Effects of telmisartan on metabolic syndrome components: a comprehensive review.

Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive activity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan, valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demonstrated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. However, larger and long-duration studies are needed to confirm these findings in long-term observational studies and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.

Molecular mechanisms and signaling pathways of black cumin (Nigella sativa) and its active constituent, thymoquinone: a review.

BACKGROUND: Nigella sativa and its main bioactive ingredient, thymoquinone, exhibit various pharmacological activities, including neuroprotective, nephroprotective, cardioprotective, gastroprotective, hepatoprotective, and anti-cancer effects. Many studies have been conducted trying to elucidate the molecular signaling pathways that mediate these diverse pharmacological properties of N. sativa and thymoquinone. Accordingly, the goal of this review is to show the effects of N. sativa and thymoquinone on different cell signaling pathways. METHODS: The online databases Scopus, PubMed and Web of Science were searched to identify relevant articles using a list of related keywords such as Nigella sativa, black cumin, thymoquinone, black seed, signal transduction, cell signaling, antioxidant, Nrf2, NF-κB, PI3K/AKT, apoptosis, JAK/STAT, AMPK, MAPK, etc. Only articles published in the English language until May 2022 were included in the present review article. RESULTS: Studies indicate that N. sativa and thymoquinone improve antioxidant enzyme activities, effectively scavenges free radicals, and thus protect cells from oxidative stress. They can also regulate responses to oxidative stress and inflammation via Nrf2 and NF-κB pathways. N. sativa and thymoquinone can inhibit cancer cell proliferation through disruption of the PI3K/AKT pathway by upregulating phosphatase and tensin homolog. Thymoquinone can modulate reactive oxygen species levels in tumor cells, arrest the cell cycle in the G2/M phase as well as affect molecular targets including p53, STAT3 and trigger the mitochondrial apoptosis pathway. Thymoquinone, by adjusting AMPK, can regulate cellular metabolism and energy hemostasis. Finally, N. sativa and thymoquinone can elevate brain GABA content, and thus it may ameliorate epilepsy. CONCLUSIONS: Taken together, the improvement of antioxidant status and prevention of inflammatory process by modulating the Nrf2 and NF-κB signaling and inhibition of cancer cell proliferation through disruption of the PI3K/AKT pathway appear to be the main mechanisms involved in different pharmacological properties of N. sativa and thymoquinone.

Pharmacokinetic of berberine, the main constituent of Berberis vulgaris L.: A comprehensive review.

Barberry (Berberis vulgaris L.) is a medicinal plant and its main constituent is an isoquinoline alkaloid named berberine that has multiple pharmacological effects such as antioxidant, anti-microbial, antiinflammatory, anticancer, anti-diabetes, anti-dyslipidemia, and anti-obesity. However, it has restricted clinical uses due to its very poor solubility and bioavailability (less than 1%). It undergoes demethylenation, reduction, and cleavage of the dioxymethylene group in the first phase of metabolism. Its phase two reactions include glucuronidation, sulfation, and methylation. The liver is the main site for berberine distribution. Berberine could excrete in feces, urine, and bile. Fecal excretion of berberine (11-23%) is higher than urinary and biliary excretion routes. However, a major berberine metabolite is excreted in urine greater than in feces. Concomitant administration of berberine with other drugs such as metformin, cyclosporine A, digoxin, etc. may result in important interactions. Thus, in this review, we gathered and dissected any related animal and human research articles regarding the pharmacokinetic parameters of berberine including bioavailability, metabolism, distribution, excretion, and drug-drug interactions. Also, we discussed and gathered various animal and human studies regarding the developed products of berberine with better bioavailability and consequently, better therapeutic effects.

Comparison of pharmacokinetic parameters of ranolazine between diabetic and non-diabetic rats.

Objectives: Diabetes mellitus (DM) affects the pharmacokinetics of drugs. Ranolazine is an antianginal drug that is prescribed in DM patients with angina. We decided to evaluate the effect of DM on the pharmacokinetics of ranolazine and its major metabolite CVT-2738 in rats. Materials and Methods: Male rats were divided into two groups: DM (induced by 55 mg/kg Streptozotocin (STZ)) and non-DM. All animals were treated with 80 mg/kg of ranolazine for 7 continuous days. The blood samples were collected immediately at 0 (prior to dosing), 1, 2, 3, 4, 8, and 12 hr after administration of the 7th dose of ranolazine. Serum ranolazine and CVT-2738 concentrations were determined using the high-performance liquid chromatography (HPLC) method. Pharmacokinetic parameters were calculated using a non-compartmental model and compared between the two groups. Results: The peak serum concentration (Cmax) and area under the curve (AUC) of ranolazine significantly decreased in DM compared with non-DM rats. DM rats showed significantly higher volumes of distribution (Vd) and clearance (CL) of ranolazine than non-DM rats. DM did not affect Ke, Tmax, and T1/2 of ranolazine. The concentration of metabolite was lower than the HPLC limit of detection (LOD). Conclusion: It was found that streptozotocin-induced DM increased Vd and CL of ranolazine, thereby decreasing the AUC of the drug. Therefore, dosage adjustment may be necessary for DM patients, which requires further clinical studies.

A dose-related positive effect of inhaled simvastatin-loaded PLGA nanoparticles on paraquat-induced pulmonary fibrosis in rats.

OBJECTIVE: Pulmonary fibrosis is an important complication of subacute paraquat (PQ) poisoning. Here, we reported a novel nanotherapeutic platform for PQ-induced pulmonary fibrosis in animal inhalation models using simvastatin (SV)-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). METHODS AND MATERIALS: Eight inhalations of normal saline, PQ (24 mg/kg), PQ plus SV (20 mg/kg), PQ plus SV-loaded PLGA NPs at doses of 5, 10 or 20 mg/kg or PQ plus PLGA NPs were given to rats. After the end of the treatment period, inflammatory factors and creatine phosphokinase as well as lung pathological changes and tracheal responsiveness were evaluated. RESULTS: Inhalation of SV-loaded PLGA NPs could significantly prevent the progression of PQ-induced pulmonary fibrosis especially at a dose of 10 mg through decreasing the serum level of inflammatory factors as well as contractile responses (p < 0.001) compared to PQ group. Pathological findings also confirmed the results. However, inhalation of non-formulated SV could not prevent tissue damage and fibrosis in comparision with SV-loaded PLGA NPs. CONCLUSION: Taken together, the present work provides us an idea about the pulmonary delivery of PLGA-SV NPs using nebulizer for the treatment of PQ poisoning. However, the efficacy of this formulation in human beings and clinical use needs to be more investigated.

Quetiapine attenuates the acquisition of morphine-induced conditioned place preference and reduces ERK phosphorylation in the hippocampus and cerebral cortex.

Background: Quetiapine is an atypical antipsychotic that antagonizes dopamine and serotonin receptors. It has been suggested that quetiapine can be used to treat substance use disorders, including opioid use disorder. Opioids modulate dopaminergic functions associated with conditioned reinforcement and these effects can be measured via the conditioned place preference (CPP) paradigm. Opioids' unconditioned effects are regulated by several proteins, including extracellular signal-regulated kinase (ERK) and cAMP-responsive element-binding (CREB).Objective: To assess the effect of quetiapine on morphine-induced CPP and motor activity levels, and on the levels of ERK and CREB proteins in the hippocampus and cerebral cortex.Methods: 42 male rats were exposed to a CPP protocol, in which they underwent a conditioning paradigm with saline, quetiapine (40 mg/kg), morphine (10 mg/kg), morphine plus quetiapine (10, 20, or 40 mg/kg), or morphine plus memantine (7.5 mg/kg, a positive control drug) (n = 6 per group). The rats were tested for CPP and exploratory activity. Levels of ERK and CREB proteins in the hippocampus and cerebral cortex were also measured.Results: Quetiapine co-administered with morphine inhibited morphine-induced CPP [F (6, 70) = 11.67, p < .001] and morphine's effects on motor activity (p < .001). Morphine enhanced ERK phosphorylation in the hippocampus (p < .001) and cerebral cortex (p < .001), an effect inhibited by quetiapine.Conclusion: Quetiapine attenuates morphine-induced CPP and locomotion and these effects are associated with a reduction of ERK phosphorylation in the hippocampus and cerebral cortex. These results suggest that quetiapine should be further explored as a potential treatment for opioid use disorder.

Melatonin improves arsenic-induced hypertension through the inactivation of the Sirt1/autophagy pathway in rat.

Arsenic (As), a metalloid chemical element, is classified as heavy metal. Previous studies proposed that As induces vascular toxicity by inducing autophagy, apoptosis, and oxidative stress. It has been shown that melatonin (Mel) can decrease oxidative stress and apoptosis, and modulate autophagy in different pathological situations. Hence, this study aimed to investigate the Mel effect on As-induced vascular toxicity through apoptosis and autophagy regulation. Forty male rats were treated with As (15 mg/kg; oral gavage) and Mel (10 and 20 mg/kg, intraperitoneally; i.p.) for 28 days. The systolic blood pressure (SBP) changes, oxidative stress markers, the aorta histopathological injuries, contractile and relaxant responses, the level of apoptosis (Bnip3 and caspase-3) and autophagy (Sirt1, Beclin-1 and LC3 II/I ratio) proteins were determined in rats aorta. The As exposure significantly increased SBP and enhanced MDA level while reduced GSH content. The exposure to As caused substantial histological damage in aorta tissue and changed vasoconstriction and vasorelaxation responses to KCl, PE, and Ach in isolated rat aorta. The levels of HO-1 and Nrf-2, apoptosis markers, Sirt1, and autophagy proteins also enhanced in As group. Interestingly, Mel could reduce changes in oxidative stress, blood pressure, apoptosis, and autophagy induced by As. On the other hand, Mel led to more increased the levels of Nrf-2 and HO-1 proteins compared with the As group. In conclusion, our findings showed that Mel could have a protective effect against As-induced vascular toxicity by inhibiting apoptosis and the Sirt1/autophagy pathway.

Cardioprotective effects of alpha-mangostin on doxorubicin-induced cardiotoxicity in rats.

The main adverse effect of doxorubicin is cardiotoxicity. Oxidative stress and apoptosis induction have been suggested as mechanisms involved in its cardiotoxicity. In this study, cardioprotective effects of alpha-mangostin against doxorubicin-induced cardiotoxicity have been investigated in rats. Forty-two rats were divided as follows: Control, doxorubicin (2 mg/kg every 48 hr), alpha-mangostin (200 mg/kg), alpha-mangostin (50, 100, 200 mg/kg) + doxorubicin (2 mg/kg every 48 hr), and vitamin E (200 IU/kg) + doxorubicin (2 mg/kg every 48 hr). Alpha-mangostin was administered by gavage for 19 days, while doxorubicin (12 days) and vitamin E (19 days) were injected intraperitoneally. Doxorubicin decreased heart rate, increased electrocardiogram signal components duration and reduced systolic and diastolic arterial blood pressure, and caused histological damage in the heart of rats. Doxorubicin decreased heart weight and heart/body weight ratio, as well as elevated creatine phosphokinase isoenzyme and lactate dehydrogenase. Doxorubicin increased malondialdehyde, inflammatory biomarkers, and caspases 3 and 9 and decreased reduced glutathione content in heart tissue but co-administration of alpha-mangostin (100 mg/kg) restored all doxorubicin toxic effects. Results show that alpha-mangostin has protective effects against doxorubicin-induced cardiotoxicity by antioxidant, antiinflammatory, and antiapoptotic effects that may ameliorate doxorubicin cardiotoxicity in human chemotherapy without reduction in its anticancer effect.

Diabetes mellitus aggravates ranolazine-induced ECG changes in rats.

PURPOSE: Diabetes mellitus (DM) is known to affect the pharmacokinetics of drugs. In this study, we evaluated the effect of DM on the liver content of CYP 3A2 enzyme. We also explored the ECG changes after administration of ranolazine in non-DM and DM rats. METHODS: First phase: 24 male Wistar rats were separated into 4 groups. The control group (n = 6) received normal saline and the DM groups (n = 18) were treated with a single dose (55 mg/kg) of streptozocin (STZ; i.p. injection), then were held for 10, 20, and 30 days, respectively. After study duration for each group, the liver CYP 3A2 protein content was determined using western blotting. Second phase: 48 male Wistar rats were classified into two groups of non-DM and DM; and each group was divided into 4 subgroups (n: 6). Experimental groups received oral doses of 20, 40, and 80 mg/kg ranolazine. DM and non-DM control groups received normal saline. Treatment lasted for 28 days, and then the ECG was recorded. RESULTS: Experimental DM induced by STZ caused a significant decrement in liver CYP3A2 protein content of rats on days 10 and 20 (P < 0.01), and 30 (P < 0.05) compared to the control animals. Significant increases in QT and corrected QT (QTc) intervals (P < 0.01), and bradycardia (P < 0.01) without any significant effect on PR and QRS intervals were observed in DM in comparison with non-DM groups after ranolazine treatment. CONCLUSIONS: In summary, DM induction in animals resulted in CYP 3A2 inhibition and the prolongation of QT and QTc interval as well as bradycardia after ranolazine treatment.

Potential role of green tea extract and epigallocatechin gallate in preventing bisphenol A-induced metabolic disorders in rats: Biochemical and molecular evidence.

BACKGROUND: Bisphenol A (BPA) is an artificial chemical widely used in the production of polycarbonate plastics and epoxy resins. Accumulating evidence indicates that BPA exposure is associated with metabolic disorders. The beneficial effects of green tea and epigallocatechin gallate (EGCG), major catechin present in green tea, on alleviating BPA-induced metabolic disorders have been shown in various studies. PURPOSE: Protective effects of green tea extract and EGCG on BPA-induced metabolic disorders and possible underlying mechanisms were investigated. METHODS: Rats were randomly divided into control, green tea extract (50 and 100 mg/kg, IP), EGCG (20 and 40 mg/kg, IP), BPA (10 mg/kg, gavage), BPA plus green tea extract (25, 50, and 100 mg/kg, IP), BPA plus EGCG (10, 20, and 40 mg/kg, IP), and BPA plus vitamin E (200 IU/kg, IP). After two months, body weight, blood pressure, biochemical blood tests, hepatic malondialdehyde (MDA), and glutathione (GSH) were assessed. By enzyme-linked immunosorbent assay, serum levels of insulin, leptin, adiponectin, TNFα, and IL-6, and by western blotting, hepatic insulin signaling (IRS-1, PI3K, Akt) were measured. RESULTS: BPA increased body weight, blood pressure, and MDA, decreased GSH, elevated serum levels of low-density lipoprotein cholesterol, total cholesterol, triglyceride, glucose, insulin, leptin, TNFα, IL-6, and liver enzymes including alanine aminotransferase and alkaline phosphatase, and lowered high-density lipoprotein cholesterol and adiponectin levels. In western blot, decreased phosphorylation of IRS-1, PI3K, and Akt was obtained. Administration of green tea extract, EGCG, or vitamin E with BPA reduced the detrimental effects of BPA. CONCLUSION: These findings indicate that green tea extract and EGCG can be effective in preventing or reducing metabolic disorders induced by BPA linked to their antioxidant and anti-inflammatory activity, regulating the metabolism of lipids, and improving insulin signaling pathways.

Protective Effect of Crocin on Malathion-induced Cardiotoxicity in Rats: A Biochemical, Histopathological and Proteomics Study.

In this study, the protective effect of crocin on malathion (MTN) induced cardiotoxicity in rats in subacute exposure was evaluated. Rats were divided into 6 groups; control (normal saline); MTN (100 mg/kg); MTN + crocin (10, 20 and 40 mg/kg) and MTN + vitamin E 200 IU/kg. Treatments were continued for two weeks. Creatine phosphokinase MB (CK-MB), malondialdehyde (MDA) and glutathione (GSH) levels were evaluated in heart tissue at the end of treatments. The effect of crocin and MTN on histopathological changes in rat cardiac tissue was also investigated. The alteration of protein profile in the heart of the animals exposed to MTN was evaluated by proteomic approach through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) software. MTN induced histopathological damages and elevated the level of cardiac marker CK-MB (P < 0.01). The level of MDA increased and the level of GSH reduced (P < 0.001). MDA levels were reduced in all crocin plus MTN groups (P < 0.001) and vitamin E plus MTN (P < 0.001) groups as compared to MTN groups. However, in the crocin (10 mg/kg) + MTN group, the content of GSH compared to MTN treated rats increased (P < 0.001). Protein abundance analysis identified proteins implicated in cardiac necrosis, tricarboxylic acid cycle, cellular energy homeostasis, arrhythmias, heart development, heart failure and cardiovascular homeostasis to be affected by MTN. In summary, MTN may induce damage in the heart tissue of rats following subacute exposure and crocin, as an antioxidant, showed protective effects against MTN cardiotoxicity.

Evaluation of green tea extract and epigallocatechin gallate effects on bisphenol A-induced vascular toxicity in isolated rat aorta and cytotoxicity in human umbilical vein endothelial cells.

This study was designed to assess bisphenol A (BPA)-induced vascular toxicity, the effectiveness of green tea extract and epigallocatechin gallate (EGCG) against BPA toxicity, and possible underlying mechanisms. In isolated rat aorta, contractile and relaxant responses as well as malondialdehyde levels were evaluated. Cell viability and effects on the protein levels of apoptotic (bax, bcl2, and caspase-3), autophagic (LC3), and cell adhesion molecules were calculated using the MTT method and western blotting in human umbilical vein endothelial cells (HUVECs). BPA increased aorta MDA levels (p < .0001) and decreased vascular responses to KCl [20 and 40 mM (p < .0001), 80 mM (p < .001)], phenylephrine [10-8 , 10-6 , and 10-5 M (p < .001), 10-7 and 10-4 M (p < .0001)], and acetylcholine [10-6 M (p < .01), 10-5 and 10-4 M (p < .0001)]. In HUVECs, BPA enhanced the levels of LC3A/B, bax/bcl2 ratio, cleaved caspase-3, and vascular cell adhesion molecule-1. Green tea extract, EGCG, and vitamin E co-treatment with BPA diminished the toxic effects of BPA. These findings provide evidence that green tea extract and EGCG possess beneficial effects in preventing BPA-induced vascular toxicity through increasing the antioxidant activities and the regulation of signaling pathways.

Effects of Nigella sativa oil and thymoquinone against bisphenol A-induced metabolic disorder in rats.

The underlying mechanisms of bisphenol A (BPA)-induced metabolic disorder and the protective impact of Nigella sativa oil (NSO) and thymoquinone (TQ) against BPA-induced metabolic disorder were investigated. Rats were treated as follows: Control, BPA (10 mg/kg), TQ (2 mg/kg), NSO (84 µL/kg), BPA + TQ (0.5, 1, 2 mg/kg), and BPA + NSO (21, 42, 84 µL/kg). BPA was administered by gavage, while, TQ and NSO were injected intraperitoneally (daily, 54 days). The weight, blood pressure, serum parameters [glucose, lipid profile, hepatic enzymes, insulin, interlukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin], malondialdehyde (MDA), glutathione (GSH) and insulin signaling pathways [insulin receptor substrate (p-IRS,IRS); kinase (p-Akt,Akt); glycogen synthase kinase (p-GS3K,GS3K)] were measured. BPA increased the blood pressure, MDA, lipid profile, hepatic enzymes, insulin, IL-6, TNF-α, and leptin, and decreased the GSH and phosphorylated forms of IRS, Akt, GS3K but did not alter weight, glucose, IRS, AKT, and GS3K in the liver. Administration of NSO or TQ with BPA reduced the blood pressure, liver level of MDA, lipid profile, hepatic enzymes, insulin, IL-6, TNF-α, leptin, and increased the liver level of GSH and p-IRS, p-AKT, p-GS3K. TQ and NSO are thought to be effective in controlling metabolic disorders induced by BPA.

Evaluation of possible effects of crocin against nitrate tolerance and endothelial dysfunction.

OBJECTIVES: One of the most important problems of taking nitroglycerin is the nitrate tolerance phenomenon and endothelial dysfunction. Oxidative stress is a high-emphasized one of tolerance mechanisms. The possible effect of crocin, one of the anti-oxidant ingredients of saffron, on the nitrate tolerance model was investigated. MATERIALS AND METHODS: In the present study, lipid peroxidation and the level of activated and deactivated forms of eNOS were measured. Animals were administered subcutaneously with 25 mg/kg of nitroglycerin, twice a day for 3 days to induce nitrate tolerance model. For evaluation of crocin effects, 20, 40 and 80 mg/kg/day of this compound were injected intraperitoneally in concomitant with nitroglycerin. In the isolated aorta test, after preparation of aorta rings, different concentrations of acetylcholine, sodium nitroprusside and nitroglycerin were added to the organ bath after inducing contraction by phenylephrine and the responsiveness of tissues was recorded. RESULTS: Findings showed that nitroglycerin administration caused a remarkable overproduction of malondialdehyde (MDA) in the cells and crocin treatment significantly decreased the MDA level. In the nitrate tolerance group, the level of activated eNOS decreased and the level of deactivated eNOS increased. Crocin partly alleviated these changes: however, its effects were not remarkable. Nitroglycerin injection for 3 days developed tolerance to nitroglycerin and cross-tolerance to acetylcholine (endothelial dysfunction) and sodium nitroprusside. Crocin failed to influence significantly on the nitrate tolerance. CONCLUSION: Crocin effectiveness is possibly time-dependent; therefore, increasing the duration of treatment with crocin may lead to a significant prevention of nitrate tolerance and endothelial dysfunction.

Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review.

Melatonin, as a neuroendocrine hormone, is produced primarily by the pineal gland. Melatonin, a pleotropic molecule, acts as a free radical scavenger, antioxidant, and regulator of circadian rhythm in mammals via several receptor-mediated and non-receptor-mediated mechanisms. This inexpensive, well-tolerated, and multi-target molecule has a great therapeutic potential against many diseases. Many evidences have proposed that melatonin plays a key role in the pathophysiology of various cardiovascular diseases. The aim of this paper is to discuss the data and experiments regarding the effects of melatonin in management of cardiovascular risk factors. PubMed, EMBASE, and Scopus have been searched for data collection using related keywords. Two hundred ten articles were included in this review from 2253 founded documents. Using these documents, the main mechanisms of action of melatonin are discussed and summarized in this article. Also, recent progresses regarding melatonin's effects on cardiovascular risk factors and diseases including diabetes, hypertension, hyperlipidemia, obesity, myocardial ischemia-reperfusion injury, pulmonary hypertension, and atherosclerosis have been reviewed. Many studies have demonstrated the beneficial effects of melatonin in prevention and improving cardiovascular risk factors, and this inexpensive and well-tolerated drug can be strongly proposed in different cardiovascular diseases as well as metabolic syndrome.

Gastroprotective effects of both aqueous and ethanolic extracts of Lemon verbena leaves against indomethacin-induced gastric ulcer in rats.

OBJECTIVES: Regarding Lemon verbena gastroprotective effects, we investigated the protective effects of Lemon verbena extracts on reducing gastric ulcer induced by indomethacin. MATERIALS AND METHODS: Rats received aqueous and ethanolic extracts of Lemon verbena (50, 100, and 200 mg/kg), zileuton (100 mg/kg), montelukast (10 mg/kg), or 1% Tween 80 in presence or absence of indomethacin (100 mg/kg). RESULTS: Indomethacin produced stomach ulcer and increased neutrophils percentage and MDA level compared with the control group (P<0.001). Co-administration of indomethacin and zileuton, montelukast and ethanolic (200 mg/kg) (P<0.001), aqueous extract (200 mg/kg) (P<0.05) reduced ulcer compared with the indomethacin group (P<0.001). Ethanolic extracts (100 and 200 mg/kg) and aqueous extract (200 mg/kg) reduced the MDA level (P<0.001). Ethanolic (50, 100, and 200 mg/kg) and aqueous extracts (200 mg/kg) significantly decreased neutrophils percentage compared with the indomethacin group (P<0.001). CONCLUSION: Aqueous and particularly ethanolic extracts of Lemon verbena have protective effects on indomethacin-induced gastric ulcers.

Preparation and Characterization of a Dry Powder Inhaler Composed of PLGA Large Porous Particles Encapsulating Gentamicin Sulfate.

Purpose: Direct delivery of aminoglycosides to the lungs was under extensive evaluations during the last decades. Because of large particle size, low density and porous structure, large porous particles (LPPs) are versatile carriers for this purpose. In this study, poly (lactic-co-glycolic acid) (PLGA) LPPs encapsulating gentamicin sulfate were prepared and in vitro characteristics of their freeze-dried powder as a dry powder inhaler (DPI) were evaluated. Methods: To prepare PLGA LPPs, a double emulsification-solvent evaporation method was optimized and gentamicin sulfate was post-loaded in the LPPs. in vitro characteristics including morphological features, thermal behavior, aerodynamic profile and cumulative drug release were evaluated by the scanning electron microscope (SEM), differential scanning calorimetry (DSC), next-generation cascade impactor (NGI) and Franz diffusion cell respectively. Results: The obtained results revealed that the preparation method was capable to produce spherical large homogenous highly porous particles. 94% of gentamicin sulfate released from LPPs up to 30 minutes. Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) were 4.9 µm and 39% respectively. Conclusion: In this study, dry powder formulation composed of PLGA LPPs encapsulating gentamicin sulfate showed a promising in vitro behavior as a pulmonary delivery carrier. Improvements on the aerodynamic behavior and in vivo evaluations recommended for further developments.

Vitis vinifera (grape) seed extract and resveratrol alleviate bisphenol-A-induced metabolic syndrome: Biochemical and molecular evidences.

The mechanisms of bisphenol-A (BPA)-induced metabolic syndrome as well as the protective role of grape seed extract (GSE) and resveratrol were investigated. Rats were treated with BPA (0 and 35 mg·kg-1 ·day-1 , gavage) plus resveratrol (25, 50, and 100 mg·kg-1 ·day-1 , i.p.) or GSE (3, 6, 12 mg·kg-1 ·day-1 , i.p.) or vitamin E (200 IU/kg/every other day, i.p.). After 2 months, mean systolic blood pressure, serum lipid profile, glycaemia, and fat index were examined. By enzyme-linked immunosorbent assay, the serum concentrations of insulin, leptin, adiponectin, and paraoxonase 1, and by real-time polymerase chain reaction as well as western blotting, key liver elements in cholesterol hemostasis (LDLR, CYP7A1, ABCG5 and 8) and insulin signaling (p-Akt/Akt and p-PI3K/PI3K) were measured. BPA increased mean systolic blood pressure, total cholesterol, and low-density lipoprotein cholesterol and reduced paraoxonase1 and the hepatic expression of both ABCG5 and ABCG8. It increased the body fat index, leptin, adiponectin, insulin, and glycaemia level and decreased the hepatic protein expression of p-Akt/Akt and p-PI3K/PI3k. GSE, resveratrol, or vitamin E coadministration along with BPA restored the detrimental effects of BPA in some levels. Herein, the predisposing effects of BPA-induced metabolic syndrome were restored by GSE and resveratrol, linked to the regulation of insulin signaling, ABCG8 expression, and their antioxidant properties.

Berberine and barberry (Berberis vulgaris): A clinical review.

Barberry (Berberis vulgaris L.) has different medicinal applications in folk medicine of Iran. Berberine, an alkaloid constituent of this plant, is present in the roots, rhizomes, stem, and bark of B. vulgaris and many other plants. There have been many clinical trials conducted that suggested a wide range of therapeutic applications. Here, we investigated the clinical uses of berberine and B. vulgaris in the treatment of different diseases in humans. An extensive search in electronic databases (PubMed, Scopus, Embase, Web of Sciences and Science Direct) was used to identify the clinical trials on B. vulgaris and berberine. Lipid-lowering and insulin-resistance improving actions are the most studied properties of berberine in numerous randomized clinical trials. There are also clinical trials regarding cardiovascular, anticancer, gastrointestinal, CNS, endocrine, and so on. Berberine has very low toxicity in usual doses and reveals clinical benefits without major side effects. Only mild gastrointestinal reactions may occur in some patients. The purpose of this review is to provide a summary concerning the clinical trials conducted on berberine to improve the clinical application of this nutraceutical in different diseases. In this review article, we used 77 clinical studies on human subjects.

Effect of Topiramate on Morphine-induced Conditioned Place Preference (CPP) in Rats: Role of ERK and CREB Proteins in Hippocampus and Cerebral Cortex.

In this study, the effect of topiramate, as an antiepileptic drug, was evaluated on morphine craving in rats. The conditioned place preference (CPP) test was used for this purpose. Repeated administration of morphine (10 mg/kg, i.p. for 4 days) induced significant CPP. Administration of topiramate (50 and 100 mg/kg, i.p. for 4 days) with each morphine administration decreased the acquisition of morphine-induced CPP. At the next step, the levels of extracellular signal-regulated kinase (ERK), p-ERK, cAMP responsive element binding (CREB), and p-CREB proteins were evaluated in hippocampus and cerebral cortex using western blot analysis. Following the repeated administration of morphine, the level of p-ERK protein markedly enhanced in both tissues, while topiramate could significantly reduce the phosphorylation of ERK in these brain regions. Additionally, the level of CREB and p-CREB proteins did not change in different groups. Memantine as a positive control reduced the acquisition of morphine-induced CPP. Also, memantine significantly decreased the level of p-ERK protein in hippocampus and cerebral cortex. These results demonstrated that topiramate can attenuate the acquisition of morphine-induced CPP in rats. This effect in part can be mediated through down regulation of p-ERK protein in hippocampus and cerebral cortex.