Immunomodulatory effect of Premna odorata volatile oils in Mycobacterium tuberculosis by inhibiting TLR4/NF-κB pathway

Introduction: The development of multi drug resistant (MDR) tuberculosis (TB) and extensively drug resistant (XDR) TB, increased the interest in the usage of medicinal plants that are complementary to antibiotics to improve anti-TB efficacy. The present study aimed to confirm the anti-TB efficacy of volatile oils (VOs) isolated from different parts of Premna odorata in vivo, and moreover, to test the possible involvement of TLR4/NF-κB signaling pathway in its anti-TB efficacy. Methods: Thirty mice were divided into six equal groups. Group 1: healthy mice (negative control). Groups 2-6 were injected intravenously with a positive TB solution of purified MeDiPro Mycobacterium tuberculosis (MTB) antigen for 7 days to induce tuberculosis. Group 3-6: TB-injected mice treated respectively with leaves VO (300 μL/d), young stems VO (300 μL/d), flowers VO and a combination of the three essential VOs (1:1:1). Various immunologic factors and antioxidant activity were evaluated and compared in the groups. Results: TB-infected mice showed a significant increase in the serum levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin (IL) 1-β and the mRNA expression levels of toll-like receptor 4 (TLR-4) & nuclear factor-κB (NF-κB) and a decrease in IL-10 & total antioxidant capacity (TAC). While pretreatment with VOs extracted from leaves, flowers, young stems and a combination of the three oils reversed these effects. Conclusion: The immunomodulatory effects of VOs extracted from different parts of P. odorata against TB infection involve the TLR-4/NFκB signaling pathway as well as, antioxidant effects, recommending that the use of this plant may help TB infected patients

The cardioprotective effects of secoisolariciresinol diglucoside (flaxseed lignan) against cafeteria diet-induced cardiac fibrosis and vascular injury in rats: an insight into apelin/AMPK/FOXO3a signaling pathways

Introduction: Fast food is a major risk factor for atherosclerosis, a leading cause of morbidity and mortality in the Western world. Apelin, the endogenous adipokine, can protect against cardiovascular disease via activating its receptor, APJ. Concurrently, secoisolariciresinol diglucoside (SDG), a flaxseed lignan extract (FLE), showed a therapeutic impact on atherosclerosis. The current study aimed to examine the effect of SDG on cafeteria diet (CAFD)-induced vascular injury and cardiac fibrosis via tracking the involvement of the apelin/APJ pathway.Methods: Thirty male rats were allocated into control, FLE-, CAFD-, CAFD/FLE-, and CAFD/FLE/F13A-treated rats, where F13A is an APJ blocker. All treatments lasted for 12 weeks.Results and discussion: The CAFD-induced cardiovascular injury was evidenced by histological distortions, dyslipidemia, elevated atherogenic indices, cardiac troponin I, collagen percentage, glycogen content, and apoptotic markers. CAFD increased both the gene and protein expression levels of cardiac APJ, apelin, and FOXO3a, in addition to increasing endothelin-1, VCAM1, and plasminogen activator inhibitor-1 serum levels and upregulating cardiac MMP-9 gene expression. Moreover, CAFD reduced serum paraoxonase 1 and nitric oxide levels, cardiac AMPK, and nuclear Nrf2 expression. FLE attenuated CAFD-induced cardiovascular injury. Such effect was reduced in rats receiving the APJ blocker, implicating the involvement of apelin/APJ in FLE protective mechanisms.Conclusion: FLE supplementation abrogated CAFD-induced cardiac injury and endothelial dysfunction in an apelin/APJ-dependent manner

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

Potential Utility of Sodium Selenate as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats: A Perspective on Protein Tyrosine Phosphatase

Metformin is widely regarded as the standard first-line antidiabetic agent, in terms of efficacy and safety profiles. However, in most patients with type II diabetes mellitus (T2DM), it was found that metformin alone is not enough to adequately control hyperglycemia. Thus, we designed this study with the aim to investigate the effect of sodium selenate, a protein tyrosine phosphatase (PTP) inhibitor, individually and as an adjunct to metformin, on a rat model that simulates the metabolic characteristics of human T2DM. T2DM model was achieved by feeding the rats with high-fat, high-fructose diet (HFFD) for 8 weeks followed by a low dose of streptozotocin (STZ) (35 mg/kg/day, i.p.). Changes in serum glucose, insulin, adiponectin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and the lipid profile were assessed. In addition, the level of reduced glutathione (GSH) and the activity of PTP were determined in the liver. Results showed that the addition of sodium selenate to metformin was able to restore hepatic GSH back to normal levels. Also, this combination therapy corrected the altered serum total cholesterol (TC), triglycerides (TG), and adiponectin levels. In conclusion, additive therapeutic effect was recorded when sodium selenate was used as an adjunct to metformin

Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations.

Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid

Octreotide ameliorates gastric lesions in chronically mild stressed rats

AIM: To evaluate the effect of chronic mild stress (CMS) on the emergence of gastric ulcers and possible modulation by octreotide, a synthetic somatostatin analogue

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the alarmingly rising clinical problems in the 21st century with no effective drug treatment until now. Taurine is an essential amino acid in humans that proved efficacy as a non-pharmacological therapy in a plethora of diseases; however, its impact on NAFLD remains elusive. The aim of the current study is to evaluate the protective mechanism of taurine in experimental steatohepatitis induced by junk food given as cafeteria-diet (CAF-D) in male albino rats. Methods: Forty adult male albino rats of local strain between 8-10 weeks old, weighing 150 ± 20 g, were divided into four equal groups: Group I (control group), Group II (Taurine group), Group III (CAF-D for 12 weeks) and Group IV (CAF-D +Taurine). CAF-D was given in addition to the standard chow for 12 weeks, where each rat was given one piece of beef burger fried in 15 g of sunflower oil, one teaspoonful of mayonnaise, and one piece of petit pan bread, weighing 60g/ piece. In the serum, liver function tests; ALT, AST, ALP, GGT and the lipid profile; TG, TC, HDL-C added to reduced glutathione (GSH) were assessed colorimetrically, while fibroblast growth factor (FGF)-21, adiponectin & interleukin (IL)-6 via ELISA. The same technique was used for the assays of the hepatic levels of FGF-21, silent information regulator (SIRT1), malondialdehyde (MDA),IL-10, tumor necrosis factor-α (TNF-α) as well as the apoptotic markers; caspase-3 and B-cell lymphoma (Bcl-2). Results: The cafeteria-diet induced steatohepatitis was reflected by significantly increased body and liver weight gain, elevation of liver enzymes; ALT, AST, ALP and GGT added to the dyslipidemic panel, presented as increased TC, TG, LDL-C and decreased HDL-C levels. The steatosis-induced inflammatory milieu, marked by elevated serum levels of FGF-21, IL-6, hepatic TNF-α, as well as reduced IL-10 and adiponectin, was associated with steatosis- induced hepatic oxidative stress, reflected by increased hepatic MDA and decreased GSH levels, along with stimulated caspase-3 and decline in BcL-2 hepatic levels. These pathological disturbances were significantly ameliorated by taurine supplementation and evidenced histopathologically. The cross talk between hepatic FGF-21 and SIRT1 and their association to the induced perturbations are novel findings in this study. Taurine's efficacy in restoration of hepatic structure and function is partially via the increase in SIRT1 and associated reduction of FGF-21. Conclusion: The findings of the current study prove the protective role of taurine in NAFLD via a novel role in the amelioration of FGF-21/ SIRT1 axis, which could be considered a new therapeutic target

Effect of diabetes (DV) and different oral drug regimens on the serum lipid profile.

<p>Effect of diabetes (DV) and different oral drug regimens, viz., phytol (DP_h, 250 mg/kg); pioglitazone (DP₅, 5 mg/kg); pioglitazone (DP₁₀, 10 mg/kg); phytol and pioglitazone (DP_hP₅); on serum levels of triglycerides, total cholesterol, LDL-C, HDL-C, ALT and TC/HDL ratio (mean of 7 animals ± S.D). As compared with non-diabetic [ND] (*) and diabetic [DV] (#) groups using one way ANOVA followed by Tukey post hoc test, <i>P</i><0.05. (^Ο) Significant interaction when P_h and P₅ were combined using Factorial Design.</p

Immunomodulatory effect of Premna odorata volatile oils in Mycobacterium tuberculosis by inhibiting TLR4/NF-κB pathway

Introduction: The development of multi drug resistant (MDR) tuberculosis (TB) and extensively drug resistant (XDR) TB, increased the interest in the usage of medicinal plants that are complementary to antibiotics to improve anti-TB efficacy. The present study aimed to confirm the anti-TB efficacy of volatile oils (VOs) isolated from different parts of Premna odorata in vivo, and moreover, to test the possible involvement of TLR4/NF-κB signaling pathway in its anti-TB efficacy. Methods: Thirty mice were divided into six equal groups. Group 1: healthy mice (negative control). Groups 2-6 were injected intravenously with a positive TB solution of purified MeDiPro Mycobacterium tuberculosis (MTB) antigen for 7 days to induce tuberculosis. Group 3-6: TB-injected mice treated respectively with leaves VO (300 μL/d), young stems VO (300 μL/d), flowers VO and a combination of the three essential VOs (1:1:1). Various immunologic factors and antioxidant activity were evaluated and compared in the groups. Results: TB-infected mice showed a significant increase in the serum levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin (IL) 1-β and the mRNA expression levels of toll-like receptor 4 (TLR-4) & nuclear factor-κB (NF-κB) and a decrease in IL-10 & total antioxidant capacity (TAC). While pretreatment with VOs extracted from leaves, flowers, young stems and a combination of the three oils reversed these effects. Conclusion: The immunomodulatory effects of VOs extracted from different parts of P. odorata against TB infection involve the TLR-4/NFκB signaling pathway as well as, antioxidant effects, recommending that the use of this plant may help TB infected patients

Effect of diabetes (DV) and different oral drug regimens on glucose homeostasis indicators.

<p>Effect of diabetes (DV) and different oral drug regimens, viz., phytol (DP_h, 250 mg/kg); pioglitazone (DP₅, 5 mg/kg); pioglitazone (DP₁₀, 10 mg/kg); phytol and pioglitazone (DP_hP₅); on serum levels of glucose, insulin, fructosamine, TNF-α, adiponectin and insulin resistance (HOMA-ratio) (mean of 7 animals ± S.D). As compared with non-diabetic [ND] (*) and diabetic [DV] (#) groups using one way ANOVA followed by Tukey post hoc test, <i>P</i><0.05. (^Ο) Significant interaction when P_h and P₅ were combined using Factorial Design.</p