Medicinus - Dexa Medica

ily inflammatory function, especially that for promoting
leukocytes infiltration to endothelium. 10 This
highlights the finding that the downregulation of NFkB
has a link to the inhibition of atheroma formation,
suggesting that DLBS1033 can be used as an antiatherogenesis
agent.
To confirm such finding, we observed other inflammation
gene TNFα that activates NF-kB. TNFα is
a cytokine that regulates many biological responses
in cells, including inflammation, proliferation, differentiation,
and cell death. 11 The production of TNFα is
regulated by p38 MAPK through NF-kB activation. As
a key mediator of inflammation, TNFα is related with
the progression of IL-6 and chemokines and the adherence
of leukocytes to the endothelium as well as
affecting lipid metabolism. 12 This study showed that
DLBS1033 decreased the expression of TNFα (Fig. 1b).
It indicated that DLBS1033 can inhibit the progression
of other cytokines that are activated by TNFα
and adherence of leukocytes to endothelium. In the
end, it will avoid the development of plaque on the
endothelium.
In this recent research, DLBS1033 was shown to
suppress the expression of P-selectin. Previous studies
suggest a causal relationship between P-Selectin
and TNFα. 13-15 P-selectin is stored within endothelial
cells may be recruited to the cell surface following
stimulation with inflammatory mediators. 16 Those pselectin
in platelets and endothelial cells mediates
adhesive interaction with leucocytes to form thrombi.
Surface expression of P-selectin in endothelial cells is
regulated by two different mechanisms with a secretagogue
and with a cytokine. Activation by secretagogue
leads the translocation P-selectin to the cell
surface, meanwhile the cytokine leads to de novo
synthesis of P-selectin. 17 Activity of DLBS1033 in decreasing
the expression of P-selectin may be related
to the suppresion of de novo synthesis of P-selectin
mediated by cytokine. In addition, it suggested that
the suppression of NF-kB and TNFα expression leads
to the decrease in the amount of of cytokines, which
therefore could lead to suppression of P-selectin. That
evidence supported the hypothesis that DLBS1033
conferred the ability as antiplatelet agent by inhibiting
the activity of P-selectin to mediate the adhesive
between platelets.
DLBS1033 suppressed the expression of VCAM-1
(Fig. 1c), a member of the immunoglobulin gene superfamily
that mediates leukocyte binding to the endothelial
cell. VCAM-1 expression is rapidly induced
by proinflammatory cytokines such as TNF-α. It activates
endothelial cell NADPH oxidase, and this activity
is required for VCAM-1-dependent lymphocyte
migration. The lymphocyte migration therefore can
trigger the atherosclerotic plaque formation. 18-19
original article
research
These findings first demonstrated the mechanism of
DLBS1033 in maintaining plaque stabilization that involves
inflammatory response.
Plaque instability is associated with high macrophage
content and a thin fibrous cap. Several genes
have been investigated including MMP-9 which has
been known to play a role in the regulation of plaque.
MMP-9 is a protease that degrades extracellular matrix
proteins including gelatin, collagen, elastin, and
laminin that are important in tissue destruction; and
also in tissue remodeling and inflammation. 20-21 It is
synthesized in atheromatous plaques and elevated
levels are present in rupture prone shoulder regions
of arterial vessels. Increased MMP9 activity has also
been correlated with CVD, 2 since it has the capability
to degrade extracellular matrix of the fibrous cap,
predisposing to plaque rupture. In our research, the
MMP9 was markedly suppressed by DLBS1033 (Fig.3).
The expression was suppressed approximately by
50% compared to that of control. MMP9 expression
is regulated by transcriptional factors including AP-1
and NF-kB which bind to the corresponding binding
sites in MMP9 promoter region. 20 The above findings
support the evidence that DLBS1033 could regulate
the uncontrolled event of plaque rupture by inhibiting
the expression of MMP9.
DLBS1033 inhibited the proliferation of the VSMC
significantly. Proliferation of VSMC is a crucial event in
the formation of atherosclerotic tissues and is regulated
by nuclear transcriptional factors including NF-kB.
Studies have shown that diffuse intimal medial thickening
is also characterized by Angiotensin II. 22-23 In
this recent study, DLBS1033 significantly reduced Angiontensin
II and therefore inhibits the intimal medial
thickening.
In addition to these findings, we observed JAK1-
STAT1 system. This system plays an important role in
the proliferation of VSMC. DLBS1033 decreased the
expression of JAK1 (Fig. 5a) and STAT1 (Fig. 5b). JAK1 is
required for myoblast proliferation and also functions
as a checkpoint to prevent myoblasts from premature
differentiation. Deliberate knockdown of JAK1 in both
primary and immortalized myoblasts induces precocious
myogenic differentiation with a concomitant
reduction in cell proliferation. 24 Inhibition of JAK1
phosphorylation could induce the inhibition of STAT1
phosphorylation. 25 These results together indicated
that DLBS1033 reduced cardiovascular events also via
reducing intimal medial thickness.
The investigation of DLBS1033 activity as for providing
an effective mean to prevent cardiovascular
disease was appeared to bring a good result. Taken
together, the data shows the anti-inflammatory effect
of DLBS1033 through the suppression of various
genes such as NF-kB. Furthermore, the data indicates
MEDICINUS 24(1), January 2011 23