206
N. N. Win and H. Morita
cells were suppressed by the addition of bisphenol A diglycidyl ether, a peroxisome
proliferator-activated receptor (PPAR) antagonist, suggesting that the action of 380
on adipocytes is mediated by PPAR. Since PPAR is a ligand-activated transcription
factor that plays a crucial role in the regulation of glucose homeostasis and lipid
metabolism and is considered to be one of the important targets for the treatment of
metabolic disorders such as type 2 diabetes, and vitexilactone has been proposed as
a novel insulin-sensitizer candidate [451].
Further work on V. trifolia by the same group in order to elucidate its antidiabetic
components has been published [455]. Three lignans, (−)-hinokinin (383) [456],
(−)-O-methylcubebin (384) [457], and (−)-cubebin (385) [460], were isolated from
the ethyl acetate extract of the leaves of V. trifolia, using various chromatographic
methods (Fig. 74). The structure of 384 was also determined by X-ray crystal structure analysis. The occurrence of these three lignans from V. trifolia and single-crystal
X-ray analysis of (–)-O-methylcubebin were reported for the first time [455].
As in the case of 380, an upregulation of intracellular lipid accumulation assay
revealed that 383–385 possess the effect of increasing intracellular lipid accumulation
in a concentration-dependent manner, in the potency order of 384 > 383 > 385.
However, interestingly, while compound 384 had the most potent effect, further
study has revealed that 384 is able to not only reduce the diameter of differentiated
adipocytes significantly but also increase the expression of adiponectin, which is
known to be an important molecule to reduce insulin resistance. Notably, the activity
of (−)-O-methylcubebin (384) was inhibited by antagonists of PPARγ and improved
by inhibitors of the classical mitogen-activated protein kinase (MAPK) pathway
and p38 MAPK pathway, while this lignan did not show any migration of GLUT4
from the cytoplasm to the cell membrane observed for ROS, even though it showed
similar effects to those of ROS. Thus, compound 384 has been proposed as a PPARγ
agonist with the effect of promoting adipogenesis via the inhibition of ERK1/2 and
p38 MAPK phosphorylation. Hence, (−)-O-methylcubebin (384) could be a lead
compound that does not show weight gain, which is a side effect of ROS [455].
2.22 Mansonia gagei Drumm.
Mansonia gagei is a tree belonging to the family Sterculiaceae. It is found in both
Thailand and Myanmar. Locally in Myanmar it is known as Kala-met (Fig. 75), and
is one of the components of TMF-15 (Thee-chay-hsay). This formulation has been
prescribed for insomnia, menopause, swelling, reducing body heat, and improving
the appetite and condition of the skin [459]. Furthermore, a liquid paste obtained
by grinding the heartwood of M. gagei with water is utilized as a popular lotion
that is effective in cooling the skin and relieving muscle pain. Several mansonone onaphthoquinones and coumarins have been reported from M. gagei, and the individual
constituents obtained from this species display antiestrogenic, larvicidal, antioxidant,
antifungal, and cytotoxic activities [460–466].
N. N. Win and H. Morita
cells were suppressed by the addition of bisphenol A diglycidyl ether, a peroxisome
proliferator-activated receptor (PPAR) antagonist, suggesting that the action of 380
on adipocytes is mediated by PPAR. Since PPAR is a ligand-activated transcription
factor that plays a crucial role in the regulation of glucose homeostasis and lipid
metabolism and is considered to be one of the important targets for the treatment of
metabolic disorders such as type 2 diabetes, and vitexilactone has been proposed as
a novel insulin-sensitizer candidate [451].
Further work on V. trifolia by the same group in order to elucidate its antidiabetic
components has been published [455]. Three lignans, (−)-hinokinin (383) [456],
(−)-O-methylcubebin (384) [457], and (−)-cubebin (385) [460], were isolated from
the ethyl acetate extract of the leaves of V. trifolia, using various chromatographic
methods (Fig. 74). The structure of 384 was also determined by X-ray crystal structure analysis. The occurrence of these three lignans from V. trifolia and single-crystal
X-ray analysis of (–)-O-methylcubebin were reported for the first time [455].
As in the case of 380, an upregulation of intracellular lipid accumulation assay
revealed that 383–385 possess the effect of increasing intracellular lipid accumulation
in a concentration-dependent manner, in the potency order of 384 > 383 > 385.
However, interestingly, while compound 384 had the most potent effect, further
study has revealed that 384 is able to not only reduce the diameter of differentiated
adipocytes significantly but also increase the expression of adiponectin, which is
known to be an important molecule to reduce insulin resistance. Notably, the activity
of (−)-O-methylcubebin (384) was inhibited by antagonists of PPARγ and improved
by inhibitors of the classical mitogen-activated protein kinase (MAPK) pathway
and p38 MAPK pathway, while this lignan did not show any migration of GLUT4
from the cytoplasm to the cell membrane observed for ROS, even though it showed
similar effects to those of ROS. Thus, compound 384 has been proposed as a PPARγ
agonist with the effect of promoting adipogenesis via the inhibition of ERK1/2 and
p38 MAPK phosphorylation. Hence, (−)-O-methylcubebin (384) could be a lead
compound that does not show weight gain, which is a side effect of ROS [455].
2.22 Mansonia gagei Drumm.
Mansonia gagei is a tree belonging to the family Sterculiaceae. It is found in both
Thailand and Myanmar. Locally in Myanmar it is known as Kala-met (Fig. 75), and
is one of the components of TMF-15 (Thee-chay-hsay). This formulation has been
prescribed for insomnia, menopause, swelling, reducing body heat, and improving
the appetite and condition of the skin [459]. Furthermore, a liquid paste obtained
by grinding the heartwood of M. gagei with water is utilized as a popular lotion
that is effective in cooling the skin and relieving muscle pain. Several mansonone onaphthoquinones and coumarins have been reported from M. gagei, and the individual
constituents obtained from this species display antiestrogenic, larvicidal, antioxidant,
antifungal, and cytotoxic activities [460–466].