Polyphenol-rich black currant and cornelian cherry juices ameliorate metabolic syndrome induced by a high-fat high-fructose diet in Wistar rats.

Diets high in fat and sugar lead to metabolic syndrome (MetS) and related chronic diseases. We investigated the effects of commercially available, cold-pressed polyphenol-rich black currant (BC) and cornelian cherry (CC) juices on the prevention of MetS in Wistar rats induced by a 10-weeks high-fat high-fructose (HFF) diet. Juice consumption, either BC or CC, with a HFF diet resulted in lower serum triglycerides compared to only the HFF consumption. Both juices also mitigated the effects of HFF on the liver, pancreas, and adipose tissue, by preserving liver and pancreas histomorphology and reducing visceral fat and adipocyte size. Furthermore, supplementation with both juices reduced glucagon and up-regulated insulin expression in the pancreas of the rats on the HFF diet, whereas the BC also showed improved glucose regulation. BC juice also reduced the expression of IL-6 and hepatic inflammation compared to the group only on HFF diet. Both juices, especially BC, could be a convenient solution for the prevention of MetS in humans.

Effects of early life overnutrition and hyperandrogenism on spatial learning and memory in a rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine and metabolic abnormalities such as obesity and insulin resistance. PCOS is also associated with psychiatric disorders and cognitive impairment. The animal model of PCOS was induced by treating rats with 5α-dihydrotestosterone (5α-DHT) and additionally modified to induce adiposity by litter size reduction (LSR). Spatial learning and memory were assessed using the Barnes Maze test, and striatal markers of synaptic plasticity were analyzed. Striatal insulin signaling was estimated by the levels of insulin receptor substrate 1 (IRS1), its inhibitory phosphorylation at Ser307, and glycogen synthase kinase-3α/ß (GSK3α/ß) activity. Both LSR and DHT treatment significantly decreased striatal protein levels of IRS1, followed by increased GSK3α/ß activity in small litters. Results of the behavioral study showed that LSR had a negative effect on learning rate and memory retention, whereas DHT treatment did not induce impairment in memory formation. While protein levels of synaptophysin, GAP43, and postsynaptic density protein 95 (PSD-95) were not altered by the treatments, DHT treatment induced an increase in phosphorylation of PSD-95 at Ser295 in both normal and small litters. This study revealed that LSR and DHT treatment suppressed insulin signaling by downregulating IRS1 in the striatum. However, DHT treatment did not have an adverse effect on learning and memory, probably due to compensatory elevation in pPSD-95-Ser295, which had a positive effect on synaptic strength. This implies that hyperandrogenemia in this setting does not represent a threat to spatial learning and memory, opposite to the effect of overnutrition-related adiposity.

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial ß-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.

AMPK Activation Is Important for the Preservation of Insulin Sensitivity in Visceral, but Not in Subcutaneous Adipose Tissue of Postnatally Overfed Rat Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a well-known reproductive syndrome usually associated with obesity, insulin resistance, and hyperinsulinemia. Although the first signs of PCOS begin early in adolescence, it is underexplored whether peripubertal obesity predisposes women to PCOS metabolic disturbances. To highlight that, we examined the impact of postnatal overfeeding-induced obesity, achieved by litter size reduction during the suckling period, on metabolic disturbances associated with visceral and subcutaneous adipose tissue (VAT and SAT) function in the 5α-dihydrotestosterone (5α-DHT)-induced animal model of PCOS. We analyzed markers of insulin signaling, lipid metabolism, and energy sensing in the VAT and SAT. Our results showed that postnatally overfed DHT-treated Wistar rats had increased VAT mass with hypertrophic adipocytes, together with hyperinsulinemia and increased HOMA index. In the VAT of these animals, insulin signaling remained unchanged while lipogenic markers decreased, which was accompanied by increased AMPK activation. In the SAT of the same animals, markers of lipogenesis and lipolysis increased, while the activity of AMPK decreased. Taken together, obtained results showed that postnatal overfeeding predisposes development of PCOS systemic insulin resistance, most likely as a result of worsened metabolic function of SAT, while VAT preserved its tissue insulin sensitivity through increased activity of AMPK.

Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats.

Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin-positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3-positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia. Also, we examined potential protective effects of antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) on the number of these cells in mPFC subregions, when applied parallel with CSIS in doses that correspond to therapeutically effective ones in patients. Immunofluorescence analysis revealed decreased number of PV+ cells in cingulate cortex area 1, prelimbic area (PrL), infralimbic area (IL) and dorsal peduncular cortex of the mPFC in isolated rats, which coincided with depressive- and anxiety-like behaviors. In addition, CSIS-induced increase in the number of CC3+ cells was detected in aforementioned subregions of mPFC. Treatments with either FLX or CLZ prevented behavioral changes, decrease in PV+ and increase in CC3+ cell numbers in PrL and IL subregions in isolated rats. These results indicate the importance of intact GABAergic signaling in these areas for resistance against CSIS-induced behavioral changes, as well as subregion-specific protective effects of FLX and CLZ in mPFC of CSIS rats.

Comparative analyses of cellular physiological responses of non-target species to cypermethrin and its formulated product: Contribution to mode of action research.

Physiological responses of bacterial, fish, rat and human hepatoma cells to the technical cypermethrin (AS), cypermethrin-based plant protection product (PPP), and the major co-formulant (solvent) were compared. The endpoints included: bioluminescence, total protein content, activity of mitochondrial dehydrogenase and cytochrome P450 (CYP) enzymes CYP1A and CYP1B, and expression of several genes encoding different CYP enzyme isoforms. Toxicity of PPP was compared with the toxicity predicted using concentration addition model. Cypermethrin disturbs the activity of mitochondrial dehydrogenase. Induction of CYP1A1-, CYP1A2- and CYP1B1-associated activity was more pronounced in PPP than in cypermethrin treatment. The predominant biotransformation pathway of cypermethrin is related to Cyp3a1 induction. Deviations between observed and predicted toxicity of PPP indicate synergistic effects of cypermethrin and a solvent. In vitro cellular assays may serve as rapid pre-screening tool and provide for a good indication of mixture effects and prompt further in vivo testing of PPPs when really needed.