PMID: 

Phytother Res. 2019 Nov 22. Epub 2019 Nov 22. PMID: 31755173

Abstract Title: 

Mangiferin: Possible uses in the prevention and treatment of mixed osteoarthritic pain.

Abstract: 

Osteoarthritis (OA) pain has been proposed to be a mixed pain state, because in some patients, central nervous system factors are superimposed upon the more traditional peripheral factors. In addition, a considerable amount of preclinical and clinical evidence has shown that, accompanying the central neuroplasticity changes and partially driven by a peripheral nociceptive input, a real neuropathic component occurs that are particularly linked to disease severity and progression. Hence, innovative strategies targeting neuroprotection and particularly neuroinflammation to prevent and treat OA pain could be introduced. Mangiferin (MG) is a glucosylxanthone that is broadly distributed in higher plants, such as Mangifera indica L. Previous studies have documented its analgesic, anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory properties. In this paper, we propose its potential utility as a multitargeted compound for mixed OA pain, even in the context of multimodal pharmacotherapy. This hypothesis is supported by three main aspects: the cumulus of preclinical evidence around this xanthone, some preliminary clinical results using formulations containing MG in clinical musculoskeletal or neuropathic pain, and by speculations regarding its possible mechanism of action according to recent advances in OA pain knowledge.

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PMID: 

Fish Physiol Biochem. 2019 Nov 28. Epub 2019 Nov 28. PMID: 31782040

Abstract Title: 

Vitamin C inhibits lipid deposition through GSK-3β/mTOR signaling in the liver of zebrafish.

Abstract: 

In this study, the mechanism that VC inhibits lipid deposition through GSK-3β/mTOR signaling was investigated in the liver of Danio rerio. The results indicated that 0.5- and 1.0-g/kg VC treatments activated mTOR signaling by inhibiting GSK-3β expression. The mRNA expression of FAS, ACC, and ACL, as well as the content of TG, TC, and NEFA, was decreased by 0.5- and 1.0-g/kg VC treatments. Moreover, to confirm GSK-3β playing a key role in regulating TSC2 and mTOR, GSK-3β RNA was interfered and the activity of GSK-3β was inhibited by 25- and 50-mg/L LiCl treatments, respectively. The results indicated that GSK-3β inactivation played a significant role in inducingmTOR signaling and inhibiting lipid deposition. VC treatments could induce mTOR signaling by inhibiting GSK-3β, and mTOR further participated in regulating lipid deposition by controlling lipid profile in the liver of zebrafish.

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PMID: 

Neurosci Lett. 2019 Nov 30:134656. Epub 2019 Nov 30. PMID: 31794791

Abstract Title: 

Deficiency of ascorbic acid decreases the contents of tetrahydrobiopterin in the liver and the brain of ODS rats.

Abstract: 

Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase and tryptophan hydroxylase, which are essential enzymes for the biosynthesis of dopamine, norepinephrine, and serotonin. It has been known that BH4 is a labile molecule and easily oxidized. As ascorbic acid (AsA) is an antioxidant that is rich in the brain, alteration in the AsA concentration in the brain may affect the proper metabolism of BH4. Here, we examined the effect of AsA deficiency on the concentration of BH4 using ODS rats, which are defective in the gene for AsA synthesis. Intake of an AsA-deficient diet for 2 weeks in ODS rats resulted in great reductions in the AsA levels up to 7% in the liver and up to 55% in the brain compared to animals fed a basal diet containing an adequate amount of AsA. The BH4 concentrations in ODS rats fed an AsA-free diet were decreased to 71% in the liver and 88% in the brain of those fed a basal diet. We found that the levels of dopamine, norepinephrine, and serotonin were also decreased compared with the ODS rats fed a basal diet. Our data showed that AsA deficiency can affect the BH4 concentrations in the liver and brain, resulting in decreases in the monoamine levels in the brain. These results suggest the importance of AsA in the pathophysiology of neuropsychiatric and cardiovascular disorders through alteration in the BH4 metabolism.

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PMID: 

Naunyn Schmiedebergs Arch Pharmacol. 2006 Oct ;374(1):11-20. Epub 2006 Sep 9. PMID: 16964520

Abstract Title: 

Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells.

Abstract: 

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species, among others in the bark of white birch Betula alba. BA was reported to display a wide range of biological effects, including antiviral, antiparasitic, antibacterial and anti-inflammatory activities, and in particular to inhibit growth of cancer cells. The aim of the study was further in vitro characterization of BA anticancer activity. In this study, we demonstrated a remarkable antiproliferative effect of BA in all tested tumor cell cultures including neuroblastoma, rabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukemia and multiple myeloma, as well as in primary cultures isolated from ovarian carcinoma, cervical carcinoma and glioblastoma multiforme. Furthermore, we have shown that BA decreased cancer cell motility and induced apoptotic cell death. We also observed decrease of bcl2 and cyclin D1 genes expression, and increase of bax gene expression after betulinic acid treatment. These findings demonstrate the anticancer potential of betulinic acid and suggest that it may be taken into account as a supportive agent in the treatment of cancers with different tissue origin.

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PMID: 

Eur J Cancer. 1997 Oct ;33(12):2007-10. PMID: 9516843

Abstract Title: 

Betulinic acid induces apoptosis in human neuroblastoma cell lines.

Abstract: 

Neuroblastoma has long been recognized to show spontaneous regression during fetal development and in the majority of stage 4s infants

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PMID: 

Br J Cancer. 2010 Jun 29 ;103(1):43-51. Epub 2010 Jun 1. PMID: 20517313

Abstract Title: 

Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma.

Abstract: 

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with the ability to resist apoptosis by the activation of survival promoting and anti-apoptotic proteins.METHODS: Efficacy of the apoptosis-inducing agent betulinic acid (BA) was determined in RMS cell cultures and in vivo by measuring cell viability, survival, apoptosis, hedgehog signalling activity, and neovascularisation.RESULTS: Betulinic acid had a strong cytotoxic effect on RMS cells in a dose-dependent manner. The BA treatment caused a massive induction of apoptosis mediated by the intrinsic mitochondrial pathway, which could be inhibited by the broad-range caspase inhibitor zVAD.fmk. Exposure of hedgehog-activated RMS-13 cells to BA resulted in a strong decrease in GLI1, GLI2, PTCH1, and IGF2 expression as well as hedgehog-responsive luciferase activity. Intraperitoneal injection of 20 mg BA per kg per day significantly retarded growth of RMS-13 xenografts in association with markedly higher counts of apoptotic cells and down-regulation of GLI1 expression compared with control tumours, while leaving microvascular density, cell proliferation, and myogenic differentiation unaffected.CONCLUSION: Our data show that induction of apoptosis and inhibition of hedgehog signalling are important features of the anti-tumourigenic effect of BA in RMS and advices this compound for the use in a multimodal therapy of this highly aggressive paediatric tumour.

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PMID: 

Br J Cancer. 2004 Apr 19 ;90(8):1672-8. PMID: 15083202

Abstract Title: 

Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice.

Abstract: 

We examined the antitumour effect of a combination of betulinic acid (BA) and vincristine (VCR) on murine melanoma B16F10 cells in vitro and in vivo. Betulinic acid, a pentacyclic triterpene, showed a synergistic cytotoxic effect on melanoma cells by combinational use of VCR. Betulinic acid and VCR induced cell cycle arrest at different points (BA at G1 phase and VCR at G2/M phase) and caused apoptosis in B16F10 melanoma cells. In the in vivo study, VCR inhibited metastasis of tumour cells to the lung. The addition of BA to VCR augmented suppression of the experimental lung metastasis of melanoma cells in C57BL/6 mice. The number of lung nodules of more than 1 mm in diameter in mice treated with BA and VCR was less than that in mice treated with VCR alone. These results suggest that BA is an effective supplement for enhancing the chemotherapeutic effect on malignant melanoma.

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PMID: 

Leukemia. 2004 Aug ;18(8):1406-12. PMID: 15201849

Abstract Title: 

Betulinic acid-induced apoptosis in leukemia cells.

Abstract: 

Betulinic acid (BA), a natural component isolated from Birch trees, effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, BA was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. No crossresistances were found between BA and any cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells paralleled the pathway found in neuroectodermal cells involving caspases, but not death receptors. In isolated mitochondria, BA induced release of both cytochrome c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia.

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Pomegranate extract provides a natural way to boost athletic performance, increasing the time to exhaustion by more than 1.5 minutes among a group of amateur cyclists

PMID: 

Int J Hyperthermia. 2002 Mar-Apr;18(2):153-64. PMID: 11911485

Abstract Title: 

Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia.

Abstract: 

Betulinic acid is a known inducer of apoptosis in human melanoma that is most effective under conditions of low pH. It was hypothesized that betulinic acid, in combination with acute acidification and/or hyperthermia, would induce higher levels of apoptosis and cytotoxicity in low pH-adapted human melanoma cells than in cells grown at pH 7.3. DB-1 human melanoma cells, adapted to a tumour-like growth pH of 6.7, were exposed to hyperthermia (2h at 42 degrees C) and/or betulinic acid (4-10 microg/ml) and compared with cells grown at a physiological pH of 7.3 or after acute acidification from pH 7.3-6.3 or pH 6.7-6.3. Betulinic acid induced higher levels of apoptosis and cytotoxicity in low pH-adapted cells than in cells grown at pH 7.3, as measured by the terminal deoxynucleotidyl transferase (TdT) DNA fragmentation assay (TUNEL), the MTS cell viability assay, and single cell survival. Acute acidification of low pH adapted cells rendered them more susceptible to betulinic acid-induced apoptosis and cytotoxicity. In the presence of hyperthermia at 42 degrees C for 2 h, cells grown at pH 7.3 were not sensitized to heat killing by betulinic acid, whereas cells grown at pH 7.3 and acutely acidified to pH 6.3, cells adapted to growth at pH 6.7 and cells adapted to growth at pH 6.7 and acutely acidified to pH 6.3 were all similarly sensitized to heat killing by betulinic acid, with survival values of 5, 9 and 2%, respectively. It is concluded that betulinic acid may be useful in potentiating the therapeutic efficacy of hyperthermia as a cytotoxic agent in acidotic areas of tumours with minimal effect in normal tissues growing at pH 7.3.

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