Multi-faceted Anti-obesity Effects of N-Methyl-D-Aspartate (NMDA) Receptor Modulators: Central-Peripheral Crosstalk.

Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABAA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity-effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food intake (p < 0.01), organ-to-liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Dxt demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABAA channels and anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic ß-cells.

Butylphthalide regulation of nerve cells in rats with cerebral infarction through jnk/p38mapk signaling pathway15.

To investigate the regulatory effect of butylphthalide (NBP) on the nerve cells of rats with cerebral infarction (CI) through the JNK/p38MAPK signaling pathway, 135 SPF SD male rats were and randomly assigned into the control group (n=45, sham surgery + peanut oil gavage), model group (n=45, CI model + peanut oil gavage), and NBP group (n= 45, CI model + NBP gavage). The comparison of the neurological function score between the model group and the NBP group, as well as the integrated locomotor ability score, Slit2 expression level, blood-brain barrier permeability, micro vessel density (MVD), CI volume, neuronal apoptosis rate of the brain tissue and expression levels of brain tissue p-JNK and p-p38MAPK protein among three groups was conducted. NBP inhibits the expression of JNK/p38MAPK signaling pathway, promotes the expression of Slit2 in CI rats, improves the neurological function and locomotor ability of CI rats, while promoting micro vascularization of the brain tissue, protecting the blood-brain barrier, reducing the volume of CI and the apoptosis of nerve cells.

Effects of 4-n-nonylphenol in liver of male and female viviparous fish (Poecilia vivipara).

4-n-Nonylphenol (NP) is one of the most toxic alkylphenols found in the environment. To evaluate the transcriptional effects of NP in the viviparous fish Poecilia vivipara, a hepatic transcriptome and qPCR analysis of genes were carried out. Guppies separated by sex were injected with two doses of NP (15 µg/g and 150 µg/g) or peanut oil (control). After 24 h, analysis of transcriptional level of Aryl Hydrocarbon Receptor (AhR), Estrogen Nuclear Receptor Alpha (ESR1), Pregnane X Receptor (PXR), Cytochromes P450 (CYP1A, CYP2K1 and CYP3A30), Glutathione S-transferase A3 and Mu 3 (GSTa3 and GSTMu3), SRY-Box Transcription Factor 9 (SOX9), Vitellogenin-1 (VIT), ATP Binding Cassette Subfamily C Member 1 (ABCC1), Multidrug Resistance-Associated Protein 2 (MRP2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1) was evaluated. 205,046 transcripts were assembled and protein prediction resulted in 203,147 predicted peptides. In females, no significant changes were detected in the transcription of some phase I biotransformation and ABC transporter genes. AhR, PXR, GSTa3 and SOX9 genes where higher in the lower dose group (15 µg/g) compared to control. In male fish, no changes were observed in the transcript levels of the nuclear receptors, in endocrine disruption and phase I biotransformation genes. GSTa3 showed lower transcription in fish treated with both doses. ABCC1 was higher in guppies treated with the lower dose while MRP2 showed less transcripts. This short-term and low-dose exposure to NP caused changes that could serve as early indicators of deleterious processes. These results indicate P. vivipara as a good sentinel in biomonitoring programs.

Shugan Huoxue Huayu Fang attenuates carbon tetrachloride-induced hepatic fibrosis in rats by inhibiting transforming growth factor-ß1/Smad signaling.

OBJECTIVE: To investigate the potential mechanism by which Shugan Huoxue Huayu Fang (SGHXHYF) ameliorates liver fibrosis. METHODS: Liver fibrosis was induced in rats by intraperitoneal injection of carbon tetrachloride (CCl4) in peanut oil solution (40%, 3 mL/kg body weight) twice a week for 8 weeks. A normal control group received the same volume of peanut oil alone. During weeks 5-8, the CCl4-injected rat groups were administered saline (vehicle control), colchicine (0.1 mg/mL, 1 mg/kg, positive control), or SGHXHYF (0.1 mg/mL; 0.3, 0.6 and 1.2 mg/kg) once daily by oral gavage. Rats were sacrificed 24 h after the last treatment. Blood samples were collected for measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB), collagen Ⅰ and collagen Ⅲ levels. Liver samples were analyzed by histopathological staining, Masson's staining of extracellular matrix proteins, and immune-ohistochemical staining of αsmooth muscle actin (α-SMA). TGF-ß1/Smad protein and mRNA levels were analyzed by Western blot and quantitative reverse transcription-polymerase chain reaction analysis, respectively. In vitro experiments were also performed using rat hepatic stellate cells (HSCs). RESULTS: Compared with the control animals, CCl4-exposed rats exhibited elevated serum levels of ALT, AST, ALP, collagen I, and collagen III; reduced serum levels of ALB; and increased collagen deposition and αSMA expression in liver sections, reflecting liver fibrosis. CCl4 also increased expression of TGF-ß1 and the activated (phosphorylated) forms of Smad2 and Smad3 but reduced expression of the negative regulator Smad7 in the liver. Notably, concomitant administration of SGHXHYF to CCl4-exposed rats was found to significantly reverse or abolish the pro-fibrotic effects of CCl4 in the liver and reduced serum transferase levels. Analysis of HSCs in vitro confirmed that, mechanistically, SGHXHYF inhibited activation of the TGF-ß1/Smad signaling pathway by downregulating phosphorylated Smad2 and Smad3 and upregulating Smad7 levels. CONCLUSION: SGHXHYF ameliorated CCl4-induced liver fibrosis by inhibiting the TGF-ß1/Smad signaling pathway. These findings suggest that SGHXHYF may have clinical utility for the treatment or prevention of liver fibrosis.

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice.

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Extraction Technology Can Impose Influences on Peanut Oil Functional Quality: A Study to Investigate the Lipid Metabolism by Sprague-Dawley Rat Model.

In this study, peanut oil was prepared by cold pressing (temperature under 60 °C), hot pressing (temperature above 105 °C), and enzyme-assisted aqueous extraction technology. Influences of an extraction technology on the oil fatty acid composition and the content of minor bioactive compounds, including tocopherols, polyphenols, and squalene, were investigated in detail. High-fat-diet Sprague-Dawley (SD) rat model was then established to probe the impact of cold-pressed peanut oil (CPO), hot-pressed peanut oil (HPO), and enzyme-assisted aqueous-extracted peanut oil (EAO) on lipid metabolism outcomes, to explore influences of different extraction technologies on lipid functional quality. Results showed that oleic acid was the predominate fatty acid in the EAO (52.57 ± 0.11%), which was also significantly higher (P < 0.05) than CPO and HPO. The HPO showed higher total tocopherol and polyphenol contents (206.84 ± 6.93 mg/kg and 47.87 ± 6.50 mg GA/kg, respectively) than CPO and EAO (P < 0.05). However, the squalene content in CPO was 475.47 ± 12.75 mg/kg, which was the highest among the three oils (P < 0.05). The animal experiment results revealed that EAO could be more prone to induce lipid accumulation in the liver, which may likely to cause nonalcoholic fatty liver disease. However, the serum lipid profiles indicated that the CPO was more beneficial than the EAO and HPO in lowering the serum low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase contents, and increasing the high-density lipoprotein cholesterol content. All of our efforts indicated that an extraction technology can affect the peanut oil lipid fatty acid composition, the bioactive compounds content, and, correspondingly, the lipid metabolism in SD rats.

Developing a Novel Two-Stage Process for Carotenoid Production by Cordyceps militaris (Ascomycetes).

Natural carotenoids are attracting increasing interest, but their widespread use is limited because of poor production. Cordyceps militaris, a traditional Chinese mushroom, contains a large amount of carotenoids, and this study aimed to increase carotenoid production by C. militaris by optimizing a liquid-state cultivation system. We developed and optimized a novel 2-stage process, including cultivation under shaking in darkness and under static irradiation on a flat panel, using response surface methodology, and we compared this process to common shake-flask cultivation. In addition, we examined the effects of different inducers (chitosan, peanut oil, tomato juice, yeast, and metal ions) on carotenoid production. Results showed that under optimal conditions (4 days of shaking in darkness, 10 days of static irradiation with a 100-mL flat panel volume), a maximum of 1217.5 ± 115.9 µg/g carotenoids were produced; only 662.9 µg/g were produced by common shake-flask cultivation. Only a large amount of chitosan (8 mg) could significantly increase carotenoid content; some of the other inducers showed inhibitory effects. This study demonstrated that this 2-stage process could effectively increase the natural carotenoid content in C. militaris, making it a potential source for commercial exploitation.

Coconut oil consumption improves fat-free mass, plasma HDL-cholesterol and insulin sensitivity in healthy men with normal BMI compared to peanut oil.

BACKGROUND & AIMS: The existing scientific evidence on coconut oil consumption and its health effects remains inconclusive due to varied reasons. In this context, we conducted a well-controlled metabolic study, eliminating some of the confounding factors and assessed the effects of the consumption of coconut oil-based diet on various anthropometric, biochemical and inflammatory markers and compared with peanut oil-diet. METHODS: Nine healthy male volunteers with BMI ≤25 kg/m2 were enrolled for this study and given balanced diets prepared with coconut oil (CO; ~35 g) for a period of eight weeks. After a wash-out period of six weeks, the same subjects were provided with diets prepared with peanut oil (~35 g) for eight weeks. Except fat source, the composition of the diets was identical in all aspects. RESULTS: Compared to basal values, there were significant increases in fat-free mass (p ≤ 0.022), plasma HDL-cholesterol (HDL-C) (p ≤ 0.047) and insulin sensitivity of the subjects at the end of CO-consumption. Further, compared to peanut oil, increase in plasma HDL-C was significant (p = 0.004) in CO treatment. On the other hand, plasma inflammatory markers-associated with cardiovascular diseases (CVD), namely soluble vascular cell adhesion molecule 1 (sVCAM1) and matrix metalloproteinase levels were reduced significantly by CO-intake. Further, these subjects displayed elevated levels of myristic acid (14:0) in plasma phospholipids at the end of CO-consumption, which correlated positively with HDL-C and negatively with sVCAM1. However, no such changes were observed after peanut oil diet consumption. CONCLUSIONS: In conclusion, compared to peanut oil, the consumption of coconut oil in a balanced diet resulted in increased fat-free mass, plasma HDL-C, elicited favourable changes on insulin sensitivity and CVD risk-associated parameters in healthy men with normal BMI.

The effects of intrauterine infusion of peanut oil on endometrial health, salivary cortisol and interovulatory period in mares.

Intrauterine infusion of peanut oil at Day 10 post-ovulation has been reported to prolong dioestrus in mares. However, the effects of peanut oil treatment on the endometrium and whether the technique is painful have not been assessed. The objectives of this study were, (i) to determine the effect of intrauterine infusion of peanut oil on endometrial health, (ii) to determine whether use of intrauterine peanut oil is painful and (iii) to confirm that peanut oil causes prolonged dioestrus. Six mares aged 3-12 years old were used in a cross-over design with each mare administered both 1 ml of intrauterine peanut oil and a sham treatment on different oestrous cycles. The effect of intrauterine infusion of 1 ml peanut oil or sham treatment were measured using interovulatory period, uterine fluid accumulation as determined by transrectal ultrasonography, serum progesterone levels, endometrial Kenney biopsy scores and histological features, endometrial eosinophil numbers and salivary cortisol measurements. The individual mare response to intrauterine infusion of peanut oil was variable. Peanut oil infusion did not statistically prolong the luteal phase, nor elevate salivary cortisol levels but did cause superficial erosion of the endometrial surface epithelium in all mares and significantly increased eosinophil numbers in the endometrium (P = 0.0068). The Kenney grade for biopsies from 2/6 mares worsened transiently following infusion. In conclusion, intra-uterine peanut oil does not statistically increase the duration of the luteal phase but results in an inflammatory response and increase in endometrial eosinophil numbers suggesting treatment may be associated with a hypersensitivity-type reaction. Those contemplating using peanut oil to suppress oestrus should also be aware of the legislative and regulatory implications.