Calycopterin

Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing.[Pubmed:32872158]

Antibiotics (Basel). 2020 Aug 28;9(9). pii: antibiotics9090550.

Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen Mycobacterium tuberculosis and produces 1.5 million deaths every year. The incidence of tuberculosis has decreased during the last decade, but the emergence of MultiDrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) strains of M. tuberculosis is generating a new health alarm. Therefore, the development of novel therapies based on repurposed drugs against MDR-TB and XDR-TB have recently gathered significant interest. Recent evidence, focused on the role of host molecular factors on M. tuberculosis intracellular survival, allowed the identification of new host-directed therapies. Interestingly, the mechanism of action of many of these therapies is linked to the activation of autophagy (e.g., nitazoxanide or imatinib) and other well-known molecular pathways such as apoptosis (e.g., cisplatin and Calycopterin). Here, we review the latest developments on the identification of novel antimicrobials against tuberculosis (including avermectins, eltrombopag, or fluvastatin), new host-targeting therapies (e.g., corticoids, fosfamatinib or carfilzomib) and the host molecular factors required for a mycobacterial infection that could be promising targets for future drug development.

Flavonoid calycopterin triggers apoptosis in triple-negative and ER-positive human breast cancer cells through activating different patterns of gene expression.[Pubmed:32617603]

Naunyn Schmiedebergs Arch Pharmacol. 2020 Nov;393(11):2145-2156.

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.

Calycopterin, a major flavonoid from Marcetia latifolia, modulates virulence-related traits in Pseudomonas aeruginosa.[Pubmed:32173496]

Microb Pathog. 2020 Jul;144:104142.

Although bacterial resistance is a worldwide growing concern, the development of bacteriostatic and bactericidal drugs has been decreasing in the last decade. Compounds that modulate the microorganism virulence, without killing it, have been considered promising alternatives to combat bacterial infections. However, most signaling pathways that regulate virulence are complex and not completely understood. The rich chemical diversity of natural products offers a good starting point to identify key compounds that shed some light on this matter. Therefore, we investigated the role of Marcetia latifolia ethanolic extract, as well as its major constituent, Calycopterin (5,4'-dihydroxy-3,6,7,8-tetramethoxylflavone), in the regulation of virulence-related phenotypes of Pseudomonas aeruginosa. Our results show that Calycopterin inhibits pyocyanin production (EC50 = 32 muM), reduces motility and increases biofilm formation in a dose-dependent manner. Such biological profile suggests that Calycopterin modulates targets that may act upstream the quorum sensing regulators and points to its utility as a chemical probe to further investigate P. aeruginosa transition from planktonic to sessile lifestyle.

Medicinal Properties and Active Constituents of Dracocephalum kotschyi and Its Significance in Iran: A Systematic Review.[Pubmed:31198431]

Evid Based Complement Alternat Med. 2019 May 6;2019:9465309.

Objectives: Dracocephalum has over 60 species and is found mainly in the temperate regions of Asia and Europe. One of these species, i.e., Dracocephalum kotschyi Boiss, is known to have a number of medicinal properties and active ingredients in many parts of the world. Despite being an endemic wild-flowering plant of great importance, the plant is currently considered endangered in Iran. Besides, there is paucity of information on the significance of the medicinal properties and active constituents of D. kotschyi among the Iranian people. On that account a systematic review of studies reporting on the medicinal properties and active ingredients and its significance to human and animal health was conducted and the existing knowledge gaps were identified. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in the search for published articles on medicinal properties and active ingredients of D. kotschyi and its significance on humans and animals in Iran. The search was confined to scientific articles from repositories of popular data bases and search engines among them PubMed, Web of Science, Google Scholar, Science Direct, SpringerLink, and Scopus. The search narrowed down on scientific journals, books, and book chapters focusing on the medicinal properties of D. kotschyi in Iran for the period between 1970 and 2018. Results: A total of 1158 scientific articles were sourced from the various databases, out of which 38 met the search criteria and qualified for this review. The studies were conducted in only 9 of the 31 provinces of Iran, with a large proportion in Isfahan province, central Iran. The studies showed that all plant parts (roots, aerial parts, flowers, and leaves) had active constituents. Essential oils and aerial plant parts were the main components studied. Nevertheless, the most frequently reported constituents were xanthomicrol, limonene, luteolin, geranial, apigenin, and Calycopterin. A number of medicinal properties were reported among them antioxidant, antibacterial, anticancerous, antinociceptive, antihyperlipidemic, antispasmodic, cytotoxic, and immunomodulatory effects. The plant was also reported to be a remedy for inflammatory pain, headaches, congestion, liver disorders, ulcer, fever, renal pain, dyspepsia, stomach ache, abdominal pain, joints pains, muscle spasm, congestion, bloating, and wound healing effects, among others. Conclusion: This review has shown that D. kotschyi is an important medicinal plant with a large number of active constituents and great potential to safeguard human and animal health in Iran. However, over utilization of the D. kotschyi plant is already endangering its existence. Nevertheless, more studies need be conducted across the country.

Phytochemical constituents and biological activities of Cleome iberica DC.[Pubmed:27731648]

Nat Prod Res. 2017 Jun;31(11):1329-1332.

Phytochemical investigation of Cleome iberica DC. aerial parts led to the isolation and characterisation of six triterpenoid including glutinol (1), lupeol (2), beta-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 muM was the strongest. The extract showed moderate antioxidant capacity in DPPH assay method (IC50 = 100.2 mug/mL) and total phenolics and total flavonoids contents of the dried extract were also determined as 39.6 and 90.7 mg/g, respectively.

Pharmacokinetics of calycopterin and xanthmicrol, two polymethoxylated hydroxyflavones with anti-angiogenic activities from Dracocephalum kotschyi Bioss.[Pubmed:27716340]

Daru. 2016 Oct 4;24(1):22.

BACKGROUND: Recently flavonoids have attracted the attention of researchers in the fight against cancer. Calycopterin and xanthomicrol, are two polymethoxylated flavonoids found in the aerial parts of Dracocephalum kotschyi Bioss.. We have recently shown that these compounds possess antiangiogenic activity and may be of value as potential anticancer agents. In order to demonstrate putative in vivo antitumor effect of these compounds we needed preliminary information on both pharmacokinetics and toxicological properties of these two agents. METHOD: A new online SPE HPLC method for measurement of Calycopterin and xanthomicrol in rat plasma was developed. Pharmacokinetic parameters of Calycopterin and xanthomicrol, after i.v. administration in rats, were determined. RESULTS: The plasma half-life for both agents was around 4 h, however, the volume of distribution of Calycopterin appeared to be about 8 times greater than xanthomicrol. This was probably due the greater hydrophobicity of the former which had other consequences such as much smaller maximum plasma concentration of Calycopterin compared to its less methoxylated congener. Preliminary toxicological study of xanthomicrol failed to show any behavioral, histological and biochemical adverse effects after repeated administrations of high doses. Pharmacokinetics of xanthomicrol in rats.

Anticancer effect of calycopterin via PI3K/Akt and MAPK signaling pathways, ROS-mediated pathway and mitochondrial dysfunction in hepatoblastoma cancer (HepG2) cells.[Pubmed:25060910]

Mol Cell Biochem. 2014 Dec;397(1-2):17-31.

Calycopterin is a flavonoid compound isolated from Dracocephalum kotschyi that has multiple medical uses, as an antispasmodic, analgesic, anti-hyperlipidemic, and immunomodulatory agents. However, its biological activity and the mechanism of action are poorly investigated. Herein, we investigated the apoptotic effect of Calycopterin against the human hepatoblastoma cancer cell (HepG2) line. We discovered that Calycopterin-treated HepG2 cells were killed off by apoptosis in a dose-dependent manner within 24 h, and was characterized by the appearance of nuclear shrinkage, cleavage of poly (ADP-ribose) polymerase and DNA fragmentation. Calycopterin treatment also affected HepG2 cell viability: (a) by inhibiting cell cycle progression at the G2/M transition leading to growth arrest and apoptosis; (b) by decreasing the expression of mitotic kinase cdc2, mitotic phosphatase cdc25c, mitotic cyclin B1, and apoptotic factors pro-caspases-3 and -9; and (c) increasing the levels of mitochondrial apoptotic-related proteins, intracellular levels of reactive oxygen species, and nitric oxide. We further examined the phosphorylation of extracellular signal-related kinase (ERK 1/2), c-Jun N-terminal kinase, and p-38 mitogen-activated protein kinases (MAPKs) and found they all were significantly increased in HepG2 cells treated with Calycopterin. Interestingly, we discovered that treated cells had significantly lower Akt phosphorylation. This mode of action for Calycopterin in our study provides strong support that inhibition of PI3K/Akt and activation of MAPKs are pivotal in G2/M cell cycle arrest and apoptosis of human hepatocarcinoma cells mediated by Calycopterin.

Antiangiogenic activity of xanthomicrol and calycopterin, two polymethoxylated hydroxyflavones in both in vitro and ex vivo models.[Pubmed:24895220]

Phytother Res. 2014 Nov;28(11):1661-70.

Our previous studies had shown xanthomicrol and Calycopterin, two plant-derived flavonoids, to have selective antiproliferative activity against some malignant cell lines. The present study is focused on the investigation of antiangiogenic potential of these two flavonoids, using in vitro and ex vivo models. Xanthomicrol and Calycopterin were found to have potent inhibitory effects on microvessel outgrowth in the rat aortic ring assay. Xanthomicrol was able to completely block microvessel sprouting at 10 microg/mL, and Calycopterin suppressed microvessel outgrowth by 89% at 5 microg/mL. Suramin and thalidomide, used at 20 microg/mL as positive controls, inhibited microvessel formation by 23% and 64%, respectively. The flavones also inhibited endothelial cell tube formation and human umbilical vein endothelial cell proliferation at 0.5, 5, and 10 microg/mL. In order to delineate the underlying mechanisms of antiangiogenic activity of these flavones, we investigated the influences of xanthomicrol and Calycopterin on expression of vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF) in endothelial cells. These flavones were able to inhibit VEGF expression at 0.5, 5, and 10 microg/mL, but they had little or no effect on b-FGF expression. These findings suggest that xanthomicrol and Calycopterin possess potent antiangiogenic activities, which may be due to their inhibitory influences on VEGF expression.

Identification and quantification of leaf surface flavonoids in wild-growing populations of Dracocephalum kotschyi by LC-DAD-ESI-MS.[Pubmed:23768339]

Food Chem. 2013 Nov 1;141(1):139-46.

Dracocephalum kotschyi Boiss. (Lamiaceae) is an aromatic and perennial herb endemic to Iran with interesting pharmacological and biological properties. The flavonoids luteolin-7-O-glucoside, apigenin-7-O-glucoside (cosmosiin), luteolin 3'-O-beta-d-glucuronide, luteolin, apigenin, cirsimaritin, isokaempferide, penduletin, xanthomicrol, Calycopterin and the polyphenol rosmarinic acid were identified among 13 natural populations of the plant by ESI-MS, LC-DAD and LC-DAD-ESI-MS. The plant extracts containing the identified compounds showed significant antioxidant activity, which was correlated with the flavonoid content. Additionally, leaf and stem size and geographical variability among the studied populations were correlated with flavonoid accumulation. Canonical correlation analysis was used to find a relationship between plant dimensions and phytochemical composition, and the plants with the lowest growth indices were found to have the highest levels of methoxylated flavonoids.

Involvement of p-CREB and phase II detoxifying enzyme system in neuroprotection mediated by the flavonoid calycopterin isolated from Dracocephalum kotschyi.[Pubmed:23639191]

Phytomedicine. 2013 Jul 15;20(10):939-46.

PURPOSE: There is an increasing amount of experimental evidence that oxidative stress has a central role in the neuropathology of neurodegenerative diseases. It has been suggested that the loss of cell function results from the increased oxidative damage to proteins and DNA. Herein, we investigated the effect of a natural neuroprotective flavonoid, Calycopterin, on H(2)O(2)-induced disruption of phase II detoxifying enzyme system and cAMP response element binding protein (CREB) phosphorylation. METHODS: PC12 cells were treated with 25, 50 and 100 muM of Calycopterin for 3h, followed by adding H(2)O(2) (150 muM) for 24 h. The extent of apoptosis was assessed by comet assay. The level of phosphorylated CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), glutamylcysteine synthetase (gamma-GCS) and heme oxygenase 1 (HO-1) were measured by western blot method. The concentration of glutathione (GSH) was determined in whole cell lysate using dithionitrobenzoic acid method. Superoxide dismutase (SOD) activity was measured by colorimetric assay. RESULT: Morphological analysis of protection induced by Calycopterin, determined by comet assay, showed that Calycopterin reduced DNA in tail. We found that H(2)O(2) decreased mitochondrial membrane potential (MMP), while, Calycopterin prevented this decrease in MMP in presence of H(2)O(2). In H(2)O(2)-treated cells, Calycopterin also suppressed cytochrome C release to cytosol that is necessary for maintaining mitochondrial homeostasis in survived cells. Moreover, Calycopterin, in presence of H(2)O(2) inhibited the decrease caused by oxidative stress in stress-sensing transcription factors, CREB and Nrf2, which play an important role in antioxidant capacity of the cell. There was also an increase in gamma-GCS and HO-1 levels in Calycopterin pretreated cells. In the presence of H(2)O(2), Calycopterin inhibited decrease in GSH level and SOD activity. CONCLUSION: We provided documentation of neuroprotective effect of a natural flavone, Calycopterin, against H(2)O(2)-induced oxidative stress in differentiated PC12 cells by modulating the level of CREB phosphorylation and Nrf2 pathway.

Antiproliferative activity of flavonoids: influence of the sequential methoxylation state of the flavonoid structure.[Pubmed:22184071]

Phytother Res. 2012 Jul;26(7):1023-8.

Dracocephalum kotschyi Boiss. has been used as part of an ethnobotanical remedy against many forms of human cancer in Iran. It has been demonstrated that a flavonoid named xanthomicrol from D. kotschyi contributes to its preferential antiproliferative activity against malignant cells. In the present study, the antiproliferative activity of its flavonoid fraction was further characterized. Using liquid-liquid extraction and a semi-preparative reversed-phase HPLC method, eight flavonoid aglycones were isolated from the aerial parts of the plant and their identities were confirmed through MS and NMR analyses as luteolin, naringenin, apigenin, isokaempferide, cirsimaritin, penduletin, xanthomicrol and Calycopterin. The in vitro antiproliferative activity of each compound was evaluated against a panel of established normal and malignant cell lines using the MTT assay and some structure-activity relationships were observed. The hydroxyflavones (luteolin, apigenin and isokaempferide) exerted comparable antiproliferative activities against malignant and normal cells, while the methoxylated hydroxyflavones (cirsimaritin, penduletin, xanthomicrol and Calycopterin) showed preferential activities against tumor cells. This activity may be of value in treating tumors as it would exert few side effects in normal tissues. Xanthomicrol selectively inhibited the growth of human gastric adenocarcinoma, while Calycopterin selectively prevented human acute promyelocytic leukemia and human colon carcinoma cells proliferation.

Calycopterin promotes survival and outgrowth of neuron-like PC12 cells by attenuation of oxidative- and ER-stress-induced apoptosis along with inflammatory response.[Pubmed:22081883]

Chem Res Toxicol. 2011 Dec 19;24(12):2280-92.

There is mounting evidence implicating the role of oxidative stress induced by reactive oxygen species (ROS) in neurodegenerative disease, including Alzheimer's disease. Herein we investigated the neuroprotective potential of a natural flavonoid, Calycopterin, against H(2)O(2)-induced cell death in differentiated PC12 cells. We pretreated PC12 cells with 25, 50, and 100 muM Calycopterin followed by the addition of H(2)O(2) as an oxidative stress agent. We measured cell viability by the MTT test and found that 50 muM is the best protective concentration of Calycopterin. Moreover, we measured six different parameters of neurite outgrowth. Interestingly, we found that Calycopterin not only protects PC12 cells against H(2)O(2)-induced apoptosis but also defends against the destructive effect of oxidative stress on the criteria of neural differentiation. Calycopterin decreased ER stress-associated proteins including calpain and caspase-12, and suppressed ERK, JNK, and p38 MAPK phosphorylation. Moreover, Calycopterin inhibited H(2)O(2)-induced nuclear translocation of nuclear factor-kappaB, a known regulator of a host of genes involved in specific stress and inflammatory responses. This observation was perfectly in agreement with the decrease of COX-2 and TNF-alpha levels. Calycopterin reduced intracellular ROS levels and increased catalase activity. The protective effect of this compound could represent a promising approach for the treatment of neurodegenerative diseases.

Synthesis of antiproliferative flavones from calycopterin, major flavonoid of Calycopteris floribunda Lamk.[Pubmed:21146994]

Bioorg Med Chem. 2011 Jan 1;19(1):186-96.

Eighteen new analogues of 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxy-flavone, a potent natural cytotoxic and antimitotic flavone, were synthesized from Calycopterin, the major flavonoid of Calycopteris floribunda Lamk., a traditional Asian medicinal plant. One of them, the 3'-amino substituted analogue, displayed almost the same activity as the reference compound. Pharmacomodulation at C-3' on the B-ring, and at C-5,6,7 and 8 on the A-ring allowed to refine structure-activity relationships within the cytotoxic flavones series.

Calycopterin, an immunoinhibitory compound from the extract of Dracocephalum kotschyi.[Pubmed:18683896]

Phytother Res. 2008 Sep;22(9):1154-8.

Medicinal plants have been widely investigated for their various effects. Dracocephalum kotschyi Boiss (Labiatae) is used in Iranian traditional medicine for the treatment of rheumatoid diseases. The inhibitory effect of D. kotschyi on the lectin-induced cellular immune response has been demonstrated previously. In this study, mitogen-treated lymphocytes were exposed to the extract of D. kotschyi and analysed for the induction of apoptosis using flow cytometry and gel electrophoresis. The data obtained indicated a dose-dependent increase of cells in the sub-G1 phase of cell cycle. Study of internucleosomal DNA fragmentation showed a typical DNA laddering in agarose gels. A bioactivity-guided fractionation assay to find the active components responsible for the inhibitory effect of D. kotschyi on mitogen-induced lymphocyte proliferation led to the isolation of Calycopterin from the ethyl acetate extract of D. kotschyi. Its structure was identified by spectroscopic methods including( 1)H-NMR, (13)C-NMR, MS and UV spectra. Calycopterin inhibited lymphocyte proliferation in a dose-dependent manner with an IC(50) value of 1.7 microg/mL. In conclusion, the results of this study suggest that D. kotschyi extract has the capacity to induce apoptosis in the lymphocytes and that isolated Calycopterin is responsible for the inhibitory effect of D. kotschyi on lymphocyte proliferation.

Bioactive constituents from Dracocephalum subcapitatum (O. Kuntze) Lipsky.[Pubmed:15787238]

Z Naturforsch C J Biosci. 2005 Jan-Feb;60(1-2):22-4.

From an EtOAc extract of Dracocephalum subcapitatum, five flavonoids, Calycopterin, xanthomicrol, isokaempferide, luteolin and apigenin, together with five terpenoids, oleanolic acid, ursolic acid, geranial, neral and limonene-10-al, were isolated. Among them, citral and limonene-10-al were the most effective components against epimastigotes of Trypanosoma cruzi, the parasitic agent of Chagas disease.