Search

Background Hypertension is a major public health problem worldwide. It is an important risk factor for other cardiovascular diseases such as coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, chronic kidney disease, and atherosclerosis. Purpose There is strong evidence that excess ROS-derived NADPH oxidase (NOX) is an important agent in hypertension. It augments blood pressure in the presence of other pro-hypertensive factors such as angiotensin II (Ang II), an important and potent regulator of cardiovascular NADPH oxidase, activates NOX via AT1 receptors. NADPH oxidase, a multi-subunit complex enzyme, is considered as a key source of ROS production in the vasculature. The activation of this enzyme is needed for assembling Rac-1, p40phox, p47phox and p67phox subunits. Since, hypertensive patients need to control blood pressure for their entire life and because drugs and other chemicals often induce adverse effects, the use of natural phenolic compounds which are less toxic and potentially beneficial may be good avenues of addition research in our understand of the underlying mechanism involved in hypertension. This review focused on several natural phenolic compounds as berberine, thymoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidine and G-hesperidine, and quercetin which are NOX inhibitors. In addition, structure activity relationship of these compounds eventually as the most inhibitors was discussed. Methods This comprehensive review is based on pertinent papers by a selective search using relevant keywords that was collected using online search engines and databases such as ScienceDirect, Scopus and PubMed. The literature mainly focusing on natural products with therapeutic efficacies against hypertension via experimental models both in vitro and in vivo was identified. Results It has been observed that these natural compounds prevent NADPH oxidase expression and ROS production while increasing NO bioavailability. It have been reported that they improve hypertension due to formation of a stable radical with ROS-derived NADPH oxidase and preventing the assembly of NOX subunites. Conclusion It is clear that natural phenolic compounds have some potential inhibitory effect on NADPH oxidase activity. In comparison to other phenolic plant compounds, the structural variability of the flavonoids should off different impacts on oxidative stress in hypertension including inhibition of nadph oxidase and direct scavenging of free radicals.

A newly designed series of imidazolyl-methyl- l-2,4-thiazolidinediones 9 (a-m) were synthesized and In Silico studies were carried out to rationalize their anti-diabetic activity. Generally, all newly synthesized thiazolidinediones had anti-hyperglycemic activity compared with a diabetic-control group, without toxicity in 3T3 cells (viability ≥ 90%). These studies revealed that the compounds 9e and 9b ( 11 ∗ 10 - 6 m o l / k g ) lowered blood glucose more effectively when compared to pioglitazone at the same dose. Following the administration of compound 9e, no weight gains or any serious side effects on liver and pancreas were observed. Moreover, the glucose consumption assay results showed a significant glucose-lowering effect (p

Due to the high frequency and mortality of breast cancer, developing efficient targeted drug delivery systems for frightening against this malignancy is among cancer research priorities. The aim of this study was to synthesize a targeted micellar formulation of docetaxel (DTX) using DTX, folic acid (FA) and polyethylene glycol (PEG) conjugates as building blocks. In the current study, two therapeutic polymers consisting of FA-PEG-DTX and PEG-DTX conjugates were synthesized and implemented to form folate-targeted and non-targeted micelles. Dissipative particle dynamics (DPD) method was used to simulate the behavior of the nanoparticle. The anti-cancer drug, DTX was loaded in to the micelles via solvent switching method in order to increase its solubility and stability. The cytotoxicity of the targeted and non-targeted formulations was evaluated against 4T1 and CHO cell lines. In vivo therapeutic efficiency was studied using ectopic tumor model of metastatic breast cancer, 4T1, in Female BALB/c mice. The successful synthesis of therapeutic polymers, FA-PEG-DTX and PEG-DTX were confirmed implementing 1HNMR spectral analysis. The size of DTX-loaded non-targeted and targeted micelles were 176.3 ± 8.3 and 181 ± 10.1 nm with PDI of 0.23 and 0.17, respectively. Loading efficiencies of DTX in non-targeted and targeted micelles were obtained to be 85% and 82%, respectively. In vitro release study at pH = 7.4 and pH = 5.4 showed a controlled and continuous drug release for both formulations, that was faster at pH = 5.4 (100% drug release within 120 h) than at pH = 7.4 (80% drug release within 150 h). The targeted formulation showed a significant higher cytotoxicity against 4T1 breast cancer cells (high expression of folate receptor) within the range of 12.5 to 200 μg/mL in comparison with no-targeted one. However, there was no significant difference between the cytotoxicity of the targeted and non-targeted formulations against CHO cell line as low-expressed cell line. In accordance with in vitro investigation, in vivo studies verified the ideal anti-tumor efficacy of the targeted formulation compared to Taxotere and non-targeted formulation. Based on the obtained data, FA-targeted DTX-loaded nano-micelles significantly increased the therapeutic efficacy of DTX and therefore can be considered as a new potent platform for breast cancer chemotherapy.

Sortase A (SrtA) is an enzyme that catalyzes the attachment of proteins to the cell wall of Gram-positive bacterial membrane, preventing the spread of pathogenic bacterial strains. Here, one class of oxadiazole compounds was distinguished as an efficient inhibitor of SrtA via the “S. aureus Sortase A” substrate-based virtual screening. The current study on 3D-QSAR was done by utilizing preparation of the structure in the Schrödinger software suite and an assessment of 120 derivatives with the crystal structure of 1,2,4-oxadiazole which was extracted from the PDB data bank. The docking operation of the best compound in terms of pMIC ( pMIC = 2.77 ) was done to determine the drug likeliness and binding form of 1,2,4-oxadiazole derivatives as antibiotics in the active site. Using the kNN-MFA way, seven models of 3D-QSAR were created and amongst them, and one model was selected as the best. The chosen model based on q 2 (pred_ r 2 ) and R 2 values related to the sixth factor of PLS illustrates better and more acceptable external and internal predictions. Values of crossvalidation (pred_ r 2 ), validation ( q 2 ), and F were observed 0.5479, 0.6319, and 179.0, respectively, for a test group including 24 molecules and the training group including 96 molecules. The external reliability outcomes showed that the acceptable and the selective 3D-QSAR model had a high predictive potential ( R 2 = 0.9235 ) which was confirmed by the Y -randomization test. Besides, the model applicability domain was described successfully to validate the estimation of the model.

Curcuminis a polyphenol with anti-inflammatory and antioxidative properties, found primarily in turmeric, a flowering plant of the ginger family. Among its numerous medical uses, curcumin has been used in the management of metabolic syndrome, and inflammatory conditions such as artrhritis, anxiety and hyperlipidemia. In this paper, we used molecular docking tools to assess the affinity of four curcumin derivatives (Curcumin, Cyclocurcumin, Demethoxycurcumin, Bisdemethoxycurcumin) as well as the endogenous ligand phosphorylcholine to C-reactive protein (CRP), a sensitive marker of systemic inflammation. Our results showed that curcumin interacts through H bond with CRP at GLN 150 and ASP 140. Similar H bond interactions were found for each of the four curcumin derivatives with CRP. Moreover, a molecular dynamic simulation were performed to further establish the interaction between CRP and the ligands in atomic details using the Nanoscale Molecular Dynamics (NAMD) and CHARMM27 force field. Importantly, our results suggest the possible interaction between curcumin and curcurmin related molecules with CRP, thus showing an important regulatory function with plausible applications in inflammatory and oxidative processes in diseases.

Centella asiatica (CA) or Gotu cola is an herbal plant from the Apiaceae family with a long history of usage in different traditional medicines. It has long been used for the treatment of various ailments such as central nervous system (CNS), skin and gastrointestinal disorders especially in the Southeast Asia. This chapter focused on the phytochemical constituent and pharmacological activities of CA based on preclinical and clinical studies. Additionally, botanical description and distribution, traditional uses, interactions, and safety issues are reviewed. Electronic databases of Google Scholar, Scopus, PubMed, and Web of Science were searched to obtain relevant studies on the pharmacological activities of CA. Approximately, 124 chemical compounds including triterpenoids, polyphenolic compounds, and essential oils have been isolated and identified from CA. Ethnomedicinal applications of CA mostly include treatment of gastrointestinal diseases, wounds, nervous system disorders, circulatory diseases, skin problems, respiratory ailments, diabetes and sleep disorders in various ethnobotanical practices. Pharmacological studies revealed a wide range of beneficial effects of CA on CNS, cardiovascular, lung, liver, kidney, gastrointestinal, skin, and endocrine system. Among them, neuroprotective activity, wound healing and treatment of venous insufficiency, as well as antidiabetic activity seem to be more frequently reported. At the moment, considering various health benefits of CA, it is marketed as an oral supplement as well as a topical ingredient in some cosmetic products. Additional preclinical studies and particularly randomized controlled trials are needed to clarify the therapeutic roles of CA.

INTRODUCTION Aggregation of amyloid-β (Aβ) peptides represents a crucial step in the pathogenesis of Alzheimer disease (AD). Compelling evidence from preclinical studies has established that statins may reduce amyloidogenesis and Aβ-mediated neurodegeneration, supporting a potential role of statin treatment in the prevention of AD. Different statins have been shown to interfere indirectly with Aβ production and clearance through either cholesterol-dependent or cholesterol-independent mechanisms. However, whether there may be a direct interaction between statins and Aβ metabolism is still unclear. MATERIALS AND METHODS To test the possible direct interaction between statins and Aβ, we performed an in silico study by testing the orientation of different ligands, including statins and sulindac (the standard ligand of Aβ), in the Aβ active site using molecular operating environment (MOE) software. RESULTS Docking experiments showed that all the tested statins could directly interact with Aβ protofibrils. Among statins, pitavastatin had the strongest interaction with Aβ (pki = 7.66), followed by atorvastatin (pk i = 7.63), rosuvastatin (pk i = 6.99), fluvastatin (pk i = 6.96), pravastatin (pk i = 6.46), lovastatin (pk i = 6.37), and simvastatin (pk i = 5.90). According to the above-mentioned results, pitavastatin, atorvastatin, rosuvastatin, and fluvastatin had a stronger binding to Aβ compared with the standard ligand sulindac (pk i = 6.62). CONCLUSION This study showed a direct interaction between statins and Aβ protofibrils, which may underlie the protective role of this widely used class of drugs against amyloidogenesis and Aβ-mediated neurodegeneration.