Isogarcinol

Inhibitory effects against SARSCoV-2 main protease (M(pro)) of biflavonoids and benzophenones from the fruit of Platonia insignis.[Pubmed:38128621]

Fitoterapia. 2024 Mar;173:105784.

The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (M(pro)). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and Isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against M(pro), displayed from no to significant activity. Compound 5 was the most potent with an IC(50) value of 0.72 muM and was more active than the positive control, Ebselen (IC(50) of 3.4 muM). It displayed weak and no cytotoxicity against THP-1 (CC(50) of 116.2 muM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

Synergistic combination of isogarcinol isolated from edible fruits of Garcinia multiflora and dexamethasone to overcome leukemia glucocorticoid resistance.[Pubmed:38039755]

Biomed Pharmacother. 2024 Jan;170:115936.

Isogarcinol (ISO), a cytotoxic polycyclic polyprenylated acylphloroglucinol isolated from the edible fruits of Garcinia multiflora. However, synergistic combination of ISO and dexamethasone (DEX) to overcome leukemia glucocorticoid resistance has never been investigated. Therefore, in this study, the effects of ISO in combination with DEX was conducted on leukemia in vivo and glucocorticoid resistance in vitro. As a result, the combination of the two compounds could efficiently inhibit leukemia progression in mice and reverse DEX resistance in acute lymphoblastic leukemia (ALL) Jurkat cells. Significantly, our findings indicated that c-Myc may be a potential target of ISO, as it is involved in cell cycle arrest and apoptosis by the combination of ISO and DEX in Jurkat cells. Furthermore, western blot analysis revealed that ISO and DEX inhibits the PI3K/Akt/mTOR signaling pathway and promotes the nuclear translocation of glucocorticoid receptor (GR), which activates target genes NR3C1 and TSC22D3, leading to apoptosis in Jurkat cells. Hence, our results suggest that ISO, as a safe and effective food-derived agent, can enhance the anti-leukemia effects of DEX.

A New Synthetic Curcuminoid Displays Antitumor Activities in Metastasized Melanoma.[Pubmed:37998354]

Cells. 2023 Nov 13;12(22):2619.

AIM: The semisynthetic derivatives MePip-SF5 and Isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis. METHODS AND RESULTS: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than its original substance of curcumin (IC(50) MePip-SF5 2.8 vs. 13.8 microM). Similarly, the melanoma cytotoxicity of Isogarcinol was increased by 40% compared to garcinol (IC(50) 3.1 vs. 2.1 microM). The in vivo toxicity of both drugs was assessed in healthy C57BL/6 mice challenged with escalating doses. Isogarcinol induced toxicity above a dose of 15 mg/kg, while MePip-SF5 showed no in vivo toxicity up to 60 mg/kg. Both drugs were tested in murine pulmonary metastatic melanoma. C57BL/6 mice (n = 10) received 500,000 B16F10 melanoma cells intravenously. After intraperitoneal injection of MePip-SF5 (60 mg/kg) or isorgarcinol (15 mg/kg) at days 8, 11 and 14 and sacrifice at day 16, the MePip-SF5-treated mice showed a significantly (p < 0.05) lower pulmonary macroscopic and microscopic tumor load than the vehicle-treated controls, whereas Isogarcinol was ineffective. The pulmonary RNA levels of the mitosis marker Bub1 and the inflammatory markers TNFalpha and Ccl3 were significantly (p < 0.05) reduced in the MePip-SF5-treated mice. Both drugs were well tolerated, as shown by an organ inspection and normal liver- and kidney-related serum parameters. CONCLUSIONS: The novel curcuminoid MePip-SF5 showed a convincing antimetastatic effect and a lack of systemic toxicity in a relevant preclinical model of metastasized melanoma.

Polycyclic Polyprenylated Acylphloroglucinols Bearing a Lavandulyl-Derived Substituent from Garcinia xanthochymus Fruits.[Pubmed:36461923]

J Nat Prod. 2022 Dec 23;85(12):2845-2855.

Many type B polycyclic polyprenylated acylphloroglucinols (PPAPs) bear a lavandulyl-derived substituent, and the configurational assignment of this side chain can be difficult and sometimes leads to erroneous conclusions. In this study, 21 PPAPs, including the new xanthochymusones A-I (1-9), have been isolated from the fruits of Garcinia xanthochymus and structurally characterized. The relative configuration of the C-30 stereocenter was assigned by a combination of chemical transformations, (1)H-(1)H coupling constants, conformational analysis, and NOE experiments. The configurational assignment of compound 7 indicates that the relative configuration at C-30 of PPAPs is not always the same. The absolute configurations of the new compounds were assigned by ECD and X-ray diffraction data, as well as by biosynthetic considerations. Analysis of NMR data enabled the configurational revision of garcicowins C and D. All the isolated PPAPs were tested for antiproliferative activity against three human hepatocellular carcinoma cell lines, including Huh-7, Hep 3B, and HepG2. Compounds 5 and 6, 7-epi-Isogarcinol (16), and coccinone C (17) exhibited moderate antiproliferative activity. Compounds 6 and 16 induced apoptosis and inhibited cell migration in Huh-7 cells, probably through downregulating the STAT3 signaling pathway. This study provides effective methods for configurational assignments of type B PPAPs.

The immunoregulatory effects of natural products on psoriasis via its action on Th17 cells versus regulatory T cells balance.[Pubmed:35810491]

Int Immunopharmacol. 2022 Sep;110:109032.

Psoriasis is an incurable, chronic inflammatory disease, which brings a substantial burden on individuals and society. Currently, the treatment of psoriasis has entered the era of biologics, but its highly targeting of inflammatory mediators may enable the immune response to circumvent the blockade, leading to disease recurrence, or other clinical and immunological characteristics. Therefore, the discovery of new therapies that have the ability of multidirectional regulation on immunity and maintain the dynamic balance of immunity in psoriasis, may be the key to the treatment of the disease. Natural products extracted from herbal medicines have synergistic effects to alleviate psoriasis and its comorbidities because of their structural diversity and multiple active mechanisms. To date, the characteristics of natural products regulating T helper 17 (Th17) cells/regulatory T (Treg) cells balance in the treatment of psoriasis have attracted more and more attention from basic and clinical studies. In this review, we systematically introduced the natural products regulating the balance of Th17/Treg and their specific mechanism of action, finding Datura metel L, Grape seed proanthocyanidin extract (GSPE), Thymol, Kaempferol, Aloperine, Abietic acid (AA), Isogarcinol, Luteolin reduced the frequency and function of Th17 cells and simultaneously increased that of Treg cells. It is expected that our work can provide a reference for clinicians in drug use.

Garcinol from Garcinia indica inhibits HIV-1 reverse transcriptase-associated ribonuclease H.[Pubmed:34008218]

Arch Pharm (Weinheim). 2021 Sep;354(9):e2100123.

The bioactive components of Garcinia indica, garcinol (camboginol), and Isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and Isogarcinol. Docking of garcinol into the active site of the enzyme was carried out to rationalize the difference in activities between the two compounds. Garcinol showed higher HIV-1-RNase H inhibition than the known inhibitor RDS1759 and retained full potency against the RNase H of a drug-resistant HIV-1 reverse transcriptase form. Isogarcinol was distinctly less active than garcinol, indicating the importance of the enolizable beta-diketone moiety of garcinol for anti-RNase H activity. Docking calculations confirmed these findings and suggested this moiety to be involved in the chelation of metal ions of the active site. On the basis of its HIV-1 reverse transcriptase-associated RNase H inhibitory activity, garcinol is worth being further explored concerning its potential as a cost-effective treatment for HIV patients.

Antiproliferative activity of a new xanthone derivative from leaves of Garcinia nobilis Engl.[Pubmed:32791845]

Nat Prod Res. 2021 Dec;35(24):5604-5611.

A new xanthone, mboudiexanthone (1), together with five known compounds, euxanthone (2), Isogarcinol (3), garcinol (4), betulinic acid (5) and zeorin (6) were isolated from the leaves of Garcinia nobilis Engl. The structures were determined by 1D and 2D NMR techniques and X-ray diffraction for 6. The in vitro antiproliferative properties of isolated compounds were evaluated against the human breast cancer cell line MCF-7. All compounds showed an antiproliferative activity with an IC(50) value down to approximately 11 microM for Isogarcinol.

Cardioprotective effects of garcinol following myocardial infarction in rats with isoproterenol-induced heart failure.[Pubmed:32749545]

AMB Express. 2020 Aug 4;10(1):137.

Myocardial infarction is a clinical form of necrosis in the myocardium caused by an imbalance between the coronary blood supply and myocardial demand. Garcinol is a polyisoprenylated benzophenone found in the fruit of Garcinia indica, which is abundant in tropical regions. This fruit contains high levels of garcinol, isoxanthochymol, Isogarcinol, hydroxycitric acid and xanthochymol. Garcinol and hydroxycitric acid have been shown to have antioxidant effects. In this study, rats were assigned to sham, control, low-dose, high-dose and positive control groups. Hemodynamic and apoptotic markers were evaluated, and histopathological analysis was conducted. The mRNA and protein levels of caspase-3, Bax, Bcl-2 and cleaved caspase-3 were quantified. Garcinol treatment increased the heart rate and improved the maximum rate of increase in left-ventricle (LV) pressure (+dp/dt(max)), maximum rate of decrease in LV pressure (-dp/dt(max)), LV ejection fraction and LV systolic pressure in rats with induced heart failure. Garcinol treatment reversed body, liver and heart weight changes, resulting in returns to near-normal levels. In the garcinol treatment group, the number of broken fibers, extent of inflammatory cell infiltration and rate of apoptosis remained within normal ranges. Garcinol reduced the cross-sectional areas of cardiomyocytes, and reduced interstitial fibrosis to a normal level. The mRNA and protein levels of cleaved caspase-3, caspase-3 and Bax were reduced, whereas those of Bcl-2 were increased, following high-dose (100 mg/kg) garcinol treatment. These findings suggest that garcinol effectively prevents apoptosis in rats with isoproterenol-induced heart failure and in cardiac H9C2 cells.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments.[Pubmed:31386266]

Chem Biodivers. 2019 Sep;16(9):e1900366.

The natural polyisoprenylated benzophenone derivatives garcinol and Isogarcinol are secondary plant metabolites isolated from various Garcinia species including Garcinia indica. This review takes stock of the recent chemical and biological research into these interesting natural compounds over the last five years. New biological sources and chemical syntheses are discussed followed by new insights into the activity of garcinol and Isogarcinol against cancer, pathogenic bacteria, parasite infections and various inflammatory diseases.

The antioxidant activity and genotoxicity of isogarcinol.[Pubmed:29502843]

Food Chem. 2018 Jul 1;253:5-12.

The antioxidant activity and genotoxicity of Isogarcinol were assessed by several in vitro tests. Its IC(50) values for DPPH and ABTS were 36.3 +/- 3.35 microM and 16.6 +/- 3.98 microM, respectively, which were all lower than those of VC and BHT. Isogarcinol had no cyctotoxic or promotional activities at 1-10 microM in the CCK-8 assay, and negligible genotoxic effects at 50-500 microM on HepG2 cells by the single-cell gel electrophoresis assay. Pre-incubation of the cells with 0.5-1.5 microM Isogarcinol, before exposure to H(2)O(2), significantly increased cell viability in a concentration-dependent manner. Isogarcinol also reduced intercellular reactive oxygen species accumulation, lactate dehydrogenase release and malondialdehyde levels, and increased superoxide dismutase activity and glutathione levels. Western-blot analysis revealed that it up-regulated pro-caspase-3 and reduced cleaved caspase-3 during H(2)O(2)-induced oxidative stress. All the above results indicate that Isogarcinol promises to be useful as a natural antioxidant.

Isogarcinol Extracted from Garcinia mangostana L. Ameliorates Imiquimod-Induced Psoriasis-like Skin Lesions in Mice.[Pubmed:28081600]

J Agric Food Chem. 2017 Feb 1;65(4):846-857.

Isogarcinol (YDIS), a natural compound extracted from Garcinia mangostana L., has a significant immunosuppressive effect on systemic lupus erythematosus and rheumatoid arthritis. This paper reports that it reduced imiquimod-induced psoriasis-like skin lesions in mice. It strongly attenuated the aberrant proliferation and differentiation of keratinocytes. Moreover, the expression of genes involving the interleukin-23 (IL-23)/T-helper 17 (Th17) axis was significantly inhibited in the dorsal skin of the YDIS-treated mice, as was that of the other pro-inflammatory factors TNF-alpha, IL-2, and even interferon (IFN)-gamma. Furthermore, YDIS prevented the abnormal distribution of T cell types and suppressed the differentiation of CD4(+) T cells into Th17 cells in the spleens of mice exposed to imiquimod. Interestingly, it elevated numbers of regulatory T cells (Tregs) in the spleen and boosted IL-10 expression in the skin. In agreement with the above, YDIS increased serum IL-10 and reduced serum IL-17. It also caused less damage to the liver and, especially, kidneys of mice than cyclosporine A (CsA). In vitro, YDIS caused more death of HaCaT keratinocytes than CsA. It also strongly inhibited inflammatory factor expression in lipopolysaccharide (LPS)-stimulated HaCaT cells. These findings suggest that YDIS is a promising immunosuppressive agent for treating psoriasis.

Amelioration of Experimental Autoimmune Encephalomyelitis by Isogarcinol Extracted from Garcinia mangostana L. Mangosteen.[Pubmed:27933873]

J Agric Food Chem. 2016 Nov 30;64(47):9012-9021.

Isogarcinol is a new natural immunosuppressant that was extracted from Garcinia mangostana L. in our laboratory. Knowledge of its effects on treatable diseases and its mechanism of action is still very limited. In this study, we explored the therapeutic effect of Isogarcinol in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Treatment with oral 100 mg/kg Isogarcinol markedly ameliorated clinical scores, alleviated inflammation and demyelination of the spinal cord, and reduced intracranial lesions in EAE mice. The percentages of Th cells and macrophages were also strongly reduced. Isogarcinol appeared to act by inhibiting T helper (Th) 1 and Th17 cell differentiation via the janus kinase/signal transducers and activators of transcription pathway and by impairing macrophage function. Our data suggest that Isogarcinol has the potential to be an effective therapeutic agent of low toxicity for treating MS and other autoimmune diseases.

Epigarcinol and isogarcinol isolated from the root of Garcinia ovalifolia induce apoptosis of human promyelocytic leukemia (HL-60 cells).[Pubmed:26592743]

BMC Res Notes. 2015 Nov 23;8:700.

BACKGROUND: Plants from garcinia genus have been used for centuries against several diseases. OBJECTIVE: This study aimed to investigate the mechanism of apoptosis induced by epigarcinol and Isogarcinol isolated from the root of Garcinia ovalifolia (Clusiaceae) on human promyelocytic leukemia (HL-60 cells). METHODS: Epigarcinol and Isogarcinol were isolated from the root of G. ovalifolia by using column chromatography method. The antiproliferative property of these molecules and fractions were assessed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The light fluorescence microscope was utilized to observe the morphological changes of HL-60 cells after 24 h treatment. Early apoptosis and cell cycle distribution were analyzed by using flow cytometry (FCM). RESULTS: The results showed that epigarcinol and Isogarcinol inhibited the proliferation of HL-60 and PC-3 cells in a concentration-dependent manner with IC50 varying between 4 and 76 microg/mL depending on the cell line and the molecule. The apoptosis rate and the number of apoptotic cells significantly increased with the augmentation of the concentration of the molecules. The results of flow cytometry (FCM) indicated that epigarcinol and Isogarcinol induced significant G2/S arrest of HL-60 cells, the disruption of mitochondrial membrane potential and reactive oxygen species (ROS) generation. CONCLUSION: These results indicated that epigarcinol and Isogarcinol demonstrated in vitro antiproliferative properties and induce apoptosis of HL-60 cells which is related to the G2/S arrest, and it exerts its apoptotic effect through the loosing of mitochondrial membrane potential.

Isogarcinol Extracted from Garcinia mangostana L. Ameliorates Systemic Lupus Erythematosus-like Disease in a Murine Model.[Pubmed:26330173]

J Agric Food Chem. 2015 Sep 30;63(38):8452-9.

Isogarcinol is a new immunosuppressant that we extracted from Garcinia mangostana L. In the present study, we elucidate its beneficial effect in chronic graft-versus-host disease (cGVHD) in mice -- a model for systemic lupus erythematosus (SLE) in human. The oral administration of 60 mg/kg Isogarcinol significantly reduced proteinuria, corrected the abnormal serum biochemical indicator, and decreased the amount of serum antibodies and lowered the renal histopathology score. In addition, Isogarcinol alleviated the abnormal activation of CD4 T cells and decreased the expression of inflammatory genes and cytokines in the kidneys and peritoneal macrophages. The mechanism of action of Isogarcinol is associated with downregulation of CD4 T cells and inflammatory effects. Therefore, we believe that Isogarcinol may be a potential therapeutic drug candidate for future treatment of SLE.

Quantification of the Polyisoprenylated Benzophenones Garcinol and Isogarcinol Using Multiple Reaction Monitoring LC/Electrospray Ionization-MS/MS Analysis of Ultrasound-Assisted Extracts of Garcinia indica Fruits.[Pubmed:25902981]

J AOAC Int. 2014 Sep-Oct;97(5):1317-22.

This paper describes a method that includes an optimized extraction process and identification and quantification of two anticancer compounds (garcinol and Isogarcinol) by LC/electrospray ionization (ESI)-MS/MS in the multiple reaction monitoring (MRM) mode. The study aimed to develop a fast, accurate, and sensitive method for the quantification of garcinol and Isogarcinol in different extracts of Garcinia indica fruits. The compounds were detected using LC/ESI-MS/MS in the positive-ion mode and quantified in the MRM mode using a transition mass of m/z 603.3/411 taken as the quantifier and 603.3/343.2 as the qualifier for garcinol and Isogarcinol. Five point calibration curves were linear in the range of 2 to 10 ng/mL for garcinol and 0.5 to 6 ng/mL for Isogarcinol, with a correlation coefficient of >/=0.990 for both. LOQ for garcinol and Isogarcinol was 0.06 and 0.05 ng/mL, respectively, while LOD was 0.021 and 0.017 ng/mL respectively. Our work demonstrated optimization of extraction procedure, fast and highly sensitive quantification (pg level LOQ), and validation of the developed method for the investigated compounds in fruit extracts of G. indica.