Deciphering Neuroprotective Effect of Rosmarinus officinalis L. (syn. Salvia rosmarinus Spenn.) through Preclinical and Clinical Studies.

Rosmarinus officinalis L. (RO, rosemary) is a well-known medicinal, aromatic, and culinary herb with traditional use in European folk medicine against memory deficits and neurodegenerative disorders. This review highlights the different neuroprotective activities of RO investigated in both preclinical and clinical studies, as well as in silico molecular docking of bioactive compounds found in RO. The neuroprotective effect of RO was searched through databases including PubMed, Web of Science (WoS), Scopus, and Clinical Trials using the keywords "Rosmarinus officinalis, rosemary, neuroprotective effect, memory, cognitive dysfunction, Alzheimer's disease." RO, which is rich in secondary metabolites that have memory-enhancing potential, has displayed neuroprotection through different molecular mechanisms such as inhibition of cholinesterase, modulation of dopaminergic and oxytocinergic systems, mediation of oxidative and inflammatory proteins, involved in neuropathic pain, among others. RO extracts exhibited antidepressant and anxiolytic activities. Also, the plant has shown efficacy in scopolamine-, lipopolysaccharide-, AlCl3-, and H2O2-induced amnesia as well as amyloid-beta- and ibotenic acid-induced neurotoxicity and chronic constriction injury-related oxidative stress memory and cognitive impairments in animal models. A few clinical studies available supported the neuroprotective effects of RO and its constituents. However, more clinical studies are needed to confirm results from preclinical studies further and should include not only placebo-controlled studies but also studies including positive controls using approved drugs. Many studies underlined that constituents of RO may have the potential for developing drug candidates against Alzheimer's disease that possess high bioavailability, low toxicity, and enhanced penetration to CNS, as revealed from the experimental and molecular docking analysis.

Dual Monoamine Oxidase and Cholinesterase Inhibitors with Different Heterocyclic Scaffolds.

For the last two decades, there has been research interest on the design of molecules possessing dual inhibitory potential on cholinesterase and monoamine oxidase enzymes, particularly for the treatment of two major neurodegenerative diseases, Alzheimer's Disease (AD) and Parkinson's disease (PD). Many compounds have been synthesized for this purpose, and some of them have been shown to display activities comparable or superior to the activities of current drugs used for the treatment of AD and PD. Within the concept of this review study, we have aimed to present the current drugs used for the treatment of AD and PD, their mechanism of action, the discussion behind the theory of designing dual inhibitor agents, and the presentation of the most active compounds with diverse heterocyclic scaffolds displayed in research studies published in the recent period.

Amendatory Effect of Flavonoids in Alzheimer's Disease Against Mitochondrial Dysfunction.

Flavonoids are chromene analogues abundantly found in plants. It has always been of interest to discover natural flavonoid structures, since living things, including humans, are routinely exposed to these compounds through many dietaries. So far, numerous studies have been conducted on flavonoids with diverse biological actions. The activity results obtained, particularly regarding the effects of flavonoids on various validated and non-validated targets of Alzheimer's Disease (AD), make these compounds promising agents either to be directly employed in clinical trials or to be utilized as important scaffolds for flavonoid-based drug design studies. Although there are many review articles on the treatment and protective effects of flavonoids on AD, within this review, the effects of flavonoids on mitochondrial dysfunction developing throughout AD have been presented concomitant to their structural organization.

A Review Focused on Molecular Mechanisms of Anxiolytic Effect of Valerina officinalis L. in Connection with Its Phytochemistry through in vitro/in vivo Studies.

Valeriana officinalis L. (Valerianaceae) is one of the most reputed ancient medicinal plants used in modern phytotherapy and traditional medicine. Its root extract is one of the most effective herbal sedatives and tranquilizers, where the plant is also used for the treatment of gastrointestinal spasms. V. officinalis has complex phytochemistry consisting of the esterified iridoid derivatives known as valepotriates (e.g., valtrate, didrovaltrate, isovalerenic acid), sesquiterpenes (e.g., valerenic acid), flavonoids (e.g., linarin, apigenin), lignans (e.g., pinoresinol, hydroxypinoresinol), alkaloids (e.g., actinidine, valerine), triterpenes (e.g., ursolic acid), monoterpenes (e.g., borneol, bornyl acetate). Among them, valerenic acid is a marker compound for standardization of the root extracts of the plant and has been reported in many in vitro/in vivo studies to be responsible for anxiolytic action of the plant. Although modulation of gamma-aminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant-based on the existence of valerenic acid, several studies described the interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid, isovaleric acid, didrovaltrate, borneol, and some lignans have also been proposed to contribute to the anxiolytic effect of the plant. In the current review, the data selectively scrutinized from the in vitro/in vivo studies about identifying anxiolytic molecular mechanisms of V. officinalis is focused.

Spiro Heterocyclic Compounds as Potential Anti-Alzheimer Agents (Part 2): Their Metal Chelation Capacity, POM Analyses and DFT Studies.

BACKGROUND: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. OBJECTIVE: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively. METHODS: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). RESULTS: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). CONCLUSION: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

Natural Products and Extracts as Xantine Oxidase Inhibitors - A Hope for Gout Disease?

Xanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy includes XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist, intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.

Inhibition of Melanogenesis by Some Well-Known Polyphenolics: A Review.

Melanogenesis is simply defined as the production of melanin in melanosomes by melanocytes through a complex process. Melanin, a pigment derived from L-tyrosine, comes into two forms, namely eumelanin (brownish to black) and pheomelanin (red to yellow). Melanin synthesis starts via the hydroxylation of L-tyrosine to L-3,4-Dihydroxyphenylalanine (DOPA) catalyzed by the enzyme known as Tyrosinase (TYR), which triggers further conversion reaction to DOPAquinone and then to DOPAchrome. Additionally, this process is also related to two more proteins, i.e., oxygenase TYR-related Protein 1 (TYRP1), and Dopachrome Tautomerase TYRP2 (or DCT). However, TYR located in the melanosomal membrane still stands as the key enzyme to initiate the whole process of melanogenesis. Due to some deficits, melanogenesis may emerge as hypo- or hyperpigmentation in the skin. High production of melanin in melanocytes leads to hyperpigmentation- related skin disorders, including freckles, melasma, melanoma, etc., that may cause displeasure in personal appearance and reduce quality of life. Consequently, several melanogenesis inhibitors of synthetic and natural origins have been developed up to date, though most of them have been reported with serious side effects. For this reason, extensive research is still going on to find novel and more effective melanogenesis inhibitors with less side effects. In this sense, particularly flavonoids, catechins, and stilbenes from plants have been a hope to discover new inhibitors which gain significant attention from scientists. In this review, promising natural products effective in melanogenesis inhibition will be scrutinized.

The Main Targets Involved in Neuroprotection for the Treatment of Alzheimer's Disease and Parkinson Disease.

With respect to the total cure failure of current drugs used in the treatment of neurodegenerative diseases, alternative strategies are followed. Particularly, neuroprotection approaches are questioned. Metal chelation, antioxidant towards oxidative stress, modulation of the amyloidogenic pathway, MAO-B inhibition, and NMDA receptor antagonism is more or less typical examples. Some of the representative drug candidates with promising neuroprotective features are assessed in clinical trials. Although initial attempts were found hopeful, none of the candidates have been found successful in each required clinical trials, particularly depending on the failures in terms of cognitive enhancement and slowing the progressive characteristics of neurodegenerative diseases. Today, neuroprotection is evaluated using multi-target ligand-based drug design studies. Within this study, the clinical outcomes of these studies, the rationale behind the design of the molecules are reviewed concomitant to the representative drug candidates of each group.

A Recent Look into Natural Products that have Potential to Inhibit Cholinesterases and Monoamine Oxidase B: Update for 2010-2019.

With respect to the unknowns of pathophysiology of Alzheimer's Disease (AD)-, and Parkinson's Disease (PD)-like neurodegenerative disorders, natural product research is still one of the valid tools in order to provide alternative and/or better treatment options. At one hand, various extracts of herbals provide a combination of actions targeting multiple receptors, on the other hand, the discovery of active natural products (i.e., secondary metabolites) generally offers alternative chemical structures either ready to be employed in clinical studies or available to be utilized as important scaffolds for the design of novel agents. Regarding the importance of certain enzymes (e.g. cholinesterase and monoamine oxidase B), for the treatment of AD and PD, we have surveyed the natural product research within this area in the last decade. Particularly novel natural agents discovered within this period, concomitant to novel biological activities displayed for known natural products, are harmonized within the present study.

Naringenin and atherosclerosis: a review of literature.

Atherosclerosis is a multifactorial disease mainly caused by deposition of low-density lipoprotein (LD) cholesterol in macrophages of arterial walls. Atherosclerosis leads to heart attacks as well as stroke. Epidemiological studies showed that there is an inverse correlation between fruit and vegetable consumption and the risk of atherosclerosis. The promising effect of high vegetable and fruit containing diet on atherosclerosis is approved by several experimental studies on isolated phytochemicals such as flavonoids. Flavonoids are known to up-regulate endogenous antioxidant system, suppress oxidative and nitrosative stress, decrease macrophage oxidative stress through cellular oxygenase inhibition as well as interaction with several signal transduction pathways and from these ways, have therapeutic effects against atherosclerosis. Naringenin is a well known flavonoid belonging to the chemical class of flavanones. It is especially abundant in citrus fruits, especially grapefruits. A plethora of evidences ascribes to naringenin antiatherosclerotic effects. Naringenin abilities to decrease LDL and triglycerides as well as inhibit glucose uptake; increase high-density lipoprotein (HDL); co-oxidation of NADH; suppress protein oxidation; protect against intercellular adhesion molecule-1(ICAM-1); suppress macrophage inflammation; inhibit leukotriene B4, monocyte adhesion and foam cell formation; induce of HO-1 and G 0/G 1 cell cycle arrest in vascular smooth muscle cells (VSMC) and down regulate atherosclerosis related genes are believed to have crucial role in the promising role against atherosclerosis. In the present review, we have summarized the available literature data on the anti-atherosclerotic effects of naringenin and its possible mechanisms of action.

Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases.

Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.

Implications of some selected flavonoids towards Alzheimer's disease with the emphasis on cholinesterase inhibition and their bioproduction by metabolic engineering.

Flavonoids are one of the most abundant secondary metabolites having a polyphenolic structure in plant and animal species with various desired pharmacological effects towards human health. Many flavonoid derivatives have been reported to possess neuroprotective activity through different mechanisms of action and, among them, cholinesterase (ChE) inhibition constitutes an important clinically applied treatment strategy of Alzheimer's disease (AD). Some flavonoid derivatives have been demonstrated to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to varying extent, which are called the sister enzymes linked to the pathogenesis of AD. On the other hand, diverse bioproduction techniques such as plant tissue culture, microbial transformation, etc. are applicable for flavonoids and, among them, production of flavonoids through metabolic engineering using special bacteria or yeast species has recently become popular. In the current review, some common flavonoids with ChE inhibitory effect as well as the examples of flavonoids obtained from metabolic engineering methods will be discussed.

Selective cholinesterase inhibitors from Buxus sempervirens L. and their molecular docking studies.

In this work, two alkaloids namely (+)-buxabenzamidienine (1) and (+)-buxamidine (2) were isolated from Buxus sempervirens, using bioassay-guided fractionation and isolation method. Their acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitory activities were studied and the compounds were found to be quite selective inhibitors of AChE. IC50 values of compound 1 for electric eel AChE and horse BChE were 0.787 and 7.68 mM, respectively; while the corresponding IC50 of compound 2 were 1.70 and 549.98 mM, respectively. Theoretical (quantum mechanical, homology modelling and docking) calculations were performed in order to explain their interactions with different AChE (electric eel and human) and BChE (horse and human). The x-ray crystal structures of electric eel AChE, human AChE, human BChE and a model of horse BChE constructed by homology with human BChE were used for docking of compounds 1 and 2. Density functional theory (DFT) calculations of the compounds were performed at the B3LYP/6- 31G** level using the program Spartan™, and their HOMO and LUMO energy levels were calculated. Docking studies exhibited that compound 1 interacts with the acyl-binding pocket of the active site gorge of huAChE, and including several other hydrophobic interactions.

Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation.

In-stent restenosis is a major problem following coronary stent implantation, and inflammation plays an active role. We evaluated the effectiveness of the inflammatory marker C-reactive protein (CRP) as a predictor of in-stent restenosis after successful stent implantation, in 86 patients with unstable angina pectoris. Plasma CRP was measured in all patients before the procedure, and at 48 - 72 h and 1, 2 and 3 months post-procedure. An angiographic loss of 50% at follow-up was accepted as in-stent restenosis. We found negative and positive predictive values of the pre-procedural plasma CRP for determining 6-month in-stent restenosis of 34% and 61%, respectively. We also found a strong correlation between the 3-month post-procedural CRP value and 6-month in-stent restenosis; the negative and positive predictive values being 8% and 76%, respectively. In conclusion, we showed that a plasma CRP value > 3 mg/l in the third month after coronary stent implantation was a strong predictor of angiographic in-stent restenosis.

The macroanatomical investigations on the aortic arch in porcupines (Hystrix cristata).

The anatomy of aortic arch in porcupine was studied. Angiography was applied to each of the three adult porcupines (two males, one female) following the injection of latex from the abdominal aorta for the examination of aortic arch. The results indicated that three arteries arose from aortic arch in porcupine. These were truncus brachiocephalicus, arteria carotis communis sinistra and arteria subclavia sinistra. The truncus brachiocephalicus in porcupine yielded arteria subclavia dextra and arteria carotis communis dextra. Truncus bicaroticus was absent. The origin of truncus costocervicalis (right) and arteria vertebralis (right) arose from a common root. Left or right axillary arteries seemed to be a continuation of subclavian arteries. The results of this study may contribute to the data in this area of science.

Cardiac tamponade caused by an ingested sewing needle. A case report.

Ingested sharp-pointed foreign bodies can cause serious complications. A case of a 16-year-old girl with cardiac tamponade due to ingestion of a sewing needle is presented. Ingested needles have often been reported as a cause of gastrointestinal injuries but in this rare case the sewing needle actually migrated into the myocardium.