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Alginates in Metabolic Syndrome


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Alginates extracted from seaweeds are widely used for nutrition, but they are underutilised for the prevention or reversal of human disease. Alginates are long chains of α-L-guluronic acid and β-D-mannuronic acid from brown seaweeds that act as readily available, low cost, non-toxic and biodegradable biopolymers. Sodium alginates are primarily used for the management of gastrointestinal tract disorders, but they are of potential use to attenuate the components of the metabolic syndrome including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver disease and dyslipidaemia. As prebiotics, alginates changed the gut microbiome to increase production of short-chain fatty acids as substrates for Bifidobacteria. Alginates inhibited pancreatic lipases and so decreased triacylglycerol breakdown and uptake. Treatment with alginates decreased food intake by inducing satiety and increased weight loss in patients on a calorie-restricted diet. Both glucose and fatty acid uptake were reduced. In rat models of hypertension, alginates decreased blood pressure. An alginate-antacid combination is an effective treatment of gastric reflux disease by forming a raft on the gastric contents. Alginates are important as drug carriers in microparticles and nanoparticles to increase drug bioavailability, for example, in drugs used for treatment of metabolic syndrome. Alginates are also used to protect cells during transplantation from immune responses of the host, allowing potential long-term control of some endocrine disorders such as type 1 diabetes and increased thermogenesis by brown adipocytes in obesity. There are many potential uses for these versatile biopolymers in the treatment of human disease.
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223© Springer Nature Singapore Pte Ltd. 2018
B.H.A. Rehm, M.F. Moradali (eds.), Alginates and Their Biomedical Applications,
Springer Series in Biomaterials Science and Engineering 11,
Chapter 9
Alginates inMetabolic Syndrome
SenthilArun Kumar andLindsayBrown
Abstract Alginates extracted from seaweeds are widely used for nutrition, but they
are underutilised for the prevention or reversal of human disease. Alginates are long
chains of α-L-guluronic acid and β-D-mannuronic acid from brown seaweeds that
act as readily available, low cost, non-toxic and biodegradable biopolymers. Sodium
alginates are primarily used for the management of gastrointestinal tract disorders,
but they are of potential use to attenuate the components of the metabolic syndrome
including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver disease
and dyslipidaemia. As prebiotics, alginates changed the gut microbiome to increase
production of short-chain fatty acids as substrates for Bidobacteria. Alginates
inhibited pancreatic lipases and so decreased triacylglycerol breakdown and uptake.
Treatment with alginates decreased food intake by inducing satiety and increased
weight loss in patients on a calorie-restricted diet. Both glucose and fatty acid
uptake were reduced. In rat models of hypertension, alginates decreased blood pres-
sure. An alginate-antacid combination is an effective treatment of gastric reux dis-
ease by forming a raft on the gastric contents. Alginates are important as drug
carriers in microparticles and nanoparticles to increase drug bioavailability, for
example, in drugs used for treatment of metabolic syndrome. Alginates are also
used to protect cells during transplantation from immune responses of the host,
allowing potential long-term control of some endocrine disorders such as type 1
diabetes and increased thermogenesis by brown adipocytes in obesity. There are
many potential uses for these versatile biopolymers in the treatment of human
Keywords Alginates • Metabolic syndrome • Gastrointestinal tract • Hypertension
• Inammation • Nanoparticle delivery • Cell transplantation
S.A. Kumar
Advanced Centre for Treatment, Research and Education in Cancer (ACTREC),
Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India
L. Brown (*)
School of Health and Wellbeing, University of Southern Queensland, Toowoomba, Australia
9.1 Introduction
The human diet in Japan, Korea, China, Vietnam and the Philippines has included
seaweeds for hundreds of years. As potential functional foods, seaweeds may pre-
vent or treat disease in addition to their nutritional advantages [1, 2], but their use-
fulness is underestimated. Seaweeds are aquatic photosynthetic plants separated
into macroalgae and microalgae, with macroalgae classied into three types: brown
algae (Phaeophyta), red algae (Rhodophyta) and green algae (Chlorophyta) [3].
Brown seaweeds contain alginates as viscous water-soluble polysaccharides that
consist of (1,4)-linked chains of α-L-guluronic acid and β-D-mannuronic acid as the
major sugar residues [4, 5]. The concentration of alginates can be high in seaweeds,
for example, 15–30% in Ascophyllum nodosum (rockweed or Norwegian kelp),
20–45% in Laminaria digitata (oarweed) and 21–42% in Alaria esculenta (dabber-
locks or winged kelp) [6]. Brown seaweeds such as Sargassum sp. are widely used
in food and have been used in Traditional Chinese Medicine for nearly 2000years
as potential anticancer, anti-inammatory, antibacterial and anti-viral medicines
[7]. Laminaria japonica, a source of alginate and fucoidan, as well as fat-soluble
components, such as fucoxanthin and fucosterol, is widely used in Japan as a healthy
food (kombu) that may prevent obesity and diabetes [8]. The physiological responses
to consumption of seaweeds containing alginates mainly involve the gastrointestinal
tract, including increased gastric distension, delayed gastric emptying and enhance-
ment of satiety together with delayed postprandial glycaemia and insulin responses
[9]. Sodium alginates have found applications in the management of gastrointestinal
and metabolic complications, primarily of the components of the metabolic syn-
drome including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver
disease and dyslipidaemia [1012]. This chapter will discuss the role of alginates to
improve health, primarily based on their changes in gastrointestinal function.
9.2 Alginates intheGastrointestinal Tract
Alginates have multiple effects on gastrointestinal function including reduction of
intestinal absorption rates and systemic effects, decreased uptake of fats and reduced
plasma cholesterol, increased faecal bile and cholesterol excretion, reduction in
blood peak glucose and plasma insulin rise, stool bulking, adsorption of toxins
found within the colon, alteration of colonic microora, direct effects on colonic
mucosa and increased sensation of satiety and reduced caloric intake [10]. Some of
these will now be further examined. Polysaccharides from seaweeds and microalgae
such as alginates, fucoidans and carrageenans may act as prebiotics [10, 13].
Prebiotics are long-chain carbohydrates that are not broken down in the stomach but
metabolised by bacteria in the colon to short-chain fatty acids such as acetate, butyr-
ate and propionate which serve as metabolic substrates for some gut bacteria [14
16]. Treatment with alginates (10g/day) in healthy male volunteers enhanced the
S.A. Kumar and L. Brown
growth of benecial gut microbes, particularly Bidobacterium species, with a con-
comitant decrease in Gram-negative Enterobacterium and Clostridium species, with
increased acetate and propionate production and decreased release of toxic metabo-
lites such as sulphide, p-cresol and indole in the faecal samples [14].
Pancreatic lipase is an important enzyme in triacylglycerol breakdown in the gas-
trointestinal tract. Therefore, inhibition of this enzyme is a potential mechanism for
the reduction of obesity as shown by orlistat, a commonly prescribed antiobesity
medication. Alginates also inhibit pancreatic lipase [10]. Alginates high in guluronic
acid from Laminaria hyperborea inhibited lipase activity more than alginates high in
mannuronic acid from Lessonia nigrescens suggesting that guluronic acid- rich algi-
nates could help in treating obesity by reducing dietary triacylglycerol uptake [17].
Interactions between the negatively charged alginates and positively charged proteins
are more likely at low pH, as in the stomach [10]. Testing alginates in a bread vehicle
using a model gut showed that alginates retained their lipase inhibitory properties
despite cooking at 150°C, showing the potential for this product in obesity [18].
Altered satiety signalling plays an important role in type 2 diabetes and obesity,
both key components of metabolic syndrome [19]. Treatment of healthy humans
with sodium alginate treatment at 9.9–15g/day reduced energy intake by inducing
a feeling of satiety, probably caused by increased viscosity causing swelling in the
gastrointestinal tract [20]. This gelling effect plays a central role in delaying the
gastric emptying by increasing stomach extension in the antrum and in slowing
down nutrient absorption in the small intestine. An increased guluronic to mannu-
ronic acid ratio increases viscosity and gel strength of the sodium alginate and so
could increase satiety [21]. A short-term trial using guluronic acid-enriched algi-
nates together with calcium or pectin for 7 days increased satiety in overweight
individuals [22, 23]. This protocol reduced daily energy intake by 134.8 kcal (7%)
associated with reductions in mean daily intake of sugar, saturated fats and proteins
[23]. In contrast, 10-day treatment with CM3 alginate, a compressed, lyophilised
sodium-alginate active complex, based on the brown seaweed Laminaria digitata,
had no effect on satiety, appetite, gastric function or gut hormone secretion [24].
There are only limited studies on weight-reducing effects of alginates, despite
newspaper articles with anecdotes that alginates in seaweeds can help control obesity
seaweed-really-help-you-lose-weight.html). The paucity of studies is surprising,
given the evidence showing weight loss with administration of prebiotics [25]. There
is solid evidence that alginates moderate many mechanisms that should assist in
weight management [10, 26], but there are few studies demonstrating an anti-obesity
effect. In a single study, patients on a calorie-restricted diet of 300kcal/day showed
a further increase in weight loss from 5.0 to 6.7kg when given 15g bre as alginates
three times a day for 12weeks, mainly as a reduction of body fat, while plasma mark-
ers of glucose and lipid metabolism and inammation were unchanged [27]. Long-
term studies remain necessary to dene the anti-obesity effects of alginates [26].
9 Alginates inMetabolic Syndrome
9.3 Alginates inMetabolic Changes
Insulin resistance or diabetes together with dyslipidaemia are used as clinical signs
to dene metabolic syndrome. High-viscosity dietary bres, including guar gum
and alginates, when incorporated in edible crispy bars containing 50 g carbohy-
drate, attenuated postprandial glycaemia without any change in gastrointestinal tol-
erance in healthy adults [28]. Supplementation with alginates and calcium in rats
attenuated postprandial glycaemic responses in streptozotocin (STZ)-induced dia-
betes in rats, probably due to increased viscosity as well as calcium-induced gel
formation [29]. This increased gelling is likely to delay gastric emptying and
decrease nutrient absorption in the small intestine, and both changes will decrease
postprandial glycaemic responses and attenuate peak insulinaemic responses [26].
In male patients, cholesterol uptake from a xed diet increased with increasing
body fat; a single administration of 1.5g sodium alginate with calcium carbonate
decreased uptake of glucose, cholesterol and triacylglycerols to the levels in healthy
subjects [30]. In rats fed a high cholesterol diet, addition of 2% calcium alginate to
the diet decreased plasma cholesterol concentrations, possibly due to an increased
bile acid excretion due to reduced intestinal reabsorption [31]. The gelling of both
high and low molecular weight alginates from Laminaria angustata in the stomach
was proposed as the mechanism for the reduced glucose uptake and insulin response
and increased cholesterol excretion from the gastrointestinal tract [32]. These stud-
ies suggest that the gastrointestinal changes induced by alginates can reduce dys-
lipidaemia in overweight/obese patients.
9.4 Alginates inHypertension
Hypertension is one of the diagnostic criteria for metabolic syndrome, and, further,
metabolic syndrome increases the risk of cardiovascular disease. Oral administra-
tion of low molecular weight potassium alginates (250 or 500mg/kg body weight)
extracted from brown seaweeds normalised the cardiovascular changes in DOCA-
salt hypertensive rats to a greater extent than the same dose of potassium chloride
[33]. Sodium alginate oligosaccharides (60 mg/kg given subcutaneously) almost
completely abolished the increased blood pressure in Dahl salt-sensitive rats fed 4%
sodium chloride; this response may be due to improved kidney function with
decreased sclerosis and vascular injury in the kidney, together with direct effects on
vascular function, rather than by reducing salt absorption [34]. Dietary sodium algi-
nate oligosaccharides given as a 4% intervention in the diet induced small changes
in systolic blood pressure in male SHR, but renal glomerular damage was markedly
decreased [35]. In obese patients, sodium alginates had no effect on borderline
hypertensive patients with a baseline systolic blood pressure of 132.7±2.2mmHg
[27]. No studies were found that reported changes in blood pressures in hyperten-
sive patients following alginate interventions.
Alginates derived from Sargassum vulgare have shown antitumour activity in
mice. However, these mice developed acute tubular necrosis, suggesting intrinsic
S.A. Kumar and L. Brown
nephrotoxicity, producing increased perfusion pressure, renal vascular resistance,
glomerular ltration rate, urinary ow and sodium, potassium and chloride excre-
tion and reduction of chloride tubular transport, possibly due to direct vascular
effects [36]. These actions could be due to direct actions on the renal vasculature, as
shown for mesenteric blood vessels [36]. No studies were found showing toxicity of
alginates in heart or liver or in humans.
9.5 Alginates inGastric Reux Disease
Alginates have been given to relieve gastric reux for many years. They precipitate upon
contact with gastric acid to produce low-viscosity gels of near-neutral pH, triggering the
sodium bicarbonate in the formulation to release carbon dioxide in the gel, which then
oats on the stomach contents as a raft close to the oesophageal- gastric junction [37].
Combination of calcium carbonate and sodium bicarbonate with sodium alginate reduced
gastric reux episodes and increased time to reux symptoms compared to patients
given antacid only [38]. This study showed that the alginate-antacid raft was localised to
below the diaphragm in these gastric reux patients [38]. Despite a substantial placebo
response, an alginate-antacid combination reduced heartburn, regurgitation and dyspep-
sia in a randomised trial of 1107 patients with mild-to-moderate symptoms [38].
9.6 Alginates inLiver Disease
Obesity increases the risk of developing non-alcoholic fatty liver disease (NAFLD),
which may develop into non-alcoholic steatohepatitis (NASH) and then progress to
hepatocellular carcinoma [39]. In monosodium glutamate-treated mice with NASH
symptoms, oral sodium alginate treatment improved liver steatosis, insulin resis-
tance and chronic inammation, and prevented the progression to carcinoma [11].
Translation to humans with NAFLD or NASH has not been reported.
9.7 Alginates inInammation
Obesity is dened as a chronic inammation [40], yet no studies have reported anti-
inammatory effects of alginates in obese rats or humans. Adjuvant-induced
arthritic rats as a model of rheumatoid arthritis when treated with alginate from
Sargassum wightii showed decreased paw oedema, reduced activities of inamma-
tory enzymes and reduced plasma inammatory biomarkers [41]. However, anti-
inammatory compounds such as indomethacin will induce gastric and small
intestinal ulcers. Sodium alginate has been proposed as a treatment to prevent
indomethacin- induced small intestinal injury as mice showed reduced intestinal
injury and reduced expression of mucin following alginate treatment [42] (Fig.9.1).
9 Alginates inMetabolic Syndrome
Fig. 9.1 Possible therapeutic effects of alginates in the attenuation of metabolic complications. NAFLD non-alcoholic fatty liver disease; () increased
response; () diminished response
S.A. Kumar and L. Brown
9.8 Alginates asDrug Carriers forTreatment ofMetabolic
Alginates are readily available, low cost, non-toxic, biodegradable and versatile bio-
polymers and are therefore useful as drug carriers for therapy, for example, as
hydrocolloids in sustained-release products [43]. Further development to produce
nanoparticles with improved drug delivery is one of the success stories in pharma-
ceutical technology in the last 20years, with a wide range of techniques being avail-
able for their preparation [44]. The effectiveness of nanoparticles depends on their
size and surface area, with a wide range of possible shapes giving a range of poten-
tial applications [45]. As an example, the oral bioavailability of insulin has been
improved by formulation as polymer-based nanoparticles, including alginate, but
these products have not reached the market [46]. The preparation of alginate mic-
roparticles and nanoparticles has been summarised, and future challenges have been
outlined [47].
There is now clear evidence that alginate-containing microparticles of oral hypo-
glycaemic drugs could be effective in type 2 diabetic patients. Metformin encapsu-
lated in alginate oating beads produced greater decreases in blood glucose
concentrations in Sprague-Dawley rats made diabetic following injection of strep-
tozotocin (60 mg/kg ip for 3days) than with metformin alone [48]. Microcapsules
of gliclazide prepared using taurocholic acid and sodium alginate decreased hyper-
glycaemic responses in alloxan-induced type 1 diabetic rats [49]. Exenatide deliv-
ered orally in microcapsules with alginates and hyaluronate to db/db mice normalised
the blood glucose concentrations for 2 h; this response could be prolonged until 4 h
with increased exenatide doses for effective control of type 2 diabetes [50]. These
studies show the potential of micro- and nanoparticles to increase treatment options
for type 2 diabetes. These techniques may also apply to insulin treatment of type 1
diabetes, now exclusively given subcutaneously. Oral administration of chitosan-
alginate insulin nanoparticles reduced blood glucose concentrations in alloxan-
diabetic mice more slowly than subcutaneous insulin, with bioavailability of
approximately 8% [51]. Liver damage is common in diabetes. One possible alterna-
tive for treatment of liver tumours is the use of alginate microspheres with the anti-
neoplastic drug, amonade, that causes serious adverse effects with oral delivery, to
achieve targeted delivery with reduced systemic toxicity [52]. Another option for
intracellular targeting of liver tumour cells is the use of microspheres with meso-
porous silica nanoparticles together with alginate providing high biocompatibility
and sustained release [53].
Alginate-containing nanoparticles may also be useful to administer lipid-
lowering drugs such as probucol [54]. The physical characteristics of these probucol
nanoparticles were appropriate for treatment [54]; similar nanoparticles of probucol
improved insulin release and decreased TNF-alpha production by pancreatic beta
cells cultured in 25.5 mM glucose [55].
Hypertension is an important component of the metabolic syndrome. Many anti-
hypertensive drugs have been formulated in alginate-containing nanoparticles for
9 Alginates inMetabolic Syndrome
oral administration to produce sustained-release characteristics, including nifedipine
[56], diltiazem [57], carvedilol [58] and propranolol [59]. Possible alternative routes
of administration include transdermal delivery of an alginate hydrogel containing
prazosin [60] and buccal absorption of nimodipine [61]. There are no reports of
studies specically targeting hypertension in patients with metabolic syndrome
using micro- or nanoparticles, but these formulations may offer advantages for spe-
cic drugs and patients. Intramyocardial injections of alginate hydrogel implants in
dogs with cardiac failure following intracoronary micro-embolisations improved
left ventricular structure and function with reduced left ventricular end-diastolic and
end-systolic volumes, improved left ventricle sphericity and an improved systolic
function with increased ejection fraction [62]. Local application of amiodarone in
an alginate-based glue to the right atrial wall of goats markedly decreased the rapid
atrial response to burst pacing, suggesting a potential use in postoperative atrial
brillation in humans [63] .
9.9 Alginates inCell Transplantation
Transplantation has a long history in endocrinology with recent studies using iso-
lated β-islet cells or stem cells showing the potential of this procedure to restore the
endocrine activity of the pancreas [64]. Procedures to improve success include treat-
ment of the cells with alginates. In immune-competent STZ-induced type 1 diabetic
C57BL/6J mice, transplantation of in vitro-derived glucose-responsive mature
β-cells from human embryonic stem cells encapsulated using chemically modied
alginates via the intraperitoneal route normalised blood glucose concentrations up
to 174days after transplantation with minimal graft rejection [65]. The develop-
ment of an oxygenated chamber system with immune-isolating alginate and poly-
membrane covers allowed the survival and function of human pancreatic islets
without immunosuppression [66]. Transplantation of these cells into a 63-year-old
man with a history of type 1 diabetes for 54years was followed by persistent graft
function and regulated insulin secretion for at least 10months, without immunosup-
pression [66].
As myocytes cannot replicate, cell transplantation is an attractive alternative to
improve cardiac function after injury. Foetal cardiomyocytes grown on porous algi-
nate scaffolds were transplanted into rats 7days after myocardial infarction [67].
After 9weeks, the transplanted cells had stimulated intense neovascularisation and
attenuated left ventricular dilatation and cardiac failure [67].
Unlike the heart, the liver can regenerate, but hepatocyte transplantation may be
needed in acute liver failure to provide short-term support. Further, these patients
may require liver transplantation, a major challenge for the health system [68].
Transplantation of rat hepatocytes microencapsulated with alginate markedly
improved liver parameters in a rat model of D-galactosamine-induced acute liver
failure; further, recovery of microbeads on day 8 after transplantation showed no
signs of adhesion or inammation [69]. Alginate-polyethylene glycol microspheres
S.A. Kumar and L. Brown
of human mesenchymal stem cells transplanted into mice delayed the development
of brosis in bile duct-ligated or carbon tetrachloride-treated mice [70]. After partial
hepatectomy in mice, the use of implanted alginate scaffolds supported the growth
of the remaining kidney, decreasing liver injury and improving survival [71].
Alginate microspheres with adipose tissue-derived stem cells could be transplanted
into recipient mice where the stem cells underwent hepatogenic differentiation to
cells that secreted albumin in the liver [72].
In contrast to white adipocytes, brown adipocytes may help control obesity [73].
The encapsulation of mouse embryonic stem cells in alginate hydrogel microstrands
allowed differentiation into brown adipocytes conrmed by the expression of
uncoupling protein 1 which is characteristic of these cells, as well as increased
expression with β3-adrenoceptor agonists [74]. Cell entrapment within alginate
microcapsules allows the cells to avoid the immune responses of the host; the use of
this technique with catabolic cells that use lipids for thermogenesis may be appli-
cable for the treatment of obesity [75]. Alginate-poly-L-lysine microencapsulated
Chinese hamster ovary (CHO)-E3 cells secreted apolipoprotein E3 when given
intraperitoneally to mice, leading to decreased cholesterol and increased HDL con-
centrations in the plasma [76]. This technology may be feasible to minimise athero-
sclerosis in obese and diabetic patients.
In conclusion, alginates are low cost, mostly non-toxic and versatile biopolymers
that can be used for treatment of many gastrointestinal problems. In addition, they
are useful in microparticles and nanoparticles as drug carriers and to protect cells
during transplantation. However, the full potential of these natural products as func-
tional foods needs to be further researched.
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9 Alginates inMetabolic Syndrome
... They could also protect cells during transplantation from immune responses of the host, and, in combination with antacid alginates, be applied in the treatment of gastric reflux disease. Moreover, alginates decrease food intake by inducing satiety, increase weight loss in patients on a calorie-restricted diet, and reduce both glucose and fatty acid uptake, and a decrease in blood pressure by alginates in rat models of hypertension was reported as well [194]. ...
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Dietary supplements and foods for special medical purposes are special medical products classified according to the legal basis. They are regulated, for example, by the European Food Safety Authority and the U.S. Food and Drug Administration, as well as by various national regulations issued most frequently by the Ministry of Health and/or the Ministry of Agriculture of particular countries around the world. They constitute a concentrated source of vitamins, minerals, polyunsaturated fatty acids and antioxidants or other compounds with a nutritional or physiological effect contained in the food/feed, alone or in combination, intended for direct consumption in small measured amounts. As nanotechnology provides “a new dimension” accompanied with new or modified properties conferred to many current materials, it is widely used for the production of a new generation of drug formulations, and it is also used in the food industry and even in various types of nutritional supplements. These nanoformulations of supplements are being prepared especially with the purpose to improve bioavailability, protect active ingredients against degradation, or reduce side effects. This contribution comprehensively summarizes the current state of the research focused on nanoformulated human and veterinary dietary supplements, nutraceuticals, and functional foods for special medical purposes, their particular applications in various food products and drinks as well as the most important related guidelines, regulations and directives. Keywords: bioactive agents; dietary supplements; foodstuffs; feed; nanoparticles; nanoformulations; nanoemulsions; nutraceuticals; encapsulation
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The gut microbiome consists of trillions of bacteria which play an important role in human metabolism. Animal and human studies have implicated distortion of the normal microbial balance in obesity and metabolic syndrome. Bacteria causing weight gain are thought to induce the expression of genes related to lipid and carbohydrate metabolism thereby leading to greater energy harvest from the diet. There is a large body of evidence demonstrating that alteration in the proportion of Bacteroidetes and Firmicutes leads to the development of obesity, but this has been recently challenged. It is likely that the influence of gut microbiome on obesity is much more complex than simply an imbalance in the proportion of these phyla of bacteria. Modulation of the gut microbiome through diet, pre- and probiotics, antibiotics, surgery, and fecal transplantation has the potential to majorly impact the obesity epidemic.
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Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects.
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The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.
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In recent years, scientists have become aware that human microbiota, in general, and gut microbiota, in particular, play a major role in human health and diseases, such as obesity and diabetes among others. A large number of evidence has come to light regarding the beneficial effects, either for the host or the gut microbiota, of some foods and food ingredients or biochemical compounds. Among these, the most promising seem to be polysaccharides (PS) or their derivatives, and include the dietary fibres. Some of these PS can be found in seaweeds and microalgae, some being soluble fibres, such as alginates, fucoidans, carrageenans and exopolysaccharides, that are not fermented, at least not completely, by colonic microbiota. This review gives an overview of the importance of the dietary fibres, as well as the benefits of prebiotics to human health. The potential of the PS from marine macro- and microalgae to act as prebiotics is discussed, and the different techniques to obtain oligosaccharides from PS are presented. The mechanisms of the benefits of fibre, in general, and the types and benefits of algal fibres in human health are highlighted. The findings of some recent studies that present the potential effects of prebiotics on animal models of algal biomass and their extracts, as well as oligo- and polysaccharides are presented. In the future, it is foreseen the possibility of using prebiotics to modulate the microbiome, and, consequently, prevent certain human diseases.
Introduction: In previous studies, we successfully designed complex multicompartmental microcapsules as a platform for the oral targeted delivery of lipophilic drugs in type 2 diabetes (T2D). Probucol (PB) is an antihyperlipidemic and antioxidant drug with the potential to show benefits in T2D. We aimed to create a novel microencapsulated formulation of PB and to examine the shape, size, and chemical, thermal, and rheological properties of these microcapsules in vitro. Method: Microencapsulation was carried out using the Buchi-based microencapsulating system developed in our laboratory. Using the polymer, sodium alginate (SA), empty (control, SA) and loaded (test, PB-SA) microcapsules were prepared at a constant ratio (1: 30). Complete characterizations of microcapsules, in terms of morphology, thermal profiles, dispersity, and spectral studies, were carried out in triplicate. Results: PB-SA microcapsules displayed uniform and homogeneous characteristics with an average diameter of 1 mm. The microcapsules exhibited pseudoplastic-thixotropic characteristics and showed no chemical interactions between the ingredients. These data were further supported by differential scanning calorimetric analysis and Fourier transform infrared spectral studies, suggesting microcapsule stability. Conclusion: The new PB-SA microcapsules have good structural properties and may be suitable for the oral delivery of PB in T2D. Further studies are required to examine the clinical efficacy and safety of PB in T2D.
Recent advances in diagnostic technologies have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious mucosal injury in the upper and lower gastrointestinal tract (including the small intestine). A drug to treat NSAID-induced small-intestinal injury (SII) is lacking. Sodium alginate is a soluble dietary fiber extracted from brown seaweed and its solution has been used as a hemostatic agent to treat gastrointestinal bleeding due to gastric ulcers. Whether sodium alginate has therapeutic effects on NSAID-induced SII and its mechanism of action are not known. Here, we investigated if administration of two forms (high-molecular-weight (HMW) and low-molecular-weight (LMW)) of sodium alginate could ameliorate indomethacin-induced SII. Pretreatment with HMW sodium alginate or LMW sodium alginate before indomethacin administration improved ulceration and the resultant intestinal shortening was associated with reduced histological severity of mucosal injury and ameliorated mRNA expression of inflammation-related molecules in the small intestine. We found that mRNAs of secretory Muc2 and membrane-associated Muc1, Muc3 and Muc4 were expressed in the small intestine. mRNA expression of Muc1–4 was increased in indomethacin-induced SII, and these increases were prevented by sodium alginate. Thus, administration of sodium alginate could be a therapeutic approach to prevent indomethacin-induced SII.
In the preparation of nanoparticles for drug delivery, it is well known that their size as welle as their surface decorations can play a major role in interaction with living media. It is less known that their shape and internal structure can interplay with cellular and in vivo fate. The scientific literature is full of a large variety of surprising terms referring to their shape and structure. The aim of this review is to present some examples of the most often encountered surprising nanoparticles prepared and usable in the pharmaceutical technology domain. They are presented in two main groups related to their physical aspects: 1) smooth surface particles, such as Janus particles, "snowmen", "dumbbells", "rattles", and "onions" and 2) branched particles, such as "flowers", "stars" and "urchins". The mode of preparation and potential applications are briefly presented. The topic has a serious, wider importance, namely in opportunity these structures have to allow exploration of the role of shape and structure on the utility (and perhaps toxicity) of these nanostructures.
We examined whether calcium alginate (Ca-Alg) reduces blood cholesterol levels in rats fed a high-cholesterol diet. First, we examined taurocholate adsorption in vitro by various types of sodium alginate (Na-Alg). High molecular-weight, guluronic acid-rich Na-Alg showed the greatest adsorption of taurocholate, and therefore the corresponding Ca-Alg was chosen for the in vivo study. Rats were fed a high-cholesterol diet or a Ca-Alg-containing diet for 2 weeks. Body weight and diet intake were measured, and the general condition of the animals was monitored during this period. After 14 d, the plasma concentration of cholesterol, portal plasma concentration of bile acid, and bile acid in feces were measured. The plasma concentration of cholesterol was significantly reduced in rats fed a 2% Ca-Alg-containing diet. Furthermore, the portal concentration of bile acid was significantly lowered in the 2% Ca-Alg group. A tendency for a Ca-Alg concentration-dependent increase in fecal excretion of bile acid was also seen, although it was not statistically significant. While several changes in biochemical parameters and histopathological findings were observed, all the values remained within the physiological range. These results indicate that Ca-Alg is effective in reducing plasma cholesterol. A possible mechanism would be enhanced fecal excretion of bile acid due to reduced intestinal reabsorption, which in turn might stimulate bile acid synthesis from cholesterol in the liver, leading to a decrease in plasma cholesterol.
Context: Gliclazide (G) is a commonly prescribed drug for Type 2 diabetes (T2D). In a recent study, we found that when G was combined with a primary bile acid, and gavaged to an animal model of Type 1 diabetes (T1D), it exerted a hypoglycemic effect. We hypothesized this to be due to metabolic activation of the primary bile acid into a secondary or a tertiary bile acid, which enhanced G solubility and absorption. The tertiary bile acid, taurocholic acid (TCA), has shown strong permeation-enhancing effects in vivo. Thus, we aimed to design, characterize, and test microcapsules incorporating G and TCA in an animal model of T1D. Methods: Microcapsules were prepared using the polymer sodium alginate (SA). G-SA microcapsules (control) and G-TCA-SA microcapsules (test) were extensively examined (in-vitro) at different pH and temperatures. The microcapsules were gavaged to diabetic rats, and blood glucose and G concentrations in serum were examined. Ex-vivo studies were also performed using a muscle cell line (C2C12), and cell viability and glucose intake post-treatment were examined. Results: G-TCA-SA microcapsules showed good stability, uniformity, and thermal and chemical excipient compatibilities. TCA did not change the size or the shape of the microcapsules, but it enhanced their mechanical resistance and reduced their swelling properties. G-TCA-SA enhanced the viability of C2C12 cells over 24 hours, and exerted a hypoglycemic effect in alloxan-induced type-1 diabetic rats. Conclusions: The incorporation of TCA into G-microcapsules resulted in functionally improved microcapsules with a positive effect on cell viability and glycemic control in Type-1 diabetic animals.
The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a β-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these "Brown-Fat-in-Microstrands" are functional. The ability to create "Brown-Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders.