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Ameliorating effects of antioxidative compounds from four plant extracts in experimental models of diabetes

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Abstract: Given that oxidative stress plays a major role in pancreatic β-cell dysfunction and ultimate destruction, as well as in different complications of diabetes, therapy with antioxidants has assumed an important place in the management of diabetes. The relatively limited effects of established antioxi- dant compounds have stimulated efforts to develop new therapeutic strategies, e.g. to increase the endogenous antioxidant defences through pharmacological modulation of key antioxidant enzymes. Plant extracts are gaining popularity in treating diabetes because many substances synthesized by higher plants and fungi possess antioxidant activities and can prevent or protect tissues against the damaging effects of free radicals. This review summarizes experimental models of diabetes and possible mechanisms that lie behind the antioxidative effects of α-lipoic acid (LA), a powerful antioxidant and compound that sti- mulates cellular glucose uptake, as well as of plant extracts from sweet chest- nut (Castanea sativa), edible mushroom (Lactarius deterrimus) and natural products containing β-glucans in the treatment of diabetes. Their roles in pre- venting pancreatic β-cell death and in ameliorating the effects of severe dia- betic complications are discussed. Keywords: diabetes; oxidative stress; lipoic acid; plant antioxidants.
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J. Serb. Chem. Soc. 78 (3) 365–380 (2013) UDC 616.379–008.64+615.8+
JSCS–4422 633.879.6:615.27
Review
365
REVIEW
Ameliorating effects of antioxidative compounds from four plant
extracts in experimental models of diabetes
SVETLANA DINIĆ*, ALEKSANDRA USKOKOVIĆ, MIRJANA MIHAILOVIĆ,
NEVENA GRDOVIĆ, JELENA ARAMBAŠIĆ, JELENA MARKOVIĆ,
GORAN POZNANOVIĆ and MELITA VIDAKOVIĆ
Department of Molecular Biology, Institute for Biological Research, University of Belgrade,
Bulevar despota Stefana 142, 11060 Belgrade, Serbia
(Received 26 October, revised 6 December 2012)
Abstract: Given that oxidative stress plays a major role in pancreatic β-cell
dysfunction and ultimate destruction, as well as in different complications of
diabetes, therapy with antioxidants has assumed an important place in the
management of diabetes. The relatively limited effects of established antioxi-
dant compounds have stimulated efforts to develop new therapeutic strategies,
e.g. to increase the endogenous antioxidant defences through pharmacological
modulation of key antioxidant enzymes. Plant extracts are gaining popularity in
treating diabetes because many substances synthesized by higher plants and
fungi possess antioxidant activities and can prevent or protect tissues against
the damaging effects of free radicals. This review summarizes experimental
models of diabetes and possible mechanisms that lie behind the antioxidative
effects of α-lipoic acid (LA), a powerful antioxidant and compound that sti-
mulates cellular glucose uptake, as well as of plant extracts from sweet chest-
nut (Castanea sativa), edible mushroom (Lactarius deterrimus) and natural
products containing β-glucans in the treatment of diabetes. Their roles in pre-
venting pancreatic β-cell death and in ameliorating the effects of severe dia-
betic complications are discussed.
Keywords: diabetes; oxidative stress; lipoic acid; plant antioxidants.
CONTENTS
1. INTRODUCTION
2. OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETES AND ITS
COMPLICATIONS
3. EXPERIMENTAL MODELS OF DIABETES MELLITUS
* Corresponding author. E-mail: sdinic@ibiss.bg.ac.rs
doi: 10.2298/JSC121026136D
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366 DINIĆ at al.
4. NUMEROUS ANTIOXIDANT COMPOUNDS AND PLANT EXTRACTS IN
DIABETES MANAGEMENT
5. NOVEL MECHANISM OF ANTIOXIDATIVE EFFECT OF LA IN DIABETES
6. POSITIVE EFFECTS OF L. deterrimus (Ld) AND C. sativa (Cs) EXTRACTS AND
THEIR COMBINATION (MIX Ld/Cs) ON β-CELL SURVIVAL
7. EFFECTS OF
β
-GLUCANS ON DIABETES AND THE ASSOCIATED
COMPLICATIONS
8. CONCLUSIONS
1. INTRODUCTION
Diabetes mellitus is a chronic metabolic disease with an aetiology linked to
both genetic and environmental factors. Diabetes has become a global health
problem due to its high incidence and latent harmful and lethal effects. Accord-
ing to the World Health Organization (WHO),1 347 million people worldwide
have diabetes, which has greatly increased the cost of treating both the disease
and its numerous devastating complications. According to the International Dia-
betes Federation (IDF), 4.6 million people die each year from the consequences
of diabetes,2 with more than 80 % of diabetes-related deaths occurring in low and
middle income countries.1 According to The Public Health Institute of Serbia
“Dr Milan Jovanović Batut”,3 630,000 people or 8.2 % of the Serbian population
suffer from diabetes and about 3,000 diabetics die each year. Type 1 diabetes
(T1D) is characterized by destruction of pancreatic β-cells and thereby loss of
insulin secretion. Type 2 diabetes (T2D) is associated with progressive insulin
resistance and β-cell dysfunction. Deficiency of insulin secretion or action in
diabetes causes prolonged hyperglycaemia that in turn leads to severe diabetic
complications, such as retinopathy, neuropathy, nephropathy, cardiovascular
problems, liver disease and limb amputation. Diabetes treatment includes insulin
injection in combination with application of hypoglycaemic drugs. However,
current control of diabetes-associated complications and mortality is not satis-
factory.
Limitations in diabetes treatment have stimulated efforts to develop new the-
rapeutic strategies. Growing evidence in both experimental and clinical studies
suggests that oxidative stress plays an important role in pancreatic β-cell des-
truction/dysfunction and subsequent complications of diabetes. Therefore, stra-
tegies for diabetes management include antioxidant protection. However, estab-
lished antioxidant compounds, such as vitamins C and E, have yielded limited
effects, indicating the necessity for examination of other antioxidant compounds.
Given that antioxidant enzyme expression and function is deregulated in dia-
betes, pharmacological modulation of key enzymes that are responsible for re-
ducing the oxygen radical load is a potentially more effective approach than the
use of systemic antioxidants.4,5 It is therefore imperative to continuously identify
new products with antioxidant activities for use in “causal” therapy of diabetes.6
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PLANT EXTRACTS IN DIABETES TREATMENT 367
Plant extracts are gaining popularity in diabetes treatment because of their effi-
cacy, low incidence of side effects, their accessibility and low cost. Identifying
new agents from plants with hypoglycaemic and antioxidative activities is of
great importance. In this review, a summary will be given of the ameliorating
effects and potential mechanisms of the actions of the known antioxidant com-
pound α-lipoic acid (LA), extracts of the sweet chestnut (Castanea sativa), edible
mushroom (Lactarius deterrimus) and their combination (MIX Cs/Ld), and of a
β-glucan-enriched extract in the treatment of diabetes, i.e., in the prevention of
pancreatic β-cell death and amelioration of the severe complications in diabetes.
Experimental models of diabetes will also be discussed.
2. OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETES
AND ITS COMPLICATIONS
Oxidative stress is generally defined as a persistent imbalance between the
concentrations of generated highly reactive free radical reactive oxygen species
(ROS) and reactive nitrogen species (RNS) on the one hand and the antioxidant
defence of the organism on the other. Hyperglycaemia promotes the formation of
elevated levels of free radicals, especially ROS, via different routes of activation:
glucose autoxidation,7 non-enzymatic protein glycation,8 increased metabolism
of glucose through the hexosamine pathway,9 excessive activation of the polyol
pathway by unused glucose,10 and by advanced glycation end-products (AGE)
formed by the interaction of glucose with proteins.11 One of the main sources of
free radicals in diabetes is glucose autoxidation.12 In a transition-metal dependent
reaction, the enediol form of glucose is oxidized to an enediol radical anion that
is converted into reactive ketoaldehydes and to superoxide anion radicals (O2).
The superoxide anion radicals undergo dismutation to hydrogen peroxide (H2O2),
which, if not degraded by catalase (CAT) or glutathione peroxidase (GSH-Px), in
the presence of transition metals can lead to the production of extremely reactive
hydroxyl radicals (OH·).13 Superoxide anion radicals can also react with nitric
oxide (NO) to form reactive peroxynitrite. Peroxynitrite is chemically unstable
under physiological conditions and reacts with all major classes of biomolecules,
mediating cytotoxicity,14 AGE signalling, through the receptor for AGE (RAGE),
and inactivation of enzymes by altering their structure,15 thereby supporting ad-
ditional free radical accumulation.16 Excess levels of free radicals damage cel-
lular proteins, lipids and nucleic acids, leading to cell death in various tissues (the
cardiovascular system, retina, kidneys, liver, peripheral nerves and skin), thus
contributing to diabetes complications. The harmful effects of ROS and RNS are
neutralized by the endogenously expressed antioxidant enzymes (superoxide dis-
mutases (SODs), CAT, GSH-Px) and non-enzymatic antioxidants (endogenous
reduced glutathione (GSH) and exogenous vitamins C and E).7
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3. EXPERIMENTAL MODELS OF DIABETES MELLITUS
Experimental models play an important role in understanding diabetes, as
well as in evaluating the pharmacological actions of different agents. Isolated rat,
mouse and human pancreatic islets are used for investigating the mechanisms
involved in β-cell dysfunction and destruction in diabetes.17–19 The use of pri-
mary β-cells in research is limited because their purification and maintenance of
native characteristics is technically demanding. To overcome these limitations,
investigators have produced immortalized β-cell lines.20 The most widely used
insulin-secreting cell lines are rat insulinoma cells (RIN and INS-1), hamster
pancreatic β-cells (HIT) and mouse insulinoma cells (MIN and βTC). Although
the properties of the cell lines differ slightly from those of primary β-cells, they
are extremely valuable tools for the study of molecular events underlying β-cell
function, including the testing of the effects of potential drugs in diabetes mana-
gement.
Several animal models have been developed for in vivo studies of diabetes
and anti-diabetic agents. Genetic models of diabetes include the spontaneous
development of diabetes in rats21,22 and genetically engineered diabetic mice to
either overexpress (transgenic) or underexpress (knockout) proteins thought to
play a key role in glucose metabolism.23,24 Surgical model of diabetes include
the complete removal of the pancreas (pancreatectomy) or partial pancreatectomy
(more than 80 % resection in rats). These models allow for the evaluation of the
effect of natural products in an animal without the interference of side effects
induced by chemical drugs used to induce experimental diabetes.25,26 However,
these models are rarely used because of the highly specialized technical skills
required and the high percentage of animal mortalities.
Chemical induction is the most popular procedure for inducing diabetes in
experimental animals and has been proven repeatedly to be useful for the study
of multiple aspects of the disease. Streptozotocin (STZ), a naturally occurring
glucosamine–nitrosourea compound is the most frequently used drug for experi-
mental diabetes induction in laboratory rats. As a glucose analogue, STZ selecti-
vely accumulates in β-cells via the glucose transporter (GLUT2). As an alkyla-
ting agent, STZ fragments DNA.27 DNA damage induces activation of the DNA
repair process that leads to enhanced ATP dephosphorylation, which supplies a
substrate for xanthine oxidase, resulting in ROS formation. The diabetogenic
effect of STZ also relies on its ability to liberate NO which participates in DNA
damage. STZ is capable of inducing T1D either by direct β-cell destruction after
administration of a single large dose of STZ (65–150 mg kg–1),28 or via an im-
mune cell-mediated mechanism using multiple low doses of STZ (40 mg kg–1).29
A single high dose of STZ causes extensive non-physiological β-cell necrosis,
whereas multiple low doses of STZ induce limited apoptosis, which elicits an
autoimmune reaction that eliminates the remaining cells.30 There is a general
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PLANT EXTRACTS IN DIABETES TREATMENT 369
consensus that the experimental model of multiple low-dose STZ-induced dia-
betes resembles more closely the in vivo state of insulinaemia, reflecting its
autoimmune nature and resulting onset of diabetes.
4. NUMEROUS ANTIOXIDANT COMPOUNDS AND PLANT EXTRACTS
IN DIABETES MANAGEMENT
A number of studies have demonstrated that treatment with antioxidants
reduces oxidative stress and alleviates diabetic complications in diabetic subjects
and animals.31 Vitamins C and E, and LA are the most studied antioxidants.
Vitamin C is the strongest physiological antioxidant. It regenerates vitamin E
through redox cycling and increases intracellular GSH levels.32 Small clinical
trials showed that vitamin E, as well as a combination of vitamin E and C,
exerted beneficial effects on the cardiovascular system in T1D patients33,34 and
improved renal function in T2D patients.35 However, in large-scale clinical trials,
i.e., Heart Outcomes Prevention Evaluation (HOPE),36 Secondary Prevention
with Antioxidants of Cardiovascular Disease in End Stage Renal Disease
(SPACE),37 the Primary Prevention Project (PPP)38 and the Study to Evaluate
Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E
(SECURE),39 vitamin E treatment failed to provide any benefit in cardiovascular
disorders or nephropathy. A multifactorial approach is more efficient than con-
ventional therapy for the prevention of oxidative stress-induced vascular compli-
cations in diabetes.40 Daily supplementation of vitamin C (250 mg), vitamin E
(100 mg), folic acid (400 mg) and chromium picolinate (100 mg) in combination
with multifactorial intensive therapy resulted in an almost 50 % decrease in
cardiovascular incidents.
LA stimulates cellular glucose uptake and possesses direct radical-scaveng-
ing and metal-chelating properties, and has the ability to regenerate other anti-
oxidants.41 Naturally occurring LA is present in low amounts in vegetables and
animal tissues where it functions as a coenzyme in pyruvate dehydrogenase and
α
-ketoglutarate dehydrogenase mitochondrial reactions. The most abundant plant
sources of LA are spinach, followed by broccoli and tomatoes. Synthetic LA has
a relatively long history of use as a nutritional supplement in European countries
and the United States, and as a therapeutic agent in the treatment of diabetic
neuropathy and retinopathy.42 Studies with LA, i.e., Alpha Lipoic Acid in Dia-
betic Neuropathy (ALADIN) I, II and III,43–45 and Deutsche Kardiale Autonome
Neuropathie (DEKAN),46 investigated the effect of LA treatment on sensory
symptoms of diabetic polyneuropathy as assessed by the Total Symptom Score
(SYDNEY)47 and meta-analysis48 led to its approval for the treatment of diabetic
neuropathy, and initial results are more promising than those obtained with vita-
min E. Parallel with LA use, questions of its safety and effectiveness have been
raised. A daily oral dose of 600 mg provides an optimum risk-to-benefit ratio in
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human diabetics.42 LA supplementation at higher doses causes a few serious side
effects, such as gastrointestinal disorders and allergic reactions. Selection of the
appropriate dose of LA for application in diabetes is critical.49 As cholestatic
hepatitis was probably caused by LA (600 mg day–1) treatment of symptomatic
diabetic neuropathy,50 the authors suggest liver enzyme levels be monitored
during LA treatment.
Phytochemicals, the bioactive non-nutrient plant compounds in fruit, vege-
tables, grains and other plant foods, have been linked to reductions in the risk of
major chronic diseases. It is estimated that more than 5,000 phytochemicals have
been identified, but that a large percentage remains unknown.51 Phytochemicals
with antioxidative effects include a variety of phytosterols, terpenes and espe-
cially polyphenols, such as flavonoids, tannins and phenylpropanoids. A direct
correlation between the total phenolic content and antioxidant capacity was esta-
blished and explained through a number of different mechanisms, such as free
radical scavenging, metal ion chelation and hydrogen donation.52–54
There is a growing interest for the use of plant extracts because purified
bioavailable phenolic compounds are difficult to obtain, and because extracts
sometimes have better antioxidant activities than the pure molecules.55 Taken
alone, the individual antioxidants studied in clinical trials do not appear to have
consistent diabetes-preventive effects. Studies of different fruit combinations
showed greater total antioxidant activity because of their additive and synergistic
relationships.51 An isolated pure compound can lose its bioactivity or may not
exhibit it in the same way as when present in whole foods. This partially explains
why no single antioxidant can replace a combination of natural phytochemicals
contained in plants in accomplishing health benefits. Although plants are rich in
antioxidants, individual “antioxidant” molecules cannot just be extracted, packed
in pills in high doses and expected to provide high levels of protection.5 Pills or
tablets cannot mimic the balanced natural combination of phytochemicals present
in plants. Phytochemicals differ in molecular size, polarity, and solubility, and
these differences may affect the bioavailability and distribution of each phytoche-
mical in different macromolecules, sub-cellular organelles, cells, organs, and tis-
sues. These observations have lead to the concept that antioxidants are better im-
plemented through whole food consumption than as expensive dietary supple-
ments. Further research on the health benefits of phytochemicals in whole foods
is of essential interest.56
Many investigations have studied the effects of antioxidant components of
plants on diabetes and its complications. Antioxidant and antihyperglycemic pro-
perties of Allium cepa L., Anoectochilus formosanus, Lycium barbarum, Cassia
fistula L., Aloe vera, Vitis aestivalis and Coffea arabica in chemical models of
diabetes have been demonstrated.57–63 In addition, Centaurium erythrea and
Aegle marmelos extracts and quercetin, a flavonoid antioxidant present in many
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PLANT EXTRACTS IN DIABETES TREATMENT 371
plants, alleviate STZ-induced cell damage and oxidative stress in rat pancreas.65–66
Medicinal plants with proven antidiabetic and related beneficial effects in dia-
betes treatment also include: Allium sativum, Eugenia jambolana, Momordica
charantia, Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium,
Tinospora cordifolia, Trigonella foenum graecum and Withania somnifera.67
5. NOVEL MECHANISM OF ANTIOXIDATIVE EFFECT OF LA IN DIABETES
Numerous studies indicate that LA exerts its antioxidant effect by increasing
the endogenous defence response of cells through enhanced synthesis of endo-
genous low molecular weight antioxidants and antioxidant enzymes.42 The levels
of antioxidant enzymes are regulated by gene expression, as well as by post-
translational modifications.68 Emerging data indicates that the post-translational
addition of β-N-acetylglucosamine (O-GlcNAc) to proteins has a role in the
aetiology of diabetes.69 O-linked glycosylation of certain proteins is increased in
hyperglycaemia because of activation of the hexosamine pathway, which pro-
duces uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), a substrate for
the glycosylation reaction. This modification is dynamic and may disturb the
normal dynamic balance between O-GlcNAcylation and O-phosphorylation that
controls enzyme activity, DNA binding, protein–protein interactions, the half-life
of proteins and their sub-cellular localization. Elucidation of the specific roles of
O-GlcNAc in transcription, cell signalling, glucose toxicity and insulin resistance
should lead to new avenues for the diagnosis and treatment of diabetes.69
A novel mechanism of the antioxidant effect of LA in diabetes progression
through decreased O-GlcNAcylation of the key proteins that are involved in
redox signalling pathways was hypothesized.70,71 In these experiments, LA was
applied at a dose of 10 mg kg–1 i.p., which corresponds to 600 mg LA day–1 in
humans for 4 weeks, starting from the last day of STZ administration (40 mg kg–1
i.p. for 5 consecutive days). These studies focused on the antioxidant defence
system of red blood cells (RBC) and kidneys. RBC are exposed to some of the
highest levels of oxidative stress in the body because they continuously transport
oxygen and are the first cellular structures to respond to increased ROS presence.
RBC damage is a reflection of the general state of oxidative stress in the whole
organism.72 In the hyperglycaemic environment, RBCs are subjected to compo-
sitional changes and are affected at the functional level.73 In agreement with
other reports, enzymatic silencing of CuZnSOD and CAT in RBC under diabetic
conditions were observed,74,75 which was associated with increased levels of O-
GlcNAc-modification of CuZnSOD and CAT, and of the heat shock proteins
HSP70 and HSP90.70 In vitro studies showed that glycosylation causes a 40 %
lowering of CuZnSOD activity in RBC.76 It was shown that LA administration to
diabetic rats preserved the structural and functional integrity of RBC by adjusting
the redox disturbance and by decreasing the O-GlcNAcylation of SOD and CAT.
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It was hypothesized that the induction of HSP90 and the lowering of the levels of
O-GlcNAc-modification of HSP70 and HSP90 as a result of the LA treatment is
an important defence mechanism in RBC, since HSPs monitor, protect and main-
tain the structure and stability of erythrocyte proteins. These results are valuable
because functional and healthy RBC could delay or inhibit further diabetic com-
plications, especially neuropathy.
The renal-protective effect of LA is associated with a reduction of oxidative
stress.77 Recently performed work revealed that LA administration activates a
coordinated cytoprotective response against diabetes-induced oxidative injury in
kidneys through an O-GlcNAc-dependent mechanism, which influences the ex-
pression and activities of CuZnSOD and CAT. The observed upregulation of the
antioxidant enzyme genes during LA treatment in diabetic kidney was accom-
panied by nuclear translocation of the nuclear factor-erythroid-2-related factor
(Nrf2), enhanced expression of HSPs and by a reduction of O-GlcNAcylation of
HSP90 and HSP70, and of the extra-cellular regulated kinase (ERK) and p38.
Under unstressed conditions, Nrf2 resides in the cytoplasm as an inactive com-
plex bound to a repressor molecule known as Keap1 (Kelch-like ECH-associated
protein 1) that facilitates its ubiquitination.78 Upon activation, Nrf2 translocates
to the nucleus where it heterodimerizes with specific cofactors and coordinates
the upregulation of cytoprotective genes through the initiation of transcription at
an antioxidant response element (ARE).79 In addition, it was reported that HSP90
interaction with Keap1 can mediate Nrf2 activation.80 LA can oxidize critical
thiols on the Keap1 dimer to halt Nrf2 degradation and to prevent Keap1 from
binding newly synthesized Nrf2. LA also activates the protein kinase signalling
pathways that lead to the phosphorylation of Ser40 on Nrf2, allowing it to dis-
sociate from Keap1 and to translocate to the nucleus.42 Inhibition of nitrogen-
activated kinases (MAPKs), ERK and p38 prevents the accumulation of Nrf2 in
the nucleus independently of its phosphorylation.81 It was suggested that MAPK-
mediated phosphorylation of molecular chaperones or some other type of
accessory protein is required for Nrf2 nuclear translocation.82 Based on our
obtained results and existing literature data, a model that illustrates the potential
mechanisms by which LA ameliorates kidney damage in diabetes by inducing
SOD and CAT expression is presented in Fig. 1.
6. POSITIVE EFFECTS OF L. deterrimus (Ld) AND C. sativa (Cs) EXTRACTS AND
THEIR COMBINATION (MIX Ld/Cs) ON β-CELL SURVIVAL
Examination of compounds and factors that can regulate β-cell survival,
growth and functioning is of great interest in the context of the prevention of
diabetes development and its progress. The antioxidant properties and beneficial
effects of extracts obtained from the edible mushroom Lactarius deterrimus (Ld),
the sweet chestnut Castanea sativa (Cs) and their combination (MIX Ld/Cs) on
STZ-induced rat pancreatic β-cell (Rin-5F cells) death have been described.83,84
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PLANT EXTRACTS IN DIABETES TREATMENT 373
Fig. 1. Potential mechanisms of LA-regulated SOD and CAT gene expression in kidneys of
diabetic rats. Pathway A illustrates LA-induced protein expression of HSPs and their
decreased O-GlcNAc modifications that could influence their interaction with Keap1, causing
a subsequent release of Nrf2 (A1) and/or formation of HSP-Nrf2 heterocomplex that
translocates to the nucleus and binds ARE (A2), promoting the transcription of genes for
MnSOD, CuZnSOD and CAT. In a LA-orchestrated O-GlcNAc-dependent mechanism
(pathway B), reduced O-GlcNAc modification of ERK and p38 could enhance their activity.
Activated ERK and p38 could phosphorylate a certain Nrf2-binding protein (Nrf2-B.P.) that
could assist the nuclear translocation of Nrf2 released from Keap1.
The Cs extract exhibited a remarkably high level of antioxidant activity in vitro,
while the Ld extract displayed good H2O2 and NO scavenging activities. MIX
Ld/Cs demonstrated strong antioxidant effects in vitro, and astonishingly, a very
effective Fe2+ chelating effect, despite the very low individual chelating activities
of the Ld and Cs extracts. This is in correlation with the concept that no single
antioxidant can replace the health benefits of a combination of natural phytoche-
micals because of their additive and synergistic effects.51 Each extract and espe-
cially their combination increased Rin-5F cell viability after the STZ treatment as
a result of a significant reduction in DNA damage and improved redox status. It
is suggested that different mechanisms underlie the antioxidant effects of Cs, Ld
and MIX Ld/Cs (Fig. 2). The antioxidant property of the Cs extract probably re-
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lies on its ROS scavenging activity.55,83,85,86 It directly correlates with the ex-
tremely high content of phenolic compounds, especially of hydrolysable tannins
(ellagic and gallic acids and their derivatives). The beneficial biological effects of
these compounds in vivo are related to the high free radical-scavenging activity
they exhibit in vitro.87 The antioxidant properties of the Ld can be explained by a
strong NO scavenging activity. The low phenolic content of the Ls extract sug-
gests that some other non-phenolic compounds or secondary metabolites88 were
responsible for its beneficial effect, such as the essential trace elements Se and
Zn. Se functions as a cofactor of some antioxidant enzymes,89 while Zn protects
enzyme sulfhydryls from oxidation and reduces the formation of the hydroxyl ra-
dical from H2O2 by competing with redox-active transition metals.90 It is sug-
gested that the MIX Ld/Cs displayed the most beneficial effect on cell survival
through the additive and synergistic effects of the different antioxidant activities
contained in Cs and Ld extracts.56 These results provide compelling evidence
that mixtures of extracts acquire new qualities with respect to the individual ex-
tracts and individual components. This feature explains the improved antioxidant
and beneficial effects that were exerted on β-cells.
Fig. 2. Potential mechanism of Cs, Ld and MIX Ld/Cs action on the improvement of Rin-5F
cell redox status and survival.
The antioxidant properties of the mushroom and chestnut extracts need to be
confirmed in vivo on a rat model of STZ-induced diabetes (work in progress).
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Duly aware of the limitations of the in vitro model system, it is proposed that the
MIX Ld/Cs can reduce oxidative stress in β-cells and that it could thereby
potentially attenuate the process that underlies the development and progression
of diabetes.
7. EFFECTS OF
β
-GLUCANS ON DIABETES AND THE ASSOCIATED
COMPLICATIONS
Natural products containing β-glucans as active components have been pro-
posed to improve general health.91–93 β-Glucans belong to a group of polysac-
charides that are characterized by their location in the cell wall. Some microor-
ganisms, mushrooms and cereals, such as barley and oats, are rich in β-glucans.94
The macromolecular structure of β-glucans depends on both the source and me-
thod of isolation. The biological activities of β-glucans are determined by their
primary structure, solubility, degree of branching, molecular weight, the charge
on their polymers and structure in aqueous media.95 On reviewing the literature,
it became obvious that the observed effects of β-glucans and glucan-containing
products are controversial.96 While there are reports that emphasize the immune
stimulatory97,98 and pro-inflammatory effects of β-glucans,99 as well as in-
creased generation of ROS,100 other studies described their free radical scaveng-
ing activities,101 and anti-inflammatory102 and antioxidative effects.103 Among
several mechanisms proposed for the protective effects of β-glucan, a major one
is related to its antioxidant activity.104
β-Glucans have shown great potential in the treatment of diabetes.92 They
are effective in lowering blood glucose concentrations and decreasing hyperlipi-
daemia and hypertension. In addition, β-glucans also promote wound healing and
alleviate ischemic heart injury. Foods containing β-glucans have been used in
clinical trials in the treatment of diabetes.105,106 Our preliminary results are based
on observations obtained after treating STZ-induced diabetic rats with a comer-
cially available β-glucan-enriched extract (80 mg kg–1 for four weeks, starting
from the last day of STZ treatment). Treating diabetic rats with β-glucan pro-
moted a systemic improvement that could be expected to increase the resistance
of the organism to the onset of diabetic complications. The beneficial effect of
the β-glucan-enriched extract against diabetes-associated liver and kidney injury
was mediated through its hyperglycaemia lowering, anti-inflammatory and anti-
oxidant actions. It was speculated that the observed properties of the applied com-
mercial β-glucan-enriched extract could be attributed to the effects of β-glucan
and other components of the preparation. Mechanisms underlying its effect on
diabetes and associated complications need to be investigated using pure β-glucan.
8. CONCLUSIONS
Despite numerous strategies designed to improve different diabetes-related
symptoms, the current control of diabetes-associated complications and mortality
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is not satisfactory. Targeting of oxidative stress in the management of diabetes
using synthetic antioxidants, such as vitamins A, C and E, yielded limited results
and the presence of side effects. This has renewed interest in the therapeutic
potential of bioavailable compounds, extracts and complex mixtures. Due to the
relatively lower number of side effects and lower cost, naturally derived sub-
stances provide a useful source of potential novel anti-diabetogenic pharmaceu-
tical entities and dietary supplements to existing therapies. Considering that phy-
tochemicals can reduce the major risk factors in diabetes, such as hypergly-
caemia, hyperlipidaemia and oxidative stress, the use of medicinal plants repre-
sents a promising approach for treating diabetes. It is therefore imperative to con-
tinuously identify naturally occurring products with antioxidant activities for use
in the “causal” therapy of diabetes.
Acknowledgement. This work was supported by the Ministry of Education, Science and
Technological Development of the Republic of Serbia, Grant No. 173020.
ИЗВОД
ПОЗИТИВНО ДЕЈСТВО АНТИОКСИДАТИВНИХ ЈЕДИЊЕЊА ИЗ БИЉНИХ
ЕКСТРАКАТА У ЕКСПЕРИМЕНТАЛНОМ МОДЕЛУ ДИЈАБЕТЕСА
СВЕТЛАНА ДИНИЋ, АЛЕКСАНДРА УСКОКОВИЋ, МИРЈАНА МИХАИЛОВИЋ, НЕВЕНА ГРДОВИЋ, ЈЕЛЕНА
АРАМБАШИЋ, ЈЕЛЕНА МАРКОВИЋ, ГОРАН ПОЗНАНОВИЋ И МЕЛИТА ВИДАКОВИЋ
Одељење за молекуларну биологију, Институт за биолошка истраживања, Универзитет у Београду,
Булевар деспота Стефана 142, 11060 Београд
Терапија антиоксидансима заузима значајно место у лечењу дијабетеса с обзиром
да оксидативни стрес у великој мери доприноси нарушавању функције и структуре β-ће-
лија панкреаса као и развоју компликација у дијабетесу. Због ограниченог дејства посто-
јећих антиоксидативних једињења трага се за новим терапијским решењима у третману
дијабетеса, као што је повећање ендогене антиоксидативне заштите организма путем
фармаколошке модулације кључних антиоксидативних ензима. Примена биљних екс-
траката у лечењу дијабетеса постаје све популарнија. Многе супстанце које се налазе у
саставу виших биљака и гљива поседују антиоксидативна својства која могу да заштите
ткива од штетних утицаја слободних радикала. У овом ревијалном раду описани су екс-
периментални модели дијабетеса као и могући механизми који леже у основи анти-
оксидативног дејства α-липонске киселине (LA), снажног антиоксиданса и једињења које
стимулише ћелијску апсорпцију глукозе, као и биљних екстраката изолованих из слатког
кестена (Castanea sativa), јестивих печурака (Lactarius deterrimus) и природних производа
који садрже β-глукан у лечењу дијабетеса. Описани су њихова улога у спречавању смрти
β-ћелија панкреаса као и благотворно дејство на компликације у дијабетесу.
(Примљено 26. октобра, ревидирано 6. децембра 2012)
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... Considering that ROS production is indispensable and at the same time potentially detrimental to normal beta-cell functioning, a suitable modulation of the antioxidant capacity of beta-cells under chronic oxidative stress (as in diabetes) could exert beneficial effects. Thus, studies using experimental models of diabetes revealed diabetes amelioration after treatment with plant extracts possessing antioxidant activity (reviewed in Dinić et al., 2013). Centaurium erythraea Rafn (CE), known by the common name centaury (fam. ...
... Due to its deleterious actions, oxidative stress is one of the potential therapeutic targets for preventing or slowing down beta-cell loss and dysfunction. An increasing amount of data indicates that oxidative stress can be mitigated by antioxidants contained in plant extract preparations either by free radical scavenging or by modulation of antioxidant enzyme activities (reviewed in Dinić et al., 2013). The results presented herein show that treatment with CEE improved insulin production and glycemic control in STZ-induced diabetic rats by improving the structural and functional properties of pancreatic islets. ...
Article
Ethnopharmacological relevance: Centaurium erythraea Rafn (CE) is used as a traditional medicinal plant in Serbia to treat different ailments due to its antidiabetic, antipyretic, antiflatulent and detoxification effects. Aim of the study: Elucidation of the mechanisms that underlie the antioxidant and pro-survival effects of the CE extract (CEE) in beta-cells and pancreatic islets from streptozotocin (STZ)-treated diabetic rats. Material and methods: Diabetes was induced in rats by multiple applications of low doses of STZ (40 mg/kg intraperitoneally (i.p.), for five consecutive days). CEE (100 mg/kg) was administered orally, in the pre-treated group for two weeks before diabetes induction, during the treatments with STZ and for four weeks after diabetes onset, and in the post-treatment group for four weeks after diabetes induction. The impact of CEE on diabetic islets was estimated by histological and immunohistochemical examination of the pancreas. Molecular mechanisms of the effects of CEE were also analyzed in insulinoma Rin-5F cells treated with STZ (12 mM) and CEE (0.25 mg/mL). Oxidative stress was evaluated by assessing the levels of DNA damage, lipid peroxidation, protein S-glutathionylation and enzymatic activities and expression of CAT, MnSOD, CuZnSOD, GPx and GR in beta-cells. The presence and activities of the redox-sensitive and islet-enriched regulatory proteins were also analyzed. Results: Treatment with CEE ameliorated the insulin level and glycemic control in STZ-induced diabetic rats by improving the structural and functional properties of pancreatic islets through multiple routes of action. The disturbance of islet morphology and islet cell contents in diabetes was reduced by the CEE treatment and was associated with a protective effect of CEE on the levels of insulin, GLUT-2 and p-Akt in diabetic islets. The antioxidant effect of CEE on STZ-treated beta-cells was displayed as reduced DNA damage, lipid peroxidation, protein S-glutathionylation and alleviation of STZ-induced disruption in MnSOD, CuZnSOD and CAT enzyme activities. The oxidative stress-induced disturbance of the transcriptional regulation of CAT, MnSOD, CuZnSOD, GPx and GR enzymes in beta-cells was improved after the CEE treatment, and was observed as readjustment of the presence and activities of redox-sensitive NFκB-p65, FOXO3A, Sp1 and Nrf-2 transcription factors. The observed CEE-mediated induction of proliferative and pro-survival pathways and insulin expression/secretion after STZ-induced oxidative stress in beta-cells could be partially attributed to a fine-tuned modulation of the activities of pro-survival Akt, ERK and p38 kinases and islet-enriched Pdx-1 and MafA regulatory factors. Conclusions: The results of this study provide evidence that CEE improves the structural and functional properties of pancreatic beta-cells by correcting the endogenous antioxidant regulatory mechanisms and by promoting proliferative and pro-survival pathways in beta-cells.
Article
Full-text available
Effect of petroleum ether extracts of kernel (NSK) and husk (NSH) of neem (Azadirachta indica A. Juss, Meliaceae) seeds on the prevention of oxidative stress caused by streptozotocin (STZ) was investigated. Diabetes mellitus was induced in adult male Wistar rats after administration of STZ (55 mg/kg b.wt., i.p., tail vein). The effect of NSK (2 gm/kg, b.wt.) and NSH (0.9 gm/kg, b.wt.) orally for 28 days was investigated in diabetic rats. Insulin-treated diabetic rats (6 U/kg, i.p., 28 days.) served as positive control. Diabetic rats given normal saline served as diabetic control. Rats that neither received STZ nor drugs served as normal control. Serum creatine phosphokinase (CPK) increased in diabetic rats was significantly decreased on insulin, NSK, and NSH treatments. The decrease in activities of superoxide dismutase (SOD) and catalase (CAT) and increase in lipid peroxidation (LPO) of erythrocytes as observed in diabetes was regained after insulin, NSH, and NSK treatments. However, there was insignificant improvement in SOD, CAT, and LPO of kidney on NSK and NSH treatment. In spite of increased CAT and SOD activities in liver and heart, LPO was also increased in diabetic rats. Insulin, NSH, and NSK treatments significantly protected animals from cardiac damage but not hepatic. Results suggest that NSH and NSK prevent oxidative stress caused by STZ in heart and erythrocytes. However, no such preventive effect was observed on renal and hepatic toxicity.
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