Biotechnological, Nutritional, and Therapeutic Applications of Quinoa (Chenopodium quinoa Willd.) and Its By-Products: A Review of the Past Five-Year Findings.

This study aimed to provide an updated critical review of the nutritional, therapeutic, biotechnological, and environmental aspects involved in the exploitation of Chenopodium quinoa Willd and its biowastes. Special attention was devoted to investigations of the therapeutic and nutritional properties of different parts and varieties of quinoa as well as of the use of the biowaste resulting from the processing of grain. Studies published from 2018 onward were prioritized. Extracts and fractions obtained from several Chenopodium quinoa matrices showed antioxidant, antidiabetic, immunoregulatory, neuroprotective, and antimicrobial effects in in vitro and in vivo models and some clinical studies. The activities were attributed to the presence of phytochemicals such as polyphenols, saponins, peptides, polysaccharides, and dietary fibers. Quinoa wastes are abundant and low-cost sources of bioactive molecules for the development of new drugs, natural antioxidants, preservatives, dyes, emulsifiers, and carriers for food and cosmetics applications. Among the demands to be fulfilled in the coming years are the following: (1) isolation of new bioactive phytochemicals from quinoa varieties that are still underexploited; (2) optimization of green approaches to the sustainable recovery of compounds of industrial interest from quinoa by-products; and (3) well-conducted clinical trials to attest safety and efficacy of extracts and compounds.

Short-term effects of sodium arsenite (AsIII) and sodium arsenate (AsV) on carbohydrate metabolism in the perfused rat liver.

The actions of arsenite and arsenate on carbohydrate metabolism in the once-through perfused rat liver were investigated. The compound inhibited lactate gluconeogenesis with an IC50 of 25 µM. It also increased glycolysis and fructolysis at concentrations between 10 and 100 µM. This effect was paralleled by strong inhibition of pyruvate carboxylation (IC50 = 4.25 µM) and by a relatively moderate diminution in the ATP levels. The inhibitory action of arsenate on pyruvate carboxylation and lactate gluconeogenesis was 103 times less effective than that of arsenite. For realistic doses and concentrations («1 mM), impairment of metabolism by arsenate can be expected to occur solely after its reduction to arsenite. Arsenite, on the other hand, can be regarded as a strong short-term modifier of lactate gluconeogenesis and other pathways. The main cause of the former is inhibition of pyruvate carboxylation, a hitherto unknown effect of arsenic compounds.

Comparative study of the antioxidant and anti-inflammatory effects of the natural coumarins 1,2-benzopyrone, umbelliferone and esculetin: in silico, in vitro and in vivo analyses.

The aim of this work was to compare the anti-inflammatory and antioxidant effects of three natural coumarins: 1,2-benzopyrone, umbelliferone and esculetin. The antioxidant capacity of coumarins was evaluated using both chemical and biological in vitro assays. Chemical assays included DPPH and ABTS∙+ radical scavenging as well as ferric ion reducing ability power (FRAP) assay. Inhibition of mitochondrial ROS generation and lipid peroxidation in brain homogenates were used as biological in vitro assays. The experimental method of carrageenan-induced pleurisy in rats was used for the in vivo investigation of the anti-inflammatory activity. In silico molecular docking analysis was undertaken to predict the affinity of COX-2 to the coumarins. Considering the antioxidant capacity, esculetin was the most efficient one as revealed by all employed assays. Particularly, the mitochondrial ROS generation was totally abolished by the compound at low concentrations (IC50 = 0.57 µM). As for the anti-inflammatory effects, the COX-2 enzyme presented good affinities to the three coumarins, as revealed by the molecular docking analyses. However, considering the in vivo anti-inflammatory effects, 1,2-benzopyrone was the most efficient one in counteracting pleural inflammation and it potentiated the anti-inflammatory actions of dexamethasone. Umbelliferone and esculetin treatments failed to reduce the volume of pleural exudate. Overall, therefore, our results support the notion that this class of plant secondary metabolites displays promising effects in the prevention and/or treatment of inflammation and other diseases associated with oxidative stress, although the singularities regarding the type of the inflammatory process and pharmacokinetics must be taken into account.

Effects of a high-fat low-carbohydrate diet under different energy conditions on glucose homeostasis and fatty liver development in rats and on gluconeogenesis in the isolated perfused liver.

The beneficial effects of high-fat low-carbohydrate (HFLC) diets on glucose metabolism have been questioned and their effects on liver metabolism are not totally clear. The aim of this work was to investigate the effects of an HFLC diet under different energy conditions on glucose homeostasis, fatty liver development, and hepatic gluconeogenesis using the isolated perfused rat liver. HFLC diet (79% fat, 19% protein, and 2% carbohydrates in Kcal%) was administered to rats for 4 weeks under three conditions: ad libitum (hypercaloric), isocaloric, and hypocaloric (energy reduction of 20%). Fasting blood glucose levels and total fat in the liver were higher in all HFLC diet rats. Oral glucose tolerance was impaired in isocaloric and hypercaloric groups, although insulin sensitivity was not altered. HFLC diet also caused marked liver metabolic alterations: higher gluconeogenesis rate from lactate and a reduced capacity to metabolize alanine, the latter effect being more intense in the hypocaloric condition. Thus, even when HFLC diets are used for weight loss, our data imply that they can potentially cause harmful consequences for the liver.

A Critical Appraisal of the Most Recent Investigations on Ora-Pro-Nobis (Pereskia sp.): Economical, Botanical, Phytochemical, Nutritional, and Ethnopharmacological Aspects.

Pereskia aculeata Miller and Pereskia grandfolia Haw, known as 'ora-pro-nobis', are unconventional vegetables belonging to the Cactaceae family, native to the Americas and common in the northeast and southeast regions of Brazil. This review attempts to present a balanced account of both the methods used for obtaining extracts from the diverse parts of the plants and the results that were obtained in terms of their applicability to foods and other products with biological activities. Attention will also be devoted to the properties of their bioactives and their applications to real food products. Methods for obtaining extracts from the diverse parts of the plants will be analyzed, as well as the chemical nature of the bioactives that were hitherto identified. Next, the applicability of ora-pro-nobis in either its integral form or in the form of extracts or other products (mucilages) to the production of food and dietary supplements will be analyzed. The species have been extensively investigated during the last few decades. But, the determination of chemical structures is frequently incomplete and there is a need for new studies on texture determination and color evaluation. Further studies exploring the fruit and flowers of P. aculeata are also required.

L-glutathione 1% promotes neuroprotection of nitrergic neurons and reduces the oxidative stress in the jejunum of rats with Walker-256-bearing tumor.

AIMS: Our main goals were to investigate the effects of L-glutathione (1%) treatment in Walker-256 tumor-bearing rats by analyzing immunoreactive neurons (IR), responsive to the nNOS enzyme and 3-Nitrotyrosine, in their jejunum myenteric plexus. Moreover, the oxidative state and inflammatory process in these animals were investigated. METHODS: Four experimental groups were utilized: control (C), control treated with L-glutathione (CGT), Walker-256 tumor-bearing rats (TW), and Walker-256 tumor-bearing rats treated with L-glutathione (TWGT). After 14 days of tumor inoculation, the jejunum was collected for immunohistochemical techniques and assessment of oxidative status. Plasma was collected to evaluate oxidative status and measure cytokines. RESULTS: The TW group exhibited a decrease of reduced glutathione in their jejunum, which was prevented in the L-glutathione treated TWGT group. TW animals presented pronounced oxidative stress by increasing levels of lipoperoxidation in their jejunum and malondialdehyde in their plasma; however, the L-glutathione treatment in TWGT group was not able to avoid it. The total antioxidant capacity was altered in groups TW and TWGT, yet the last one had a better index in their plasma. The IL-10, and TNF-α levels increased in TWGT animals. The nNOS-IR neuron density decreased in the jejunum myenteric plexus of the TW group, which was avoided in the TWGT group. The nNOS +3-Nitrotyrosine neurons quantification did not show significative alterations. CONCLUSION: The treatment with L-glutathione (1%) imposed an important defense to some parameters of oxidative stress induced by TW-256, leading to neuroprotection to the loss in the nNOS-IR neuron density.

Inhibition of Gluconeogenesis by Boldine in the Perfused Liver: Therapeutical Implication for Glycemic Control.

The alkaloid boldine occurs in the Chilean boldo tree (Peumus boldus). It acts as a free radical scavenger and controls glycemia in diabetic rats. Various mechanisms have been proposed for this effect, including inhibited glucose absorption, stimulated insulin secretion, and increased expression of genes involved in glycemic control. Direct effects on glucose synthesis and degradation were not yet measured. To fill this gap, the present study is aimed at ensuring several metabolic pathways linked to glucose metabolism (e.g., gluconeogenesis) in the isolated perfused rat liver. In order to address mechanistic issues, energy transduction in isolated mitochondria and activities of gluconeogenic key enzymes in tissue preparations were also measured. Boldine diminished mitochondrial ROS generation, with no effect on energy transduction in isolated mitochondria. It inhibited, however, at least three enzymes of the gluconeogenic pathway, namely, phosphoenolpyruvate carboxykinase, fructose-bisphosphatase-1, and glucose 6-phosphatase, starting at concentrations below 50 µM. Consistently, in the perfused liver, boldine decreased lactate-, alanine-, and fructose-driven gluconeogenesis with IC50 values of 71.9, 85.2, and 83.6 µM, respectively. Conversely, the compound also increased glycolysis from glycogen-derived glucosyl units. The hepatic ATP content was not affected by boldine. It is proposed that the direct inhibition of hepatic gluconeogenesis by boldine, combined with the increase of glycolysis, could be an important event behind the diminished hyperglycemia observed in boldine-treated diabetic rats.

Toxicogenic effects of the mushroom Ganoderma lucidum on human liver and kidney tumor cells and peripheral blood lymphocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (Curtis) P. Karst., a bioactive mushroom with medicinal properties, is known to exert immunomodulatory, anti-inflammatory, hypocholesterolemic, hypoglycemic, and hepatoprotective effects. AIM OF THE STUDY: In this study, the effects of the G. lucidum fruiting body dry extract (GLE) on human liver (HepG2/C3A) and kidney (786-O) tumor cells and peripheral blood lymphocytes were evaluated. MATERIALS AND METHODS: MTT-based cytotoxicity, trypan blue-based cell viability, comet, and cytokinesis-block micronucleus cytome assays were performed, and the production of reactive oxygen species was evaluated in vitro. RESULTS: GLE was toxic to the tumor cells, decreasing their viability by increasing their production of reactive oxygen species and inducing damage to their DNA. By contrast, only high concentrations of GLE were toxic to lymphocytes and decreased their viability, whereas low concentrations increased lymphocyte viability. Moreover, primary DNA damage was induced by GLE only at the highest concentration tested. CONCLUSIONS: G. lucidum shows potential antitumor effects against cancerous kidney and liver cells, exhibiting cytotoxic and genotoxic activity at low concentrations, whereas the same effects in lymphocytes are mediated only at high concentrations. This mushroom has the potential to be biotechnologically developed into a therapeutic agent for diseases, such as cancer.

Delayed administration of Trichilia catigua A. Juss. Ethyl-acetate fraction after cerebral ischemia prevents spatial memory deficits, decreases oxidative stress, and impacts neural plasticity in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua A. Juss (Meliaceae) is used in Brazilian folk medicine to alleviate fatigue and emotional stress and improve memory. Previous studies from our laboratory reported that an ethyl-acetate fraction (EAF) of T. catigua that was given before cerebral ischemia in vivo prevented memory loss and reduced oxidative stress and neuroinflammation. Despite the value of these findings of a neuroprotective effect of T. catigua, treatment that was given immediately before or immediately after ischemia limits its clinical relevance. Thus, unknown is whether T. catigua possesses a specific time window of efficacy (TWE) when administered postischemia. AIM OF THE STUDY: Given continuity to previous studies, we investigated whether an EAF of T. catigua maintains its neuroprotective properties if treatment begins at different time windows of efficacy after ischemia. We also evaluated, for the first time, whether T. catigua possesses neuroplasticity/neurotrophic properties. MATERIAL AND METHODS: Rats were subjected to transient global brain ischemia (TGCI) and then given a single dose of the EAF (400 mg/kg) or vehicle (1 ml/kg) orally 1, 4, or 6 h postischemia. The levels of protein PCG, GSH, and GSSG, and activity of SOD and CAT were assayed as markers of oxidative stress on the day after ischemia. In another experiment, naive rats underwent spatial learning training in a radial maze task and then subjected to TGCI. Delayed treatment with the EAF began 4 or 6 h later and continued for 7 days. Retrograde memory performance was assessed 10, 17, and 24 days postischemia. Afterward, brains were examined for neurodegeneration and neuronal dendritic morphology in the hippocampus and cerebral cortex. Another group received the EAF at 4 h of reperfusion, and 4 days later their brains were examined for GFAP and Iba-1 immunoreactivity. Lastly, ischemic rats received the EAF 4 h after ischemia and neural plasticity-related proteins, BDNF, SYN, PSD 95, and NeuN were measured in the hippocampus 7 and 14 days after ischemia. RESULTS: A single EAF administration 1, 4, or 6 h postischemia alleviated oxidative stress that was caused by ischemia, expressed as a reduction of the amount of the PCG and GSSG, normalization of the GSH/GSSG ratio, and the restoration of SOD activity. Ischemia caused the persistent loss of memory (i.e., amnesia), an outcome that was consistently ameliorated by treatment with the EAF that was initiated 4 or 6 h postischemia. The 4 h delay in EAF treatment positively impacted dendritic morphology in neurons that survived ischemia. TGCI reduced BDNF, SYN, PSD-95, and NeuN protein levels in the hippocampus and cerebral cortex. The EAF normalized SYN and PSD-95 protein levels. Ischemia-induced neurodegeneration and glial cell activation were not prevented by EAF treatment. CONCLUSION: The present study corroborates prior data that demonstrated the neuroprotective potential of T. catigua and extends these data by showing that the delayed administration of EAF postischemia effectively prevented memory impairment and decreased oxidative stress, dendritic deterioration, and synaptic protein loss within a TWE that ranged from 1 to 6 h. This specific TWE in preclinical research may have clinical relevance by suggesting the possible utility of this plant for the development of neuroprotective strategies in the setting of ischemic brain diseases. Another innovative finding of the present study was the possible neurotrophic/neuroplastic properties of T. catigua.

A Critical Appraisal of the Most Recent Investigations on the Hepatoprotective Action of Brazilian Plants.

Conventional treatments for liver diseases are often burdened by side effects caused by chemicals. For minimizing this problem, the search for medicines based on natural products has increased. The objective of this review was to collect data on the potential hepatoprotective activity of plants of the Brazilian native flora. Special attention was given to the modes of extraction, activity indicators, and identification of the active compounds. The databases were Science direct, Pubmed, and Google Academic. Inclusion criteria were: (a) plants native to Brazil; (b) studies carried out during the last 15 years; (c) high-quality research. A fair number of communications met these criteria. Various parts of plants can be used, e.g., fruit peels, seeds, stem barks, and leaves. An outstanding characteristic of the active extracts is that they were mostly obtained from plant parts with low commercial potential, i.e., by-products or bio-residues. The hepatoprotective activities are exerted by constituents such as flavonoids, phenolic acids, vitamin C, phytosterols, and fructose poly- and oligosaccharides. Several Brazilian plants present excellent perspectives for the obtainment of hepatoprotective formulations. Very important is the economical perspective for the rural producers which may eventually increase their revenue by selling increasingly valued raw materials which otherwise would be wasted.

The short-term effects of berberine in the liver: Narrow margins between benefits and toxicity.

Berberine is a plant alkaloid to which antihyperglycemic properties have been attributed. It is also known as an inhibitor of mitochondrial functions. In this work short-term translation of the latter effects on hepatic metabolism were investigated using the isolated perfused rat liver. Once-through perfusion with a buffered saline solution was done. At low portal concentrations berberine modified several metabolic pathways. It inhibited hepatic gluconeogenesis, increased glycolysis, inhibited ammonia detoxification, increased the cytosolic NADH/NAD+ ratio and diminished the ATP levels. Respiration of intact mitochondria was impaired as well as the mitochondrial pyruvate carboxylation activity. These results can be regarded as evidence that the direct inhibitory effects of berberine on gluconeogenesis, mediated by both energy metabolism and pyruvate carboxylation inhibition, represent most likely a significant contribution to its clinical efficacy as an antihyperglycemic agent. However, safety concerns also arise because all effects occur at similar concentrations and there is a narrow margin between the expected benefits and toxicity. Even mild inhibition of gluconeogenesis is accompanied by diminutions in oxygen uptake and ammonia detoxification and increases in the NADH/NAD+ ratio. All combined, desired and undesired effects could well in the end represent a deleterious combination of events leading to disruption of cellular homeostasis.

Protein Restriction in the Peri-Pubertal Period Induces Autonomic Dysfunction and Cardiac and Vascular Structural Changes in Adult Rats.

Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (p = 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (p = 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (p = 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (p = 0.062 and p = 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (p = 0.044) and increased interstitial fibrosis (p = 0.028) compared with controls. Reduced protein carbonyls (PC) (p = 0.030) and catalase activity (p = 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (p = 0.002) and the activity of superoxide dismutase and catalase (p = 0.044 and p = 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (p = 0.039 and p = 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.

Protein restriction during lactation causes transgenerational metabolic dysfunction in adult rat offspring.

Introduction: Protein restriction during lactation can induce metabolic dysfunctions and has a huge impact on the offspring's phenotype later in its life. We tested whether the effects of a maternal low-protein diet (LP) in rats can be transmitted to the F2 generation and increase their vulnerability to dietary insults in adulthood. Methods: Female Wistar rats (F0) were fed either a low-protein diet (LP; 4% protein) during the first 2 weeks of lactation or a normal-protein diet (NP; 23% protein). The female offspring (F1 generation) were maintained on a standard diet throughout the experiment. Once adulthood was reached, female F1 offspring from both groups (i.e., NP-F1 and LP-F1) were bred to proven males, outside the experiment, to produce the F2 generation. Male F2 offspring from both groups (NP-F2 and LP-F2 groups) received a standard diet until 60 days old, at which point they received either a normal fat (NF; 4.5% fat) or a high fat diet (HF; 35% fat) for 30 days. Results: At 90 days old, LPNF-F2 offspring had increased lipogenesis and fasting insulinemia compared to NPNF-F2, without alteration in insulin sensitivity. HF diet caused increased gluconeogenesis and displayed glucose intolerance in LPHF-F2 offspring compared to LPNF-F2 offspring. Additionally, the HF diet led to damage to lipid metabolism (such as steatosis grade 3), higher body weight, fat pad stores, and hepatic lipid content. Discussion: We concluded that an F0 maternal protein restricted diet during lactation can induce a transgenerational effect on glucose and liver metabolism in the F2 generation, making the offspring's liver more vulnerable to nutritional injury later in life.

Insulin degludec and glutamine dipeptide modify glucose homeostasis and liver metabolism in diabetic mice undergoing insulin-induced hypoglycemia.

This study investigated whether a 30-day co-treatment with 1 g/kg glutamine dipeptide (GdiP) and 1 U/kg regular (rapid acting) or 5 U/kg degludec (long acting) insulins modifies glucose homeostasis and liver metabolism of alloxan-induced type 1 diabetic (T1D) male Swiss mice undergoing insulin-induced hypoglycemia (IIH). Glycemic curves were measured in fasted mice after IIH with 1 U/kg regular insulin. One hour after IIH, the lipid profile and AST and ALT activities were assayed in the serum. Morphometric analysis was assessed in the liver sections stained with hematoxylin-eosin and glycolysis, glycogenolysis, gluconeogenesis and ureagenesis were evaluated in perfused livers. T1D mice receiving GdiP or the insulins had a smaller blood glucose drop at 60 minutes after IIH, which was not sustained during the subsequent period up to 300 minutes. The 30-day treatment of T1D mice with insulin degludec, but not with regular insulin, improved fasting glycemia, body weight gain and serum activity of AST and ALT. Treatments with insulin degludec, GdiP and insulin degludec + GdiP decreased the liver capacity in synthesizing glucose from alanine. GdiP, in combination with both insulins, was associated with increases in the serum triglycerides and, in addition, regular insulin and GdiP increased AST and ALT activities, which could be the consequence of hepatic glycogen overload. GdiP and the insulins improved the IIH, although to a small extent. Caution is recommended, however, with respect to the use of GdiP because of its increasing effects on serum triglycerides and AST plus ALT activities.

Effects of a Myrciaria jaboticaba peel extract on starch and triglyceride absorption and the role of cyanidin-3-O-glucoside.

The purpose of this study was to perform a parallel and comparative investigation of the effects of a Myrciaria jaboticaba (common name jabuticaba) peel extract and of its constituent cyanidin-3-O-glucoside on the overall process of starch and triglyceride intestinal absorption. The peel extract inhibited both the porcine pancreactic α-amylase and the pancreatic lipase but was 13.6 times more potent on the latter (IC50 values of 1963 and 143.9 µg mL-1, respectively). Cyanidin-3-O-glucoside did not contribute significantly to these inhibitions. The jabuticaba peel extract inhibited starch absorption in mice at doses that were compatible with its inhibitory action on the α-amylase. No inhibition of starch absorption was found with cyanidin-3-O-glucoside doses compatible with its content in the extract. The extract also inhibited triglyceride absorption, but at doses that were considerably smaller than those predicted by its strength in inhibiting the pancreatic lipase (ID50 = 3.65 mg kg-1). In this case, cyanidin-3-O-glucoside was also strongly inhibitory, with 72% inhibition at the dose of 2 mg kg-1. When oleate + glycerol were given to mice, both the peel extract and cyanidin-3-O-glucoside strongly inhibited the appearance of triglycerides in the plasma. The main mechanism seems, thus, not to be the lipase inhibition but rather the inhibition of one or more steps (e.g., transport) in the events that lead to the transformation of free fatty acids in the intestinal tract into triglycerides. Due to the low active doses, the jabuticaba peel extract presents many favourable perspectives as an inhibitor of fat absorption and cyanidin-3-O-glucoside seems to play a decisive role.

Pterostilbene influences glycemia and lipidemia and enhances antioxidant status in the liver of rats that consumed sucrose solution.

AIMS: The present study investigated the potential effects of pterostilbene (PT) on glycemic and lipid profiles, fat storage, cardiovascular indices, and hepatic parameters of rats fed with sucrose solution. MAIN METHODS: 24 male Wistar rats received either drinking water or a 40% sucrose solution over a period of 140 days. After this period, animals were randomly allocated into four groups (n = 6): Control (C), C + Pterostilbene (PT), Sucrose (S), and S + PT. Pterostilbene (40 mg/kg) was given orally for 45 consecutive days. KEY FINDINGS: Pterostilbene did not influence morphometric and nutritional parameters. The insulin sensitivity index TyG was elevated in the C + PT group (p < 0.01) and reduced in S + PT group (p < 0.05). Basal glucose levels were lower in the S + PT group (p < 0.05), and the glycemic response was improved with PT treatment in glucose provocative tests. Conversely, rats from the C + PT group showed impaired glucose disposal during those tests. Lipid profile was partially improved by PT treatment. Hepatic oxidative stress in the S group was improved after PT treatment. In the C group, PT reduced SOD activity, glutathione levels, and increased catalase activity. Collagen content was reduced by PT treatment. SIGNIFICANCE: PT effects depends on the type of diet the animals were submitted. In rats fed with sucrose-solution, PT confirmed its positive effects, improving glucose and lipid profile, and acting as a potent antioxidant. The effects of PT on rats that consumed a normal diet were very discrete or even undesirable. We suggest caution with indiscriminate consume of natural compounds by healthy subjects.

Actions of multiple doses of resveratrol on oxidative and inflammatory markers in plasma and brain of healthy and arthritic rats.

The actions of resveratrol in brain and plasma of rats with adjuvant-induced arthritis were investigated. Resveratrol was administered orally during a period of 23 days. A major concern of the present work was to explore an ample range of daily doses (10-200 mg/kg). Several oxidative and inflammatory markers were measured. Important effects of resveratrol treatment were the normalization of the plasma myeloperoxidase activity (inflammatory marker), the normalization of the brain xanthine oxidase activity (reactive oxygen species source) and the near-normalization of the catalase activity in the brain (antioxidant defence). These effects presented obvious dose dependencies in the range up to 200 mg/kg. Resveratrol also reduced protein and lipid damage within the lowest dose ranges investigated, and its action as a free radical scavenger activity was enhanced in brain mitochondria of arthritic rats. Resveratrol failed in restoring the diminished albumin levels and plasma protein thiols in arthritic rats. The latter, however, were substantially increased in healthy rats at low doses (up to 50 mg/kg), a sign of antioxidant action. This increase was reversed at higher doses, a sign of pro-oxidant action. The observations agree with the notion that low doses of resveratrol might be useful as an adjuvant to the conventional antirheumatic drugs.

Long-term sucrose solution consumption causes metabolic alterations and affects hepatic oxidative stress in Wistar rats.

As the number of overweight and obese people has risen in recent years, there has been a parallel increase in the number of people with metabolic syndrome, diabetes and non-alcoholic fatty liver disease. The consumption of artificially sweetened beverages contributes to these epidemics. This study investigated the long-term effects of ingestion of a 40% sucrose solution on serum and hepatic parameters in male Wistar rats (Rattus norvegicus). After 180 days, the glycemic response, lipid profile and hepatic oxidative stress were compared to those of rats maintained on water. Sucrose ingestion led to higher body weight, increased fat deposits, reduced voluntary food intake and reduced feeding efficiency. Rats that received sucrose solution showed early signs of glucose intolerance and insulin resistance, such as hyperinsulinemia. Serum triacylglycerol (TG), very-low density lipoprotein (VLDL), cholesterol, ALT and AST levels increased after sucrose consumption. Elevated malondialdehyde and superoxide dismutase (SOD) levels and reduced glutathione levels characterize the hepatic oxidative stress due to sucrose ingestion. Liver sample histology showed vacuolar traces and increased fibrotic tissue. Our data showed the harmful effects of chronic consumption of sucrose solution, which can cause alterations that are found frequently in obesity, glucose intolerance and non-alcoholic hepatic disease, characteristics of metabolic syndrome.

Kinetics of the metabolic effects, distribution spaces and lipid-bilayer affinities of the organo-chlorinated herbicides 2,4-D and picloram in the liver.

Tordon® is the commercial name of a mixture of two organo-chlorinated herbicides, 2,4-D and picloram. Both compounds affect energy transduction in isolated mitochondria and the present study aimed at characterizing the actions of these two compounds on liver metabolism and their cellular distribution in the isolated perfused rat liver. 2,4-D, but not picloram, increased glycolysis in the range from 10 to 400 µM. The redox potential of the cytosolic NAD+-NADH couple was also increased by 2,4-D. Both compounds inhibited lactate gluconeogenesis. Inhibitions by 2,4-D and picloram were incomplete, reaching maximally 46% and 23%, respectively. Both compounds diminished the cellular ATP levels. No synergism between the actions of 2,4-D and picloram was detected. Biotransformations of 2,4-D and picloram were slow, but their distributions occurred at high rates and were concentrative. Molecular dynamics simulations revealed that 2,4-D presented low affinity for the hydrophobic lipid bilayers, the opposite occurring with picloram. Inhibition of energy metabolism is possibly a relevant component of the toxicity of 2,4-D and of the commercial product Tordon®. Furthermore, the interactions of 2,4-D with the membrane lipid bilayer can be highly destructive and might equally be related to its cellular toxicity at high concentrations.

The food additive BHA modifies energy metabolism in the perfused rat liver.

A study of the effects of butylated hydroxyanisole (BHA) on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism and mitochondrial reactive oxygen species production. The experimental systems were the isolated perfused rat liver and isolated mitochondria. It was found that BHA inhibits biosynthetic pathways (gluconeogenesis) and ammonia detoxification, which are dependent on ATP generated within the mitochondria. Conversely, the compound stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, BHA diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Inhibition of gluconeogenesis started at the concentration of 50 µM and was generally pronounced at concentrations under 200 µM. Several effects, however, were prominent only at the concentrations of 500 and 750 µM. BHA can be considered, thus, a mild metabolic agent that becomes toxic only at high doses. An aggravating factor could be the observation that BHA exerts a net stimulating action on reactive oxygen species (ROS) production in isolated mitochondria, an observation that contradicts the general notion that the compound acts primarily as an antioxidant. Considerable time was required for the reversion of most effects after removal of the compound from the circulation. In toxicological terms, besides the lack of circulating glucose, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis and possible excessive ROS production.