Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Safety assessment of high fructose corn syrup and fructose used as sweeteners in foods.

High Fructose Corn Syrup (HFCS) and Fructose (FR) are widely used sweeteners in many foods and beverages. This study aimed at investigating the cytotoxic effects of HFCS (5%-30%) and FR (62.5-2000 µg/mL) using MTT assay in Human Hepatocellular Carcinoma (HepG2) cells, and genotoxic effects of using Chromosome Aberrations (CAs), Sister Chromatid Exchanges (SCEs), Micronuclei (MN) and comet assays in human lymphocytes. HFCS significantly reduced the cell viability in HepG2 cells at between 7.5% and 30% for 24 and 48 h. 30% HFCS caused a very significant toxic effect. FR had a cytotoxic effect in HepG2 cells at all treatments. However, as fructose concentration decreased, the cell viability decreased. HFCS (10%-20%) and FR (250-2000 µg/mL) decreased the mitotic index at higher concentrations. IC50 value was found to be a 15% for 48 h. IC50 value of FR was detected as 62.5 µg/mL for 24 h and 48 h. HFCS significantly increased CAs frequency at 15% and 20%. FR significantly increased the frequency of CAs at 250, 1000, and 2000 µg/mL for 48 h. Both sweeteners increased the frequency of SCEs at all concentrations. HFCS (15% and 20%) and FR (250, 1000, and 2000 µg/mL) induced MN frequency at higher concentrations. HFCS caused DNA damage in comet assay at 10% -30%. FR increased tail intensity and moment at 125-2000 µg/mL and tail length at 62.5, 250 and 500 µg/mL. Therefore, HFCS and FR are clearly seen to be cytotoxic and genotoxic, especially at higher concentrations.

HFCS and FR exhibited cytotoxic effect at HepG2 and human lymphocytes at higher concentrations.Both sweeteners increased the frequencies of CAs and SCEs at higher concentrations.HFCS caused DNA damage at 10% -30% concentrations.HFCS (15% and 20%) and FR (250, 1000, and 2000 µg/mL) induced MN frequency.

PKC-δ-dependent mitochondrial ROS attenuation is involved as 9-OAHSA combats lipoapotosis in rat hepatocytes induced by palmitic acid and in Syrian hamsters induced by high-fat high-cholesterol high-fructose diet.

Metabolic-associated fatty liver disease (MAFLD) is a global concern, often undetected until reaching an advanced stage. Palmitic acid (PA) is a type of fatty acid that increases and leads to liver apoptosis in MAFLD. However, there is currently no approved therapy or compound for MAFLD. Recently, branched fatty acid esters of hydroxy fatty acids (FAHFAs), a group of bioactive lipids, have emerged as promising agents to treat associated metabolic diseases. This study utilizes one type of FAHFA, oleic acid ester of 9-hydroxystearic acid (9-OAHSA), to treat PA-induced lipoapoptosis in an in vitro MAFLD model using rat hepatocytes and a high-fat high-cholesterol high-fructose (HFHCHFruc) diet in Syrian hamsters. The results indicate that 9-OAHSA rescues hepatocytes from PA-induced apoptosis and attenuates lipoapoptosis and dyslipidemia in Syrian hamsters. Additionally, 9-OAHSA decreases the generation of mitochondrial reactive oxygen species (mito-ROS) and stabilizes the mitochondrial membrane potential in hepatocytes. The study also demonstrates that the effect of 9-OAHSA on mito-ROS generation is at least partially mediated by PKC-δ signaling. These findings suggest that 9-OAHSA shows promise as a therapy for MAFLD.

Long-term high fructose intake promotes lacrimal gland dysfunction by inducing gut dysbiosis in mice.

The lacrimal gland is essential for maintaining ocular surface health through the secretion of the aqueous layer of the tear film. It is therefore important to explore the intrinsic and extrinsic factors that affect the structure and function of the lacrimal gland and the mechanisms underlying them. With the prevalence of Westernized diets characterized by high sugar and fat content, the susceptibility to many diseases, including ocular diseases, is increased by inducing dysbiosis of the gut microbiome. Here, we found that the composition, abundance, and diversity of the gut microbiome was significantly altered in mice by drinking 15% high fructose water for one month, as determined by 16S rRNA sequencing. This was accompanied by a significant increase in lipid deposition and inflammatory cell infiltration in the extraorbital lacrimal glands (ELGs) of mice. Transcriptome analysis based on bulk RNA-sequencing revealed abnormal activation of some of several metabolic and immune-related pathways. In addition, the secretory response to stimulation with the cholinergic receptor agonist pilocarpine was significantly reduced. However, when the composition and diversity of the gut microbiome of high fructose intake (HFI)-treated mice were improved by transplanting feces from normal young healthy mice, the pathological alterations in ELG structure, inflammatory cell infiltration, secretory function and transcriptome analysis described above were significantly reversed compared to age-matched control mice. In conclusion, our data suggest that prolonged HFI may cause pathological damage to the structure and function of the ELG through the induction of gut dysbiosis. Restoration of intestinal dysbiosis in HFI-treated mice by fecal transplantation has a potential role in ameliorating these pathological impairments.

Could vitamin D protect against high fat diet induced damage in the arcuate nucleus in the rat: histological, immunohistochemical and ultrastructural study.

Obesity is a serious health issue. As regard, the central nervous system, obesity induces neuronal damage. Vitamin D has well-known anti-inflammatory and neuroprotective effects. To detect if vitamin D protects against damage in the arcuate nucleus induced by a high fat-high fructose diet. Forty adult rats were used, and four groups were formed. Group I (negative control) kept on a standard chow diet for six weeks, Group II (positive control) received vitamin D orally once every other day for six weeks, Group III (high fat-high fructose treated group) was given high fat-high fructose diets for six weeks and Group IV (high fat-high fructose and vitamin D treated group) were given high fat-high fructose diets concomitantly with vitamin D for six weeks. High fat-high fructose diet markedly caused histological changes in arcuate neurons as nuclei appeared darkly stained and shrunken with condensed chromatin, and the nucleolus became less prominent. The cytoplasm appeared rarefied with loss of most of the organelles. An increase in neuroglial cells was noticed. The synaptic area showed sparse degenerated mitochondria and a disrupted presynaptic membrane. A high-fat diet has a damaging effect on arcuate neurons and vitamin D alleviates these effects.

Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming.

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Prophylactic Use of Natural Products against Developmentally Programmed Metabolic Syndrome.

Parental dietary choices and/or nutritional interventions in the offspring are critical to early life development, especially during the periods of active developmental plasticity in the offspring. Exposure to a high-fructose, high-fat diet during the fetal or neonatal period predisposes the affected individuals to the development of one or more features of metabolic syndrome, such as dyslipidemia, insulin resistance, diabetes, and associated cardiovascular diseases, later in their life. Owing to the increasing global prevalence of metabolic syndrome and multiple side effects that accompany conventional medicines, much attention is directed towards medicinal plants and phytochemicals as alternative interventions. Several studies have investigated the potential of natural agents to prevent programmed metabolic syndrome. This present review, therefore, highlights an inextricable relationship between the administration of medicinal plants or phytochemicals during the intrauterine or neonatal period, and the prevention of metabolic dysfunction in adulthood, while exploring the mechanisms by which they exert such an effect. The review also identifies plant products as a novel approach to the prevention and management of metabolic syndrome.

Protective effect of Coleus forskohlii leaf-extract compound on progression of cataract against Fructose-Induced experimental cataract in rats.

The present study was designed to determine protective effects of Coleus forskohlii hydroalcoholic leaf-extract along with its fractions against fructose-induced cataract rat model. The Coleus forskolii leaf extract was subjected to silica gel column chromatography and fractions were collected. A major high yielding fraction of the leaf extract, designated as fraction B6 was pharmacologically evaluated in Sprague Dawley albino rats at three doses 0.1, 1 and 10 mg/kg respectively. Compound B2; isolated from B6 fraction, identified as 'gallic acid' was also pharmacologically evaluated at three different doses. Cataract was induced by concurrent administration of fructose solution (10% w/v, per oral, dissolved in drinking water) for eight consecutive weeks. Mean arterial pressure, blood glucose level and lenticular opacity were determined. At the end of eight weeks, C. forskohlii leaf extract fraction and gallic acid reduced mean arterial pressure and glucose level in a dose dependent manner. In addition, C. forskohlii led to significant restoration of lens antioxidants enzyme level and reduced cataract formation in rats. These results showed the concentration dependent protective effect by C. forskohlii leaf extract against cataract formation due to restoration of oxidative stress markers.

Crassocephalum rubens (Juss. Ex Jacq.) S. Moore improves pancreatic histology, insulin secretion, liver and kidney functions and ameliorates oxidative stress in fructose-streptozotocin induced type 2 diabetic rats.

Crassocephalum rubens (C. rubens) is a traditional leafy vegetables (TLV) eaten in parts of Africa for the management of symptoms of diabetes mellitus. This study was done to investigate the in vivo anti-diabetic activity of the aqueous extract of C. rubens aerial parts (CRAQ). Type 2 diabetes (T2D) was induced in male Sprague Dawley (SD) rats by feeding them with a 10% fructose solution for two weeks followed by single dose (40 mg/kg body weight) intraperitoneal injection of streptozotocin. After confirmation of T2D, animals were treated with a low and a high dose (150 and 300 mg/kg body weight) of extract for five weeks. Parameters used as markers of hyperglycemia were analyzed in the samples collected from rats. Hematoxylin-eosin staining was used in analyzing the morphological changes of the pancreas. Treatment with high dose of the extract significantly (p < 0.05) lowered blood glucose level, increased oral glucose tolerance level and pancreatic ß-cell function, while restoring the morphology of the pancreatic tissue damage. The high dose also increased insulin secretion, liver glycogen, antioxidant enzyme activities in serum and organs, and prevented liver and renal damages compared to the untreated diabetic animals. Data from this study suggest that C. rubens possesses impressive anti-diabetic activity and could be useful in ameliorating some complications associated with T2D therefore this plant can be exploited in finding new alternative therapies for the treatment of T2D.

Evaluation of the toxicology, anti-lipase, and antioxidant effects of Callistemon citrinus in rats fed with a high fat-fructose diet.

CONTEXT: Callistemon citrinus Skeels (Myrtaceae) exhibits many biological activities. OBJECTIVE: This study analyzes for the first time, the toxicity, obesogenic, and antioxidant effects of C. citrinus in rats fed with a high fat-fructose diet (HFFD). MATERIALS AND METHODS: Four studies using male Wistar rats were conducted: (a) 7 groups (n = 3): control (corn oil) and ethanol extract of C. citrinus leaf (single oral dose at 100-4000 mg/kg) for acute toxicity; (b) 2 groups (n = 8): control (corn oil) and C. citrinus (1000 mg/kg/day) for 28 days for subacute toxicity; (c) 3 groups (n = 4) with single oral dose of lipid emulsion: control (lipid emulsion), C. citrinus and orlistat (250 and 50 mg/kg, respectively) for lipid absorption; (d) 4 groups (n = 6): control (normal diet) and 3 groups fed with HFFD: HFFD only, C. citrinus and simvastatin (oral dose 250 and 3 mg/kg, respectively) for 13 weeks. Antioxidant enzymes and biomarkers were evaluated and inhibition of pancreatic lipase was determined in vitro. RESULTS: Toxicological studies of C. citrinus showed no differences in biochemical parameters and lethal dose (LD50) was higher than 4000 mg/kg. C. citrinus inhibited pancreatic lipase activity, with IC50 of 392.00 µg/mL, and decreased lipid absorption by 70%. Additionally, it reduced the body weight 22%, restored the activities of antioxidant enzymes, and reduced the biomarkers of oxidative stress. CONCLUSIONS: Callistemon citrinus showed an effect against oxidative stress by reducing biomarkers and induced antioxidant system, without toxic effects.

Dietary interventions to prevent high-fructose diet-associated worsening of colitis and colitis-associated tumorigenesis in mice.

Diet is believed to be an important factor in the pathogenesis of inflammatory bowel disease. High consumption of dietary fructose has been shown to exacerbate experimental colitis, an effect mediated through the gut microbiota. This study evaluated whether dietary alterations could attenuate the detrimental effects of a high-fructose diet (HFrD) in experimental colitis. First, we determined whether the procolitic effects of a HFrD could be reversed by switching mice from a HFrD to a control diet. This diet change completely prevented HFrD-induced worsening of acute colitis, in association with a rapid normalization of the microbiota. Second, we tested the effects of dietary fiber, which demonstrated that psyllium was the most effective type of fiber for protecting against HFrD-induced worsening of acute colitis, compared with pectin, inulin, or cellulose. In fact, supplemental psyllium nearly completely prevented the detrimental effects of the HFrD, an effect associated with a shift in the gut microbiota. We next determined whether the protective effects of these interventions could be extended to chronic colitis and colitis-associated tumorigenesis. Using the azoxymethane/dextran sodium sulfate model, we first demonstrated that HFrD feeding exacerbated chronic colitis and increased colitis-associated tumorigenesis. Using the same dietary changes tested in the acute colitis setting, we also showed that mice were protected from HFrD-mediated enhanced chronic colitis and tumorigenesis, upon either diet switching or psyllium supplementation. Taken together, these findings suggest that high consumption of fructose may enhance colon tumorigenesis associated with long-standing colitis, an effect that could be reduced by dietary alterations.

Mulberroside A repairs high fructose diet-induced damage of intestinal epithelial and blood-brain barriers in mice: A potential for preventing hippocampal neuroinflammatory injury.

Our previous studies showed that high fructose diet (HFrD)-driven gut dysbiosis caused fecal short-chain fatty acids (SCFAs) reduction and intestinal epithelial barrier (IEB) damage in mice, which might play an important role in hippocampal neuroinflammatory injury. Mulberroside A is reported to have neuroprotective effects in animal experiments, while the underlying mechanisms are not yet fully elucidated. Here, we investigated whether and how mulberroside A prevented HFrD-induced neuroinflammatory injury. HFrD-fed mice were treated orally with mulberroside A (20 and 40 mg/kg) for 8 weeks. Mulberroside A was found to inhibit hippocampal neuroinflammation and neurogenesis reduction in HFrD-fed mice. It reshaped gut dysbiosis, increased fecal and serum SCFAs contents, reactivated signaling of the colonic NLR family, pyrin domain containing 6 (NLRP6) inflammasome, and up-regulated Muc2 expression to prevent IEB damage, as well as subsequently, reduced serum endotoxin levels in this animal model. Additionally, mulberroside A inhibited oxidative stress in colon of HFrD-fed mice and hydrogen peroxide (H2 O2 )-stimulated Caco-2 cells. Blood-brain barrier (BBB) structure defects were also observed in HFrD-driven hippocampal neuroinflammatory injury of mice. Interestingly, mulberroside A maintained astrocyte morphology and up-regulated tight junction proteins to repair BBB structure defects in hippocampus dentate gyrus (DG). Our results demonstrated that mulberroside A was capable of preventing HFrD-induced damage of IEB and BBB in mice, which might contribute to the suppression of hippocampal neuroinflammatory injury.

Aqueous extract of large cardamom inhibits vascular damage, oxidative stress, and metabolic changes in fructose-fed hypertensive rats.

PURPOSE: Since metabolic abnormalities such as elevated glucose level and imbalanced lipid profiles increase the risk for hypertension and cause endothelial dysfunction, we evaluated the effect of aqueous extract of large cardamom (AELC) on fructose-induced metabolic hypertension and oxidative stress. METHODS: The male Sprague-Dawley rats were divided into 6 groups with 5 rats in each group, and each group was fed with 10% fructose in drinking water for 8 weeks. Starting from week 5, animals were treated with 50, 100, and 200 mg/kg/day AELC or Losartan (10 mg/kg/day). Systolic, diastolic, and mean arterial blood pressure was measured once in every seven days using the tail-cuff method. Vascular function, plasma nitric oxide (NO), glucose, lipid profiles, serum biochemical, and anti-oxidant parameters were also evaluated. RESULTS: Rats fed with fructose showed higher blood pressure, serum cholesterol, and triglyceride levels, but decreased in the AELC or Losartan treatment group. Treatments with AELC prevented exaggerated plasma glucose and oxidative stress and restored the nitric oxide level in fructose-fed rats. Besides, it also reduced vascular proliferation and improved the relaxation response of acetylcholine in the aorta pre-contracted with phenylephrine. CONCLUSION: In summary, the obtained results suggest that AELC can prevent and reverse the high blood pressure induced by fructose, probably by restoring nitric oxide level and by improving altered metabolic parameters.

Anti-apoptotic and pro-survival effects of longan flower extracts on rat hearts with fructose-induced metabolic syndrome.

The aim of this study was to investigate the effects of longan flower (LF) water extract on cardiac apoptotic and survival pathways in rat models of fructose-induced metabolic syndrome. The study findings revealed that the levels of glucose, insulin, triglyceride, and cholesterol and TUNEL-positive apoptotic cells were significantly increased in the HF group compared with the control group; whereas, the levels were decreased in the HFLF group. The expressions of Fas, FADD, and activated caspases 8 and 3, as well as the expressions of Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspases 9 and 3 were increased in the HF group were significantly reversed in HFLF administrated group. Furthermore, LF extract increased IGF-1R, p-PI3K, p-Akt, Bcl-2, and Bcl-xL expression compared to HF group. Taken together, the present findings help identify LF as a potential cardioprotective agent that can be effectively used in treating fructose-induced metabolic syndrome.

Lactobacillus plantarum ATG-K2 and ATG-K6 Ameliorates High-Fat with High-Fructose Induced Intestinal Inflammation.

Obesity has become a worldwide health problem, and many significant inflammatory markers have been associated with the risk of side effects of obesity and obesity-related diseases. After a normal diet or high-fat diet with high-fructose water (HFHF) for 8 weeks, male Wistar rats were divided randomly into four experimental groups according to body weight. Next, for 8 weeks, a normal diet, HFHF diet, and HFHF diet with L. plantarum strains ATG-K2 or ATG-K6 were administered orally. Compared to the control group, the HFHF diet group showed significantly increased visceral fat, epididymal fat, and liver weight. The mRNA and protein expression levels of FAS and SREBP-1c were higher in the HFHF diet group than in the HFHF diet with L. plantarum strains ATG-K2 and ATG-K6. The HFHF diet with L. plantarum strain ATG-K2 showed significantly decreased inflammatory cytokine expression in the serum and small intestine compared to the HFHF diet group. Furthermore, histological morphology showed minor cell injury, less severe infiltration, and longer villi height in the small intestine ileum of the HFHF diet with L. plantarum strains groups than in the HFHF diet group. These results suggest that L. plantarum strains K2 and K6 may help reduce intestinal inflammation and could be used as treatment alternatives for intestinal inflammatory reactions and obesity.

Altered Gut Microbiota and Its Metabolites in Hypertension of Developmental Origins: Exploring Differences between Fructose and Antibiotics Exposure.

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin-angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.

The use of combined high-fructose diet and glyphosate to model rats type 2 diabetes symptomatology.

An ideal food-chemical combination that will promote insulin resistance and its consequent development of pancreatic beta-cell dysfunction may open a new vista for Type 2 diabetes (T2D) research. Thus, we investigated the modulatory effects of a high-fructose diet (FRC) combined with glyphosate (GP). Male albino Wistar rats were randomly divided into five groups of eight/group and received distilled water, FRC, GP, and their combinations orally for eight consecutive weeks. We assessed the changes in fasting blood glucose levels (FBGLs), biochemical indices, oxidative stress parameters, and organ histopathology. From the results obtained, FBGLs and serum insulin levels were increased in the FRC-GP (2.3-3.1 and 1.9-2.2 folds) treated rats compared with the control baseline group. Also, the FRC-GP high dose increased FBGLs (1.9 folds), insulin (1.4 folds), triglycerides (1.5 folds), and uric acid (2 folds) levels compared with the FRC group. Malondialdehyde levels increased in the pancreas (54% and 78%) and liver (31.3% and 56.6%) of the FRC-GP treated rats. The FRC-GP treatments reduced serum high-density lipoprotein (57%), total protein (47%), and antioxidant parameters (non-enzymatic and enzymatic, 1.6-1.9 folds) respectively in the treated animals. The weight of the pancreas relative to the body increased (2-3 folds) while we observed mild inflammation and vascular congestion in vital organs in the treated rats. Overall, these results demonstrate the potential of FRC-GP-diet to induce conditions of rats T2D. Also, this novel finding suggests a cost-effective GP as an alternative in this model type and provides further insight into understanding FRC-GP interactions.

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats.

BACKGROUND: Inflammation is a common pathophysiological trait found in both hypertension and cardiac vascular disease. Recent evidence indicates that fractalkine (FKN) and its receptor CX3CR1 have been linked to inflammatory response in the brain of hypertensive animal models. Here, we investigated the role of CX3CR1-microglia in nitric oxide (NO) generation during chronic inflammation and systemic blood pressure recovery in the nucleus tractus solitarii (NTS). METHODS: The hypertensive rat model was used to study the role of CX3CR1-microglia in NTS inflammation following hypertension induction by oral administration of 10% fructose water. The systolic blood pressure was measured by tail-cuff method of non-invasive blood pressure. The CX3CR1 inhibitor AZD8797 was administered intracerebroventricularly (ICV) in the fructose-induced hypertensive rat. Using immunoblotting, we studied the nitric oxide synthase signaling pathway, NO concentration, and the levels of FKN and CX3CR1, and pro-inflammatory cytokines were analyzed by immunohistochemistry staining. RESULTS: The level of pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, FKN, and CX3CR1 were elevated two weeks after fructose feeding. AZD8797 inhibited CX3CR1-microglia, which improved the regulation of systemic blood pressure and NO generation in the NTS. We also found that IL-1ß, IL-6, and TNF-α levels were recovered by AZD8797 addition. CONCLUSION: We conclude that CX3CR1-microglia represses the nNOS signaling pathway and promotes chronic inflammation in fructose-induced hypertension. Collectively, our results reveal the role of chemokines such as IL-1ß, IL-6, and TNF-α in NTS neuroinflammation with the involvement of FKN and CX3CR1.

Acute Exposure to Fructose Impairs Endothelium-Dependent Relaxation via Oxidative Stress in Isolated Rat Aortic Rings.

INTRODUCTION: Although both glucose and fructose are hexoses, their catabolism is quite different: the catabolism of fructose is initiated by ketohexokinase and is not regulated by negative feedback, which results in oxidative stress. OBJECTIVE: We hypothesized that fructose impairs endothelium-dependent relaxation via oxidative stress in rat aortic rings. METHODS: Sprague-Dawley rats were offered 20% fructose solution or tap water for 2 weeks, after which vascular reactivity was measured in isolated aortic rings. In a separate experiment, vascular reactivity was measured after acute exposure to ∼10 mM fructose in isolated aortic rings from untreated rats. RESULTS: Although high-fructose intake statistically significantly increased blood pressure and body weight, it did not affect contraction and relaxation in aortic rings. The substitution of fructose for glucose in Krebs solution inhibited vascular relaxation in aortic rings, which was abolished by pretreatment with antioxidants. Decreasing the glucose concentration in Krebs solution inhibited vascular relaxation, whereas decreasing the fructose concentration in Krebs solution improved vascular relaxation in the aortic rings. Pretreatment with antioxidants improved the vascular relaxation in Krebs solution with fructose substituted for glucose. CONCLUSIONS: These results indicate that fructose impairs endothelium-dependent relaxation via oxidative stress in isolated rat aortic rings.

Therapeutic potential of cPLA2 inhibitor to counteract dilated-cardiomyopathy in cholesterol-treated H9C2 cardiomyocyte and MUNO rat.

BACKGROUND AND PURPOSE: The pathogenesis of cardiomyopathy in metabolically unhealthy obesity (MUO) has been well studied. However, the pathogenesis of cardiomyopathy typically associated with high cholesterol levels in metabolically unhealthy nonobesity (MUNO) remains unclear. We investigated whether cholesterol-generated LysoPCs contribute to cardiomyopathy and the role of cytosolic phospholipase A2 (cPLA2) inhibitor in cholesterol-induced MUNO. EXPERIMENTAL APPROACH: Cholesterol diet was performed in Sprague-Dawley rats that were fed either regular chow (C), or high cholesterol chow (HC), or HC diet with 10 % fructose in drinking water (HCF) for 12 weeks. LysoPCs levels were subsequently measured in rats and in MUNO human patients. The effects of cholesterol-mediated LysoPCs on cardiac injury, and the action of cPLA2 inhibitor, AACOCF3, were further assessed in H9C2 cardiomyocytes. KEY RESULTS: HC and HCF rats fed cholesterol diets demonstrated a MUNO-phenotype and cholesterol-induced dilated cardiomyopathy (DCM). Upregulated levels of LysoPCs were found in rat myocardium and the plasma in MUNO human patients. Further testing in H9C2 cardiomyocytes revealed that cholesterol-induced atrophy and death of cardiomyocytes was due to mitochondrial dysfunction and conditions favoring DCM (i.e. reduced mRNA expression of ANF, BNP, DSP, and atrogin-1), and that AACOCF3 counteracted the cholesterol-induced DCM phenotype. CONCLUSION AND IMPLICATIONS: Cholesterol-induced MUNO-DCM phenotype was counteracted by cPLA2 inhibitor, which is potentially useful for the treatment of LysoPCs-associated DCM in MUNO.