Xanthone Inhibitors of Unfolded Protein Response Isolated from Calophyllum caledonicum.

The unfolded protein response (UPR) is a key component of fungal virulence. The prenylated xanthone γ-mangostin isolated from Garcinia mangostana (Clusiaceae) fruit pericarp, has recently been described to inhibit this fungal adaptative pathway. Considering that Calophyllum caledonicum (Calophyllaceae) is known for its high prenylated xanthone content, its stem bark extract was fractionated using a bioassay-guided procedure based on the cell-based anti-UPR assay. Four previously undescribed xanthone derivatives were isolated, caledonixanthones N-Q (3, 4, 8, and 12), among which compounds 3 and 8 showed promising anti-UPR activities with IC50 values of 11.7 ± 0.9 and 7.9 ± 0.3 µM, respectively.

Phytochemicals from the Stem Bark of Calophyllum havilandii P.†F. Stevens and their Biological Activities.

The genus Calophyllum from the family Calophyllaceae has been extensively investigated in the past due to its rich source of bioactive phenolics such as coumarins, chromanones, and xanthones. In this study, phytochemical investigation on the stem bark of Calophyllum havilandii has afforded a new 4-propyldihydrocoumarin derivative, havilarin (1) together with calolongic acid (2), caloteysmannic acid (3), isocalolongic acid (4), euxanthone (5), and ß-sitosterol (6). The chemical structure of compound 1 was elucidated and established based on detailed spectroscopic techniques, including MS, IR, UV, 1D and 2D NMR. The results of anti-bacillus study indicated that the chloroform extract showed promising activities with MIC value ranging between 0.5 to 1 µg/mL on selected bacillus strains. Besides, the plant extracts and compounds 1-4 were assessed for their cytotoxicity potential on HL-7702 cell line. All the tested plant extracts and respective chemical constituents displayed non-cytotoxic activity on HL-7702 cell line.

A new chromanone acid derivative from the nut oil resin of Calophyllum inophyllum.

One novel chromanone acid derivative, namely inocalophylline C (1), together with one known compound calophyllolide (2), were isolated from the methanolic extract of nut oil resin of Calophyllum inophyllum L., a medicinal plant widely distributed in Vietnam. The isolated compound structures were elucidated by spectroscopic methods and the absolute configuration of 1 was established by the single-crystal X-ray crystallography as ethyl (R) 3-((2 R,3R,6R)-4-hydroxy-2,3-dimethyl-6-((R)-5-methyl-2-(prop-1-en-2-yl)hex-4-en-1-yl)-6-(3-methylbut-2-en-1-yl)-5,7-dioxo-3,5,6,7-tetrahydro-2H-chromen-8-yl)-3-phenylpropanoate.

Pyranochromones with Anti-Inflammatory Activities in Arthritis from Calophyllum membranaceum.

Eleven new pyranochromones, calomembranone A-K (1-11), two new pyranocoumarins, calopolyanolide E and F (12 and 13), together with six known analogues (14-19) were isolated from the leaves of Calophyllum membranaceum. Their structures and absolute configurations were elucidated by analysis of spectroscopic data, computational calculations, as well as X-ray crystallography of 4 and 9. The anti-inflammatory activities of all the isolates were evaluated by measuring their NO inhibitory effects in LPS-stimulated RAW 264.7 cells. Structure-activity relationships are also discussed. Compound 7 showed the strongest NO inhibition (IC50 = 0.92 µM). Oral administration of 7 dose-dependently reduced the paw swelling and downregulated neutrophil-to-lymphocyte ratio in the carrageenan-induced acute arthritis mice model. Molecular dynamics simulation and cellular thermal shift assay results indicated that 7 participated in a robust and stable interaction with the active site of TLR4. Compound 7 also suppressed the inflammation in arthritis through the regulation of TLR4 mediated signal transduction via IKK/NF-κB signaling pathway and the consequent reduction of IL-2, IL-4, and IL-5.

Calofolic Acid-A from Calophyllum scriblitifolium Bark Has Vasorelaxant Activity via Indirect PKA Activation Caused by PI-3 Kinase Inhibition in Rat Vascular Smooth Muscle Cells.

Previously, we isolated 2R,3S,15R-calofolic acids (CAs) from Calophyllum scriblitifolium bark, which showed vasorelaxant activity on phenylephrine (PE)-precontracted rat aortic rings. Although the effect was suggested to be induced via an extracellular Ca2+-independent manner and mainly acts on vascular smooth muscle, the exact mechanism of action of CAs remained unclear. Thus, this study investigated the detailed mechanism of calofolic acid-A (CA-A) induced vasorelaxation in an aortic ring specimen using rat vascular smooth muscle cells (VSMCs). The levels of PE-induced phosphorylation on MLC Ser19 decreased in VSMCs pretreated with CA-A. CA-A also decreased the phosphorylation of MYPT1 Thr696 and MYPT1 Thr853. On the other hand, CA-A increased the PE-induced phosphorylation of MYPT1 Ser695 and MYPT1 Ser668, which are reported to be phosphorylated by a cAMP-dependent protein kinase (PKA). CA-A slightly increased PKA substrate phosphorylation in a concentration-dependent manner. Furthermore, CA-A enhanced isoproterenol (ISO)-induced cAMP accumulation and PKA substrate phosphorylation. Treatment with PI-3 kinase (PI3K) inhibitor, LY294002, enhanced ISO-induced cAMP accumulation and PKA substrate phosphorylation in the same manner as CA-A treatment. Furthermore, CA-A was found to directly inhibit PI3K enzyme activity in a dose-dependent manner. Taken together, the present study indicated that CA-A induces vasorelaxation through an indirectly activated PKA-MYPT1 pathway caused by inhibition of PI3K activity.

Xanthones from Calophyllum Polyanthum Wallich ex Choisy with CYP1 Enzymes Inhibitory Activity.

Three new xanthone compounds, 1,3,5-trihydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-4-(3-methylbut-2-enyl)xanthone (1), toxyloxanthone E (2), dehydrocycloguanandin B (3) along with 15 known xanthones (4-18) were isolated from the aerial parts of Calophyllum polyanthum Wall. ex Choisy. Their structures were fully characterised using spectroscopic data, as well as comparison with the previous literature data. All isolated compounds had inhibitory effects against CYP1A1, CYP1A2 and CYP1B1 enzymes at working concentration of 10 µM, 1 µM and 10 µM, respectively. Among them, compounds 10, 11, and 12 exhibited better CYP1A2 enzyme inhibitory effects than that of the positive control α-naphthoflavone, with 51.05 %, 56.82 % and 44.93 % inhibition, respectively.

Two New Xanthones from the Twigs of Calophyllum membranaceum and Their Anti-Inflammatory Activities in HESC Cells.

Two new xanthones, calmemxanthone A (1) and calmemxanthone B (2), along with eleven known compounds were isolated from the dried twigs of Calophyllum membranaceum Gardn. et Champ. The structures of compounds 1 and 2 were established by analysis of spectra and mass spectrometry data. The absolute configuration of compound 1 was confirmed by electronic circular dichroism (ECD) spectral analysis. The anti-inflammation action of these compounds were evaluated on lipopolysaccharide (LPS)-induced inflammatory damage to human endometrial stromal cells (HESCs), and the structure-activities of 1-13 were also discussed. Compound 10 presented the anti-inflammation action with an IC50 value of 20.3 µM, that might be relevant to the regulation of NF-κB signaling pathway via the suppression of TRIF, IKKα, and IκBα.

Simultaneous removal of lead and cadmium ions from simulant and industrial waste water: using Calophyllum Inophyllum plant materials as sorbents.

NOVELTY STATEMENT: The merit of this investigation is that simple and effective bio-sorbents based on Calophyllum inophyllum plant materials with high sorption capacities, are developed for the simultaneous removal of the toxic Pb2+ and Cd2+ at neutral or nearly neutral pHs. These sorbents are successful in water remediation of Pb2+ and Cd2+ ions from real effluents from industries. These findings have great significance as the identified bio-sorbents are simple, effective and renewable in extracting highly toxic lead and cadmium ions from the effluents from industries or polluted water.

Exposure of Calophyllum antillanum seeds to liquid nitrogen delays seedling emergence and decreases leaf anthraquinones.

BACKGROUND: Trees within the Calophyllum genus are multi-use trees that produce valuable wood, phytochemicals with a range of biological activities, and seed oil as a source of biodiesel. As a consequence of climate change, there is a need to develop strategies to preserve valuable plant genetic resources. Cryopreservation represents the most suitable option for the long-term storage of germplasm with minimal space and maintenance requirements. OBJECTIVE: To determine appropriate methods to cryopreserve seeds of Calophyllum antillanum and maintain secondary compound production. MATERIALS AND METHODS: Seeds at a moisture content of 6% were used to evaluate two treatments: seeds immersed in liquid nitrogen and control seeds. Biosynthetic pathway efficiency was assessed post-cryo by determining anthraquinone contents in roots, stems and leaves following 30 and 75 d of seedling growth. RESULTS: The results indicated that exposure to liquid nitrogen delayed germination and seedling emergence for a period of up to 45 d after seed sowing. By 60 d of cultivation, no significant differences in plant growth were observed for cryostored and control seeds. The levels of anthraquinones, which were also measured in seeds and seedlings, were lower in plants regenerated from cryostored seeds following 30 d of growth, but there were no differences in roots and stems by 75 d of growth. Furthermore, the difference in leaf anthraquinone levels for cryopreserved and control seeds at 75 d was much smaller than at 30 d. CONCLUSION: The low initial anthraquinone levels in emerging seedlings correlated with the initial slow growth of cryopreserved seeds.

Using 13 C-NMR dereplication to aid in the identification of xanthones present in the stem bark extract of Calophyllum brasiliense.

INTRODUCTION: Xanthones are metabolites with a variety of biological properties. The Clusiaceae family, which until recently included the genus Calophyllum, is recognised for its production of monohydroxylated and polyhydroxylated xanthones. Presently, C. brasiliense is the only Calophyllum spp. known to occur in the Yucatan peninsula. OBJECTIVE: To use a combination of traditional phytochemical methods and carbon-13 nuclear magnetic resonance (13 C-NMR) dereplication analysis to identify xanthones in the stem bark of C. brasiliense. MATERIAL AND METHODS: Initial fractionation and purification of the stem bark extract of C. brasiliense produced macluraxanthone (1). Additional xanthones, together with chromanones and terpenoids, were identified using 13 C-NMR dereplication analysis in different semipurified fractions obtained from the low and medium polarity fractions of the stem bark extract of C. brasiliense. RESULTS: Initial identification of macluraxanthone (1) was confirmed by 13 C-NMR dereplication analysis; additionally, 13 C-NMR dereplication analysis allowed the identification of a number of monohydroxylated and polyhydroxylated xanthones, together with chromanones and terpenoids. CONCLUSION: This study confirms C. brasiliense as a rich source of xanthones and the 13 C-NMR dereplication analysis as a suitable method to quickly identify the presence of different families of secondary metabolites in semipurified fractions.

Mammea type coumarins isolated from Calophyllum brasiliense induced apoptotic cell death of Trypanosoma cruzi through mitochondrial dysfunction, ROS production and cell cycle alterations.

Chagas Disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi which affects 6-8 million people, mostly in Latin America. The medical treatment is based on two nitroimidazole compounds, which have limited effectiveness in the chronic phase of the disease and produce several adverse effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Previous reports had shown that natural coumarins, especially mammea A/BA isolated from the tropical tree Calophyllum brasiliense, is a promissory molecule for developing new drugs, due to its potent activity, higher than benznidazole, selectivity, and its low toxicity in mice. However, its mode of action is still unknown. In the present work, we evaluated the mechanism of action of the coumarin mammea A/BA (93.6%), isolated from the tropical tree C. brasiliense on Querétaro strain (Tc1) of T. cruzi. This compound was tested in vitro on epimastigotes and trypomastigotes of T. cruzi for intracellular esterase activity, plasma membrane integrity, phosphatidylserine exposure, ROS production, mitochondrial membrane potential, caspase-like activity, DNA integrity, cell cycle and autophagy. Mammea A/BA showed a 50% lethal concentration (LC50) of 85.8 and 36.9 µM for epimastigotes and trypomastigotes respectively. It affected intracellular esterase activity, produced important plasma membrane damage and induced phosphatidylserine exposure. An increase in reactive oxygen species (ROS) and decrease in mitochondrial membrane potential were detected. Caspase-like activity was present in both parasite forms producing DNA integrity damage. This compound also induced a cell cycle arrest in the G1 phase and the presence of autophagy vacuoles. The above data suggest that mammea A/BA induce cell death of T. cruzi by autophagy and apoptosis-like phenomena and support our suggestion that mammea A/BA could be a promising molecule for the development of new drugs to treat Chagas Disease.

Vegetable butters and oils in skin wound healing: Scientific evidence for new opportunities in dermatology.

The use of vegetable butters and oils shows promising results in the treatment of skin wounds, as they have an effective impact on the phases of the wound-healing process through their antimicrobial, anti-inflammatory, and antioxidative activities and by promoting cell proliferation, increasing collagen synthesis, stimulating dermal reconstruction, and repairing the skin's lipid barrier function. In this article, in vitro and in vivo studies of argan (Argania spinosa), avocado (Persea americana), black cumin (Nigella sativa), calophyllum (Calophyllum inophyllum), coconut (Cocos nucifera), cranberry (Vaccinium macrocarpon), grape (Vitis vinifera), green coffee (Coffea arabica), lentisk (Pistacia lentiscus), linseed (Linum usitatissimum), lucuma (Pouteria lucuma), mango (Mangifera indica), olive (Olea europaea), pomegranate (Punica granatum), pumpkin (Cucurbita pepo), rapeseed (Brassica napus), sea buckthorn (Hippophae rhamnoides), and sunflower (Helianthus annuus) oils were reviewed. In many cases, vegetable oils proved to be more effective than synthetic wound-healing compounds used as controls. The fatty-acid components of vegetable oils are assumed to play a major role in the wound-healing process, in particular polyunsaturated fatty acids such as linoleic acid. Evidence shows that oils with a higher linoleic to oleic acid ratio are more effective for lipid barrier repair. However, in depth studies are needed to gain knowledge about vegetable oils' effects on the skin and vice versa.

Chemical constituents from Vietnamese mangrove Calophyllum inophyllum and their anti-inflammatory effects.

In a search for anti-inflammatory activity in resources from Vietnamese mangroves, we found that a methanolic extract from the leaves of Calophyllum inophyllum (CIL) showed significant anti-inflammatory effects in vitro. Using various chromatographic techniques, we subsequently isolated 12 compounds (1-12) from a methanolic extract of CIL, including two novel compounds (1-2). The inhibitory effects of these compounds on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells were also evaluated. Compound 1 significantly suppressed NO production (IC50 = 2.44 ±â€¯0.88 µM), the secretion of pro-inflammatory cytokines (including interleukin-1 beta and tumor necrosis factor alpha), and the expression of inducible nitric oxide synthase through downregulation of nuclear factor-kappa-B signaling cascades. These results suggest that C. inophyllum leaves might be a useful resource for the development of drugs for the treatment of inflammation.

Network Pharmacology Uncovers Anticancer Activity of Mammea-Type Coumarins from Calophyllum brasiliense.

Mammea-type coumarins are a particular type of secondary metabolites biosynthesized by the tropical rainforest tree Calophyllum Brasiliense, which is distributed from South America to Mexico. Particularly, mammea A/BA and A/BB (alone or as a mixture) possess biological properties such as cytotoxic and antitumoral activities, however, most of its molecular targets remain unknown. In this context, novel bioinformatic approaches, such as network pharmacology analysis, have been successfully used in herbal medicine to accelerate research in this field, and the support of experimental validations has been shown to be quite robust. In the present study, we performed a network pharmacology analysis to assess the possible molecular biological networks that interact with mammea A/BA and A/BB. Moreover, we validated the most relevant networks experimentally in vitro on K562 cancer cells. The results of the network pharmacology analysis indicate that mammea A/BA and A/BB interacts with cell death, PI3K/AKT, MAPK, Ras, and cancer pathways. The in vitro model shows that mammea A/BA and A/BB induce apoptosis through the overexpression of the proapoptotic proteins Bax and Bak, disrupt the autophagic flux as seen by the cytosolic accumulation of LC3-II and p62, disrupting the mitochondria ultrastructure and concomitantly increase the intracellular calcium concentration. Additionally, docking analysis predicted a possible interaction with a rapamycin-binding domain of mTOR. In conclusion, we validated network pharmacology analysis and report, for the first time, that mammea A/BA and A/BB coumarins induce apoptosis through the inhibition of the autophagic flux, possibly interacting with mTOR.

Tamanu oil potentiated novel sericin emulgel of levocetirizine: repurposing for topical delivery against DNCB-induced atopic dermatitis, QbD based development and in vivo evaluation.

The present study was aimed at preparing and evaluating levocetirizine (LCZD) loaded emulgel containing tamanu oil and sericin for atopic dermatitis (AD) therapy. The emulgel envisaged topical delivery of LCZD utilising natural antioxidants for superior therapeutic outcomes when compared with other conventional therapy. Tamanu oil based microemulsion (ME) was optimised utilising Box-Behnken design (BBD). The OPT-ME displayed globule size 379.5 ± 2.33 nm, polydispersity index 0.284, drug loading 0.41 ± 0.01% w/w, entrapment efficiency 94.34 ± 2.11% w/w and drug release 86.24 ± 4.90% respectively over a period of 24 h. The optimised formulation (OPT-ME) was further incorporated into sericin gel to form emulgel (LSE). In vivo pharmacodynamic studies revealed enhanced therapeutic potential of emulgel in terms of reduced scratching frequency and erythema score when compared with conventional gel. The superior therapeutic potential was further witnessed through histopathological and biochemical studies. The emulgel can be an alternative appropriate dosage form for the treatment of AD.

Report: Cytotoxic activity of phytochemicals from the stem bark of Calophyllum castaneum.

Phytochemical investigation on the dichloromethane stem bark extract of Calophyllum castaneum resulted in the isolation of five compounds, namely isoblancoic acid (1), blancoic acid (2), euxanthone (3), friedelin (4) and friedelinol (5). All these compounds were isolated for the first time from this plant. Their chemical structures were elucidated based on the spectroscopic analyses. The cytotoxicity of compounds 1-5 was assessed on a panel of cancer cell lines including bone (Saos-2, mg63), colorectal (HT29, Caco-2, HCC2998, SW48, HCT116, KM12), liver (HepG2), lung (H1299, Calu-3), and brain (C6), using 5-fluorouracil as positive control. Pronounced antiproliferative activities were observed for compound 1 which exhibited a comparable activity with the positive control, against brain (C6) and colorectal (SW48, KM12, HCT116) cancer cell lines showing IC50 values in the range of 14 to 65µM. Meanwhile, compound 5 displayed a greater cytotoxic effect showing at least 2-fold more strongly than the positive control, against C6 brain cancer cells. The assay findings have unveiled the therapeutic value of phytochemicals from Calophyllum castaneum as anti-cancer agents.

Calophyllum brasiliense Modulates the Immune Response and Promotes Leishmania amazonensis Intracellular Death.

Calophyllum brasiliense is a plant from the Brazilian rain forests and has been used in folk medicine for the treatment of various diseases, including leishmaniasis. This infectious disease depends on the Leishmania sp. and the host immune response. C. brasiliense antileishmanial activity is well known, but the effects on immune response remain to be investigated. This study showed the leishmanicidal and immunomodulatory effects of a 30 µg/mL of hydroalcoholic extract of C. brasiliense in murine macrophages before and after Leishmania (Leishmania) amazonensis infection. The semiquantitative cytokine RNA expression was determined by RT-PCR and the anti-Leishmania activity was measured by infection index (IF). Hydroalcoholic extract of C. brasiliense reduced more than 95% of IF when used before and after Leishmania infection, with 3 and 24 h of treatment (p < 0.05). C. brasiliense inhibited or reduced significantly (p < 0.05) the TNF-α, IL-1ß, IL-18, and IL-10 mRNA expression. The antileishmanial and anti-inflammatory effects showed the potential of C. brasiliense as an alternative therapy for leishmaniasis and it must be investigated.

C-glycosides from the stems of Calophyllum membranaceum.

Three new C-glycosides, calophymembransides D-F (1-3), were isolated from the stems of Calophyllum membranaceum Gardn. et Champ.. The structures were assigned on the basis of spectroscopic data. RXRα transcriptional inhibition and α-glucosidase inhibition assays indicated that all the isolates were inactive.

In situ temperature relationships of biochemical and stomatal controls of photosynthesis in four lowland tropical tree species.

Net photosynthetic carbon uptake of Panamanian lowland tropical forest species is typically optimal at 30-32 °C. The processes responsible for the decrease in photosynthesis at higher temperatures are not fully understood for tropical trees. We determined temperature responses of maximum rates of RuBP-carboxylation (VCMax ) and RuBP-regeneration (JMax ), stomatal conductance (Gs ), and respiration in the light (RLight ) in situ for 4 lowland tropical tree species in Panama. Gs had the lowest temperature optimum (TOpt ), similar to that of net photosynthesis, and photosynthesis became increasingly limited by stomatal conductance as temperature increased. JMax peaked at 34-37 °C and VCMax ~2 °C above that, except in the late-successional species Calophyllum longifolium, in which both peaked at ~33 °C. RLight significantly increased with increasing temperature, but simulations with a photosynthesis model indicated that this had only a small effect on net photosynthesis. We found no evidence for Rubisco-activase limitation of photosynthesis. TOpt of VCMax and JMax fell within the observed in situ leaf temperature range, but our study nonetheless suggests that net photosynthesis of tropical trees is more strongly influenced by the indirect effects of high temperature-for example, through elevated vapour pressure deficit and resulting decreases in stomatal conductance-than by direct temperature effects on photosynthetic biochemistry and respiration.

Photosynthetic acclimation to warming in tropical forest tree seedlings.

Tropical forests have a mitigating effect on man-made climate change by acting as a carbon sink. For that effect to continue, tropical trees will have to acclimate to rising temperatures, but it is currently unknown whether they have this capacity. We grew seedlings of three tropical tree species over a range of temperature regimes (TGrowth = 25, 30, 35 °C) and measured the temperature response of photosynthetic CO2 uptake. All species showed signs of acclimation: the temperature-response curves shifted, such that the temperature at which photosynthesis peaked (TOpt) increased with increasing TGrowth. However, although TOpt shifted, it did not reach TGrowth at high temperature, and this difference between TOpt and TGrowth increased with increasing TGrowth, indicating that plants were operating at supra-optimal temperatures for photosynthesis when grown at high temperatures. The high-temperature CO2 compensation point did not increase with TGrowth. Hence, temperature-response curves narrowed with increasing TGrowth. TOpt correlated with the ratio of the RuBP regeneration capacity over the RuBP carboxylation capacity, suggesting that at high TGrowth photosynthetic electron transport rate associated with RuBP regeneration had greater control over net photosynthesis. The results show that although photosynthesis of tropical trees can acclimate to moderate warming, carbon gain decreases with more severe warming.