Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.

BACKGROUND: The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. OBJECTIVE: This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. METHODS: Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. RESULTS: In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2nd hr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. CONCLUSION: This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.

The Promise of Precision Nutrition for Modulation of the Gut Microbiota as a Novel Therapeutic Approach to Acute Graft-versus-host Disease.

Acute graft-versus-host disease (aGVHD) is a severe side effect of allogeneic hematopoietic stem cell transplantation (aHSCT) that has complex phenotypes and often unpredictable outcomes. The current management is not always able to prevent aGVHD. A neglected actor in the management of aGVHD is the gut microbiota. Gut microbiota dysbiosis after aHSCT is caused by many factors and may contribute to the development of aGVHD. Diet and nutritional status modify the gut microbiota and a wide range of products are now available to manipulate the gut microbiota (pro-, pre-, and postbiotics). New investigations are testing the effect of probiotics and nutritional supplements in both animal models and human studies, with encouraging results. In this review, we summarize the most recent literature about the probiotics and nutritional factors able to modulate the gut microbiota and we discuss the future perspective in developing new integrative therapeutic approaches to reducing the risk of graft-versus-host disease in patients undergoing aHSCT.

Modulation of gut microbiota: The effects of a fruits and vegetables supplement.

The consumption of an optimal amount of fruits and vegetables is known to improve physical fitness and physiological body functions. Healthy eating habits, including intake of fruits and vegetables, can modify gut microbiota. This study aimed to demonstrate the effectiveness of a formulated fruit and vegetable supplement (FVS) in modulating the antioxidant capacity and the gut microbiota composition. We enrolled 30 healthy volunteer subjects, matched for age, gender, BMI, and smoking habits, and randomized them into the FVS and the placebo (PLA) groups. Among the serum vitamins, the folic acid level was significantly higher (p = 0.001) in the FVS group than in the PLA group, whereas the vitamin B2 level was significantly higher in the PLA group than in the FVS group (p = 0.028). The antioxidant capacity, measured by using the oxygen radical absorbance capacity (ORAC) method, was also slightly higher in the FVS group than in the PLA group but did not reach statistical significance. The dietary intake, assessed by 24-h recalls, did not show any significant changes after the supplementation in both the groups. The gut microbiome composition, measured by 16S rDNA sequencing, showed no difference in both alpha and beta diversities, whereas the LEfse analysis revealed a microbial shift after the treatment, with a decreased abundance of the genus Ruminococcus from the Lachnospiraceae family (p = 0.009), and the unclassified genus from the family Erysipelotrichaceae (UC36, p = 0.003) in the FVS group compared with the PLA group (confirmed by SIAMCAT analysis, AUC = 74.1%). With a minor effect, the genus Faecalibacterium and unclassified genus and family from the order Lactobacillales (UC31) were also increased in the FVS group compared with the PLA group (p = 0.0474, p = 0.0352, respectively). SCFA measurement by gas chromatography-mass spectrometry showed an increased level of 2-methylbutyrate in the FVS group compared with the PLA group (p = 0.0385). Finally, the Spearman correlation analysis showed that in the FVS group, the genus Faecalibacterium positively correlated with 2-methyl butyrate (p = 0.040). In the PLA group, none of the significant bacteria correlated with either SCFA or serum biomarkers. The network analysis confirmed the positive correlation between genus Faecalibacterium and 2-methyl butyrate. We can conclude that the FVS in healthy individuals modified the gut microbiota composition and metabolites, and it can potentially contribute to reduce the pro-inflammatory response along with the antioxidant capacity.

The influence of the prebiotic gum acacia on the intestinal microbiome composition in rats with experimental chronic kidney disease.

Chronic kidney disease (CKD) is a globally common and important disease and there are evidence for a bidirectional relationship between microbiota and CKD. The aim of the study was to examine the influence of prebiotic - gum acacia (GA) on the intestinal microbiota in rats with adenine-induced CKD. Animals were randomly distributed into four equal groups (n = 6): control, adenine, GA and adenine + GA groups. CKD was induced by adenine (0.75% w/w) given in the diet daily for four weeks, and GA was administered in drinking water at a concentration of 15% w/v. The 16s rRNA analysis was performed on Illumina Miseq targeting V3-V4 region to characterize microbial composition. The abundance of Actinobacteria, Proteobacteria, Tenericutes and Verrucomicrobia bacteria was increased in adenine-induced CKD, and GA treatment successfully reversed those levels. Interestingly, alpha and beta diversity index were both reduced with GA treatment in rats with CKD. Short chain fatty acids (SCFAs) measurement and PICRUSt analysis have shown that GA treatment completely restored the depleted butyrate level and various perturbated functional pathways, respectively, in CKD rats. Taking together, our results suggest that GA supplementation has a beneficial role in treating CKD, through an increased production of butyrate, as well as its anti-inflammatory, antioxidant capacity and anti-nitrosative properties.

Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: possible involvement of PKC-MAPK signaling pathway.

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -ß2-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -ß2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-ß, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -ß2-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Curcumin attenuates diabetic nephropathy by inhibiting PKC-α and PKC-ß1 activity in streptozotocin-induced type I diabetic rats.

SCOPE: We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-ß1 activity-ERK1/2 pathway. METHODS AND RESULTS: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-ß1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-ß1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin. CONCLUSION: These results prove that curcumin produces dual blockade of both PKC-α and PKC-ß1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.