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Fulltext Garcinia subelliptica Merr. (Fukugi): A multipurpose coastal tree with promising medicinal properties

Inoue T, Kainuma M, Baba K, Oshiro N, Kimura N, Chan EW

J Intercult Ethnopharmacol, 2017 Jan 3;6(1):121-127.
PMID: 28163970 DOI: 10.5455/jice.20161229060034

In this short review, the current knowledge on the botany, ecology, uses, and medicinal properties of the multipurpose Garcinia subelliptica (Fukugi) is updated. As yet, there are no reviews on this indigenous and heritage coastal tree species of the Ryukyu Islands in Japan, which has ethnocultural, ecological, and pharmacological significance. Planted by the Okinawan people some 300 years ago, Fukugi trees serve as windbreaks and accord protection against the destructive typhoons. The species has become a popular ornamental tree, and its bark has been used for dyeing fabrics. It forms part of the food chain for mammals and insects and serves as nesting sites for birds. Endowed with bioactive compounds of benzophenones, xanthones, biflavonoids, and triterpenoids, G. subelliptica possesses anticancer, anti-inflammatory, anti-tyrosinase, trypanocidal, antibacterial, DNA topoisomerase inhibitory, DNA strand scission, choline acetyltransferase enhancing, hypoxia-inducible factor-1 inhibitory, and antiandrogenic activities. Fukugetin and fukugiside are two novel biflavonoids named after the species. The chemical constituents of Fukugi fruits when compared with those of mangosteen yielded interesting contrasts.

Matched MeSH terms: Hypoxia-Inducible Factor 1
Bortezomib attenuates HIF-1- but not HIF-2-mediated transcriptional activation

Abd-Aziz N, Stanbridge EJ, Shafee N

Oncol Lett, 2015 Oct;10(4):2192-2196.
PMID: 26622817

Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism for its action is that it prevents the proteasomal degradation of proapoptotic proteins, leading to enhanced apoptosis. Although the α subunit of hypoxia-inducible factor (HIF)-1 is not degraded with bortezomib treatment, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for the survival of hypoxic tumor cells. The majority of reports have focused on the effects of bortezomib on the transcriptional activities of HIF-1, but not HIF-2. The present study investigated the effects of bortezomib on HIF-2 activity in cancer cells with different levels of HIF-1α and HIF-2α subunits. HIF-α subunit levels were detected using specific antibodies, while HIF transcriptional activities were evaluated using immunodetection, reverse transcription-polymerase chain reaction and luciferase reporter assay. Bortezomib treatment was found to suppress the transcription and expression of CA9, a HIF-1-specific target gene; however, it had minimal effects on EPO and GLUT-1, which are target genes of both HIF-1 and HIF-2. These data suggest that bortezomib attenuates the transcriptional activity only of HIF-1, and not HIF-2. This novel finding on the lack of an inhibitory effect of bortezomib on HIF-2 transcriptional activity has implications for the improvement of design and treatment modalities of bortezomib and other PI drugs.

Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit
Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Mohamed AS, Hanafi NI, Sheikh Abdul Kadir SH, Md Noor J, Abdul Hamid Hasani N, Ab Rahim S, et al.

Cell Biochem Funct, 2017 Oct;35(7):453-463.
PMID: 29027248 DOI: 10.1002/cbf.3303

In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca2+ ]i ), and sphingosine-1-phosphate (S1P)-receptor via Gαi -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca2+ ]i , and S1P-Gαi -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl2 ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gαi inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl2 on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl2 -induced [Ca2+ ]i dynamic alteration. Pharmacological inhibition of the Gαi -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl2 detrimental effects, except for cell viability and [Ca2+ ]i . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl2 effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl2 -induced [Ca2+ ]i dynamic changes. We conclude that UDCA cardioprotection against CoCl2 -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gαi -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl2 -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.

Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
Fulltext Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats

Mehrabani M, Najafi M, Kamarul T, Mansouri K, Iranpour M, Nematollahi MH, et al.

Cell Prolif, 2015 Oct;48(5):532-49.
PMID: 26332145 DOI: 10.1111/cpr.12209

OBJECTIVES: Both excessive and insufficient angiogenesis are associated with progression of diabetic complications, of which poor angiogenesis is an important feature. Currently, adipose-derived stem cells (ADSCs) are considered to be a promising source to aid therapeutic neovascularization. However, functionality of these cells is impaired by diabetes which can result from a defect in hypoxia-inducible factor-1 (HIF-1), a key mediator involved in neovascularization. In the current study, we sought to explore effectiveness of pharmacological priming with deferoxamine (DFO) as a hypoxia mimetic agent, to restore the compromised angiogenic pathway, with the aid of ADSCs derived from streptozotocin (STZ)-induced type 1 diabetic rats ('diabetic ADSCs').
MATERIALS AND METHODS: Diabetic ADSCs were treated with DFO and compared to normal and non-treated diabetic ADSCs for expression of HIF-1α, VEGF, FGF-2 and SDF-1, at mRNA and protein levels, using qRT-PCR, western blotting and ELISA assay. Activity of matrix metalloproteinases -2 and -9 were measured using a gelatin zymography assay. Angiogenic potential of conditioned media derived from normal, DFO-treated and non-treated diabetic ADSCs were determined by in vitro (in HUVECs) and in vivo experiments including scratch assay, three-dimensional tube formation testing and surgical wound healing models.
RESULTS: DFO remarkably enhanced expression of noted genes by mRNA and protein levels and restored activity of matrix metalloproteinases -2 and -9. Compromised angiogenic potential of conditioned medium derived from diabetic ADSCs was restored by DFO both in vitro and in vivo experiments.
CONCLUSION: DFO preconditioning restored neovascularization potential of ADSCs derived from diabetic rats by affecting the HIF-1α pathway.

Matched MeSH terms: Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*