated by glucose and fructose, while sucrose occurs only at a minor level. Tyrosine, several additional amino acids, and a variety of carboxylic acids were identified and their concentrations estimated. A linear diarylheptanoid was detected as a trace component, marking the first time this type of secondary product in Hemodoraceae has been found.