Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases.

The mechanisms underlying multifactorial diseases are always complex and challenging. Neurodegenerative disorders (NDs) are common around the globe, posing a critical healthcare issue and financial burden to the country. However, integrative evidence implies some common shared mechanisms and pathways in NDs, which include mitochondrial dysfunction, neuroinflammation, oxidative stress, intracellular calcium overload, protein aggregates, oxidative stress (OS), and neuronal destruction in specific regions of the brain, owing to multifaceted pathologies. The co-existence of these multiple pathways often limits the advantages of available therapies. The nutraceutical-based approach has opened the doors to target these common multifaceted pathways in a slow and more physiological manner to starve the NDs. Peer-reviewed articles were searched via MEDLINE and PubMed published to date for in-depth research and database collection. Considered to be complementary therapy with current clinical management and common drug therapy, the intake of nutraceuticals is considered safe to target multiple mechanisms of action in NDs. The current review summarizes the popular nutraceuticals showing different effects (anti-inflammatory, antioxidant, neuro-protectant, mitochondrial homeostasis, neurogenesis promotion, and autophagy regulation) on vital molecular mechanisms involved in NDs, which can be considered as complementary therapy to first-line treatment. Moreover, owing to its natural source, lower toxicity, therapeutic interventions, biocompatibility, potential nutritional effects, and presence of various anti-oxidative and neuroprotective constituents, the nutraceuticals serve as an attractive option to tackle NDs.

Biakamides A-D, Unique Polyketides from a Marine Sponge, Act as Selective Growth Inhibitors of Tumor Cells Adapted to Nutrient Starvation.

Biakamides A-D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (Petrosaspongia sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two N-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A-D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A-D showed selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain.

The long road to leptin.

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation and temperature dysregulation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin-deficient patients. Leptin acts on neurons in the hypothalamus and elsewhere to elicit its effects, and mutations that affect the function of this neural circuit cause Mendelian forms of obesity. Leptin levels fall during starvation and elicit adaptive responses in many other physiologic systems, the net effect of which is to reduce energy expenditure. These effects include cessation of menstruation, insulin resistance, alterations of immune function, and neuroendocrine dysfunction, among others. Some or all of these effects are also seen in patients with constitutively low leptin levels, such as occur in lipodystrophy. Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe metabolic disease, and has also shown potential for the treatment of other types of diabetes. In addition, leptin restores reproductive capacity and increases bone mineral density in patients with hypothalamic amenorrhea, an infertility syndrome in females. Most obese patients have high endogenous levels of leptin, in some instances as a result of mutations in the neural circuit on which leptin acts, though in most cases, the pathogenesis of leptin resistance is not known. Obese patients with leptin resistance show a variable response to exogenous leptin but may respond to a combination of leptin plus amylin. Overall, the identification of leptin has provided a framework for studying the pathogenesis of obesity in the general population, clarified the nature of the biologic response to starvation, and helped to advance our understanding of the neural mechanisms that control feeding.

Genetic identification of a neural circuit that suppresses appetite.

Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice. However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic and pharmacogenetic tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

Deciphering a neuronal circuit that mediates appetite.

Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y and γ-aminobutyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABA(A) receptor signalling in the PBN within a critical adaptation period. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT(3)) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl D-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.

Effect of starvation on the survival of male and female mice.

We previously observed that female mice survived significantly longer than male mice under fasting conditions. To elucidate the mechanism underlying the sex different effect of fasting, we analyzed various events induced in male and female mice. Kinetic analysis revealed that fasting elicited hypothermia and decreased muscle weight more apparently in male than in female mice. The life-time of male was increased by administration of estradiol while that of female was decreased by ovariectomy. Although plasma levels of estradiol were below detectable levels in male mice, those in female were significantly high and remained unchanged for a fairly long time. Generation of ketone bodies was enhanced more markedly in female than in male animals. The increased generation of ketone bodies in female was strongly inhibited by ovariectomy while that in male animals was increased by administration of estradiol. Expression of uncoupling protein-1 (UCP-1) in brown adipose tissue increased markedly in female mice while it was low in male animals. These results suggest that estrogen is a major factor that increases the life-time of animals under fasting conditions by increasing fatty acid oxidation, ketone body production and heat generation that support the energy metabolism and homeostasis required for the survival of animals.

Effects of lactulose and lactitol on coliform bacteria and bacterial translocation in the caecum during 72-h starvation in rats.

Lactulose and lactitol, non-absorbable disaccharides, prevent bacterial translocation (BT) arising from the gut. In contrast, lack of food into the gut leads to coliform bacterial overgrowth and even if it does not cause BT, can induce the risk from other stimuli for BT. In this study, we tested whether lactulose and lactitol affected populations of coliform bacteria in the caecum during starvation in Sprague-Dawley rats. Three groups of rats were starved for 72 h and given oral 2 ml undiluted lactulose (670 mg/ml), 2 ml undiluted lactitol (666 mg/ml) or 2 ml physiological saline, respectively, once a day. The caecum and mesenteric lymph nodes (MLNs) were removed for microbiological and histopathological analyses. The highest degree of coliform bacterial overgrowth, BT to MLNs and histopathological damage were observed in lactulose-treated rats, followed by the group treated with lactitol. As a result of this study, both drugs, especially lactulose augmented the proliferation and translocation tendency of coliform bacteria in the caecum during 72-h starvation in rats.

Melanocortin system and eating disorders.

The melanocortin (MC) system is involved in the regulation of energy balance and in the development of obesity. Here we briefly review why we became interested in investigating whether the MC system - more particularly, the increased activity of the MC system - is also involved in disorders of negative energy balance. We provide evidence that suppression of increased MC receptor activity by treatment with the inverse agonist agouti-related peptide (AgRP) (83-132) rescues rats exposed to an animal model known as activity-based anorexia. Furthermore, we found a polymorphism, Ala67Thr AgRP, that was observed more frequently in anorexia nervosa.

Effect of leptin on LH and FSH release in ovariectomized rats.

We compared the estradiol/progesterone-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release between normally fed and leptin-supplemented starved ovariectomized female rats and studied also the effect of hyper-leptinaemia on the steroid-induced hormonal release in normally fed ovariectomized rats. Three days' starvation completely abolished steroid-induced LH and FSH release. Significant recovery of the hormonal release was shown in the leptin-supplemented starved group. The magnitudes of LH and FSH release in the normally fed animals with a higher dose of leptin were statistically the same as those in the normally fed group without leptin. These observations indicate that physiological concentrations of circulating leptin exert a stimulatory effect on steroid-induced LH and FSH release.

Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation.

A number of acute wasting conditions are associated with an upregulation of the ubiquitin-proteasome system in skeletal muscle. Eicosapentaenoic acid (EPA) is effective in attenuating the increased protein catabolism in muscle in cancer cachexia, possibly due to inhibition of 15-hydroxyeicosatetraenoic acid (15-HETE) formation. To determine if a similar pathway is involved in other catabolic conditions, the effect of EPA on muscle protein degradation and activation of the ubiquitin-proteasome pathway has been determined during acute fasting in mice. When compared with a vehicle control group (olive oil) there was a significant decrease in proteolysis of the soleus muscles of mice treated with EPA after starvation for 24 h, together with an attenuation of the proteasome "chymotryptic-like" enzyme activity and the induction of the expression of the 20S proteasome alpha-subunits, the 19S regulator and p42, an ATPase subunit of the 19S regulator in gastrocnemius muscle, and the ubiquitin-conjugating enzyme E2(14k). The effect was not shown with the related (n-3) fatty acid docosahexaenoic acid (DHA) or with linoleic acid. However, 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-, 12- and 15-lipoxygenases also attenuated muscle protein catabolism, proteasome "chymotryptic-like" enzyme activity and expression of proteasome 20S alpha-subunits in soleus muscles from acute fasted mice. These results suggest that protein catabolism in starvation and cancer cachexia is mediated through a common pathway, which is inhibited by EPA and is likely to involve a lipoxygenase metabolite as a signal transducer.

Effects of succinic acid dimethyl ester infusion on metabolic, hormonal, and enzymatic variables in starved rats.

BACKGROUND: Succinic acid dimethyl ester (SAD) is efficiently metabolized in several cell types as pancreatic islet cells, hepatocytes, and colonocytes. The purpose of this study was to assess the overall nutritional value of SAD in the whole organism. METHODS: SAD was infused at a rate of 80 micromol/g body weight per day in rats starved for either 2 or 4 days. For comparison, similar experiments were conducted in starved rats receiving an equimolar infusion of D-glucose. RESULTS: The ester failed to prevent the starvation-induced fall in body weight, paraovarian fat mass, and liver or muscle protein content. The infusion of SAD minimized, however, the decrease in plasma glucose and insulin concentrations, liver glycogen content, hepatic glucokinase activity, and islet secretory responsiveness to glucose, otherwise caused by starvation. Likewise, the infusion of SAD delayed the rise in free fatty acid and beta-hydroxybutyrate plasma concentration occurring during starvation. Nevertheless, SAD was less efficient than glucose, infused in an equimolar amount, in preventing the starvation-induced fall in liver glycogen content, decrease in the pancreatic B-cell secretory responsiveness to glucose, and stimulation of lipolysis and ketogenesis. CONCLUSIONS: SAD displays a significant nutritional value when infused in starved rats. It could thus be used as a tool to prevent the imbalance between ATP generation and use in selected metabolic situations.

Evaluation of the effect of ketoprofen on experimentally induced ephemeral fever in dairy heifers.

OBJECTIVE: To evaluate ketoprofen for the therapy of ephemeral fever. DESIGN: A blind controlled clinical trial. ANIMALS: Sixteen cattle (one immature Holstein bull, eight Holstein and seven Jersey heifers). PROCEDURE: Ephemeral fever was induced by the intravenous injection of blood leucocyte layer from a clinical case. Ketoprofen solution or a coded placebo was injected intramuscularly at the rate of 3 mg/kg daily for three days. RESULTS: Ketoprofen reversed locomotor dysfunctions significantly compared with controls, but did not have any effect on rectal temperatures, leucocyte counts, plasma fibrinogen concentrations, ionised Ca-concentrations or the presence of dyspnoea. CONCLUSION: Ketoprofen is a safe and effective drug for the treatment of locomotor symptoms of milk fever, but has no effect on the duration of clinical respiratory abnormalities.

Correlation between echographic gastric emptying and appetite: influence of psyllium.

The correlation between ultrasonographic gastric emptying and appetite was studied. Echographic evaluation of gastric emptying by measurement of the antral vertical diameter and assessment of sensations of hunger and satiety using analogue visual scales were performed simultaneously in 12 healthy volunteers. Measurements were carried out after the intake of 10.8 g psyllium or placebo in a randomised, crossover, double blind trial. The correlation between echographic gastric emptying and sensations of hunger and satiety was excellent (p < 0.001) after the intake of either psyllium or placebo. Psyllium significantly delayed gastric emptying from the third hour after a meal. It increased the sensation of satiety and decreased hunger at the sixth hour after the meal. The association between echographic measurement and visual scales is a simple method of evaluating the relationship between the stomach and appetite. The pharmacodynamic effect of psyllium should be confirmed by longterm therapeutic trials.

[The possibility of intensifying endogenous nitrogen reutilization in protein starvation by the parental administration of small doses of methionine and threonine]. / Vozmozhnost' usileniia reutilizatsii éndogennogo azota v usloviiakh belkovogo golodaniia parenteral'nym vvedeniem malykh doz metionina i treonina.

Experiments conducted on albino Wistar male rats showed that endogenous nitrogen reutilization can be intensified by parenteral administration of regulatory amino acids methionine and threonine and their mixture in doses of 100-200 mg/kg in short-term protein deprivation. The data obtained may be used in clinical practice to reduce nitrogen excretion from the patient's organism with the patient deprived of food in the early postoperative period.

[Factors influencing the serum levels of cholesterol and beta-lipoproteins in starving rabbits]. / O faktorakh, vliiaiushchikh na uroven' kholesterina i beta-lipoproteidov v syvorotke krovi golodaiushchikh krolikov.

The influence of starvation on the lipid metabolism was studied on male rabbits under usual conditions and in the presence of pyroxidine deficiency (4-deoxypyridoxine administration) and of thiamine (oxythiamine administration), and also in administration of neurotropic preparations (phenamine, seduxen). Starvation for 7 to 10 days led to increase of cholesterol and beta-lipoproteins level in the serum. Pyridoxine deficiency and phenamine administration caused a greater increase of cholesterol and especially or beta-lipoproteins. On the other hand, thiamine deficiency and seduxen administration limited an increase of cholesterol and beta-lipoproteins during hungry stress. Administration of aerovit for prophylactic purpose promoted a decrease of the metabolic shifts. The amount of cholesterol increased in the liver of hungry animals, especially after the phenamine administration and in the presence of pyridoxine deficiency; aerovit administration prevented increased cholesterol accumulation in the liver. The differences in the cholesterol level in the serum and and the liver can be explained by the changes of its biosynthesis during hungry stress.

[Possible role of adenine nucleotide transport in regulating the respiration of rat liver mitochondria]. / Vozmozhnaia rol' transporta adeninukleotidov v reguliatsii dykhaniia mitokhondrii pecheni krys

Studies with liver mitochondria from rats which starved for 48 hours showed the rate of ADP-stimulated respiration to be 20% lower than in the presence of an uncoupler. This effect was eliminated by preincubation of mitochondria with carnitine. Mitochondria from fed rats were characterized by a considerable decrease of states 3 and 4 respiration. In this case carnitine produced no effect. Preincubation of mitochondria from the liver of fed rats with alpha-ketoglutarate resulted in a substantial increase of the states 3 and 4 respiratory rates. There proved to exist at least two types of regulation of adenine nucleotide transport through the inner mitochondrial membrane depending on the metabolic state of the organism, i.e. by inhibition of adenine-nucleotide translocase by cytoplasmic acyl-CoAs and by control of intramitochondrial adenine nucleotide pool.