Novel 4,5-diaryl-3-hydroxy-2(5H)-furanones as anti-oxidants and anti-inflammatory agents

In order to study the effect of phenol moieties on biological activities of ascorbic acid derivatives, we synthesized 13 novel 4,5-diaryl-3-hydroxy-2(5H)-furanones 5a-m with various substitution patterns. Compound 5 g bearing a 2,3-dihydroxy phenyl ring on the 5-position of the heterocycle appeared to be the most powerful anti-oxidant furanone with reducing activity against DPPH (IC(50)=10.3 microM), superoxide anion quenching capacity (IC(50)=0.187 mM) and lipid peroxidation inhibitory effect (IC(50)=0.129 mM). To ascertain determinant molecular features for anti-oxidant activities, structure-activity relationships were studied. Lipophilicity and molecular parameters related to electron distribution and structure (difference in heats of formation between the compound and its radical or its cation radical, energy of the highest occupied molecular orbital, HOMO) were found to correlate with the anti-oxidant action of compounds 5 in the different tests used. Oxygen-derived free radicals are known to contribute to inflammatory disorders; therefore we have investigated effects of compounds 5 in two models of inflammation: phorbol ester-induced ear edema in mice (TPA-test) and carrageenan-induced paw edema in rat. At 100 mg/kg ip in the TPA-test, the anti-inflammatory activity of compounds 5 was potent compared with that of indomethacin and ketorolac and all the results suggested a cyclooxygenase inhibition in the emergence of such properties. The combined pharmacological actions of compounds 5 associated with a favorable therapeutic index prompt with interesting perspectives for their use in heart and brain disorders as well as in inflammatory diseases.     

Synaptic Plasticity in Neurodegenerative Diseases Evaluated and Modulated by In Vivo Neurophysiological Techniques

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico?Csubcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.     

Therapeutic application of rTMS in neurodegenerative and movement disorders: A review

Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that makes use of the magnetic field generated when an electric current passes through a magnetic coil placed over the scalp. It can be applied as a single stimulus at a time, in pairs of stimuli, or repetitively in trains of stimuli (repetitive TMS, rTMS). RTMS can induce changes in brain activity, whose after-effects reflect the processes of long-term potentiation and long-term depression, as certain protocols, namely those using low frequencies (≤1 Hz) seem to suppress cortical excitability, while those using high frequencies (>1 Hz) seem to enhance it. It is a technique with very few and mostly mild side-effects, whose effects can persist for long time periods, and as such, it has been studied as a potential treatment option in a multitude of neurodegenerative diseases, including those affecting movement. Although rTMS has received approval as a treatment strategy of only a few aspects in movement disorders in the latest guidelines, its further use seems to also be promising in their context. In this review, we gathered the available literature on the therapeutic application of rTMS in movement disorders, namely Parkinson’s disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Dystonia, Tic disorders and Essential Tremor.     

Multiple biological activities of curcumin: a short review

Turmeric (Curcuma longa rhizomes), commonly used as a spice is well documented for its medicinal properties in Indian and Chinese systems of medicine. It has been widely used for the treatment of several diseases. Epidemiological observations, though inconclusive, are suggestive that turmeric consumption may reduce the risk of some form of cancers and render other protective biological effects in humans. These biological effects of turmeric have been attributed to its constituent curcumin that has been widely studied for its anti-inflammatory, anti-angiogenic, anti-oxidant, wound healing and anti-cancer effects. As a result of extensive epidemiological, clinical, and animal studies several molecular mechanisms are emerging that elucidate multiple biological effects of curcumin. This review summarizes the most interesting in vitro and in vivo studies on the biological effects of curcumin.     

Magnetic field therapy: a review

There is increasing interest in using permanent magnets for therapeutic purposes encouraged by basic science publications and clinical reports. Magnetotherapy provides a non invasive, safe, and easy method to directly treat the site of injury, the source of pain and inflammation, and other types of disease. The physiological bases for the use of magnetic fields for tissue repair as well as physical principles of dosimetry and application of various magnetic fields are subjects of this review. Analysis of the magnetic and electromagnetic stimulation is followed by a discussion of the advantage of magnetic field stimulation compared with electric current and electric field stimulation.     

Magnetic stimulation modulates structural synaptic plasticity and regulates BDNF–TrkB signal pathway in cultured hippocampal neurons

Repetitive transcranial magnetic stimulation (rTMS) is a neuropsychiatric tool that can be used to investigate the neurobiology of learning and cognitive function. Few studies have examined the effects of low frequency (?1 Hz) magnetic stimulation (MS) on structural synaptic plasticity of neurons in vitro, thus, the current study examined its effects on hippocampal neuron and synapse morphology, as well as synaptic protein markers and signaling pathways. Similarly, both intensities of low frequency magnetic stimulation (1 Hz) activated brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) pathways, including the pathways for mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and for phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Specifically, low intensity magnetic stimulation (LIMS, 1.14 Tesla, 1 Hz) promoted more extensive dendritic and axonal arborization, as well as increasing synapses density, thickening PSD (post synaptic density) and upregulation of synaptophysin (SYN), growth associated protein 43 (GAP43) and post synaptic density 95 (PSD95). Conversely, high intensity magnetic stimulation (HIMS, 1.55 Tesla, 1 Hz) appeared to be detrimental, reducing dendritic and axonal arborization and causing apparent structural damage, including thinning of PSD, less synapses and disordered synaptic structure, as well as upregulation of GAP43 and PSD95, possibly for their ability to mitigate dysfunction. In conclusion, we infers that low frequency magnetic stimulation participates in regulating structural synaptic plasticity of hippocampal neurons via the activation of BDNF–TrkB signaling pathways.     

Traitement des troubles psychiatriques par la stimulation magnétique transcrântenne

Transcranial magnetic stimulation is a noninvasive way to produce an electric stimulation of the cerebral cortex. This stimulation results in many biological effects in the stimulated cortical zone and also at distant subcortical centers. Some of these effects are shared with antidepressants and electroconvulsive shocks. But some technical difficulties remain (e.g. to stimulate precisely the anatomic targets, in spite of interindividual variability) and stimulation protocols are in progression, which prevent a large use of TMS outside research labs. Clinical trials in depression show modest effects with resistant depressive episodes. The most important and lasting clinical effects of TMS seem to be the treatment of medication resistant auditive hallucinations in schizophrenia.     

Influence of phytochemicals on the biocompatibility of inorganic nanoparticles: a state-of-the-art review

Inorganic nanoparticles (NPs) are among the most produced NPs that could be used in consumer products and as healthcare materials, however, the intrinsic toxicity particularly through the mechanism associated oxidative stress raises the health concern about inorganic NP exposure. Phytochemicals are bioactive metabolites derived from plants as well as non-pathogenic microorganisms living within plants and have been shown to be beneficial to human health with their anti-aging, anti-cancer, anti-inflammation and anti-oxidant properties. In the present review, the influence of on the biocompatibility of inorganic NPs was discussed. It has been shown that phytochemicals could be used as bio-friendly capping agents for green synthesis of inorganic NPs, and phytochemical coated inorganic NPs were remarkable stable and biocompatible with high therapeutic efficiency. Meanwhile, the presence of phytochemicals was also able to reduce the side effects and enhance the therapeutic abilities of inorganic NPs, which is likely attributed to the anti-oxidative properties of phytochemicals. Thus, using phytochemicals could be a promising and plausible way to reduce side effects and increase the biocompatibility of inorganic NPs for biomedical applications.     

Anti-atherosclerotic and anti-diabetic properties of probucol and related compounds

Probucol is a diphenolic compound with anti-oxidant and anti-inflammatory properties that reduces atherosclerosis and restenosis. Unfortunately, adverse effects on blood lipoproteins and cardiac electrophysiology have curtailed its use as a drug. Compounds related to probucol that have improved efficacy without the adverse effects offer promise as novel therapies of cardiovascular disease. Recent results suggest that these compounds may be used for the prevention of type 2 diabetes, a disease that is increasing in prevalence and importance world-wide. In this review, the molecular mechanisms underlying the beneficial activities of probucol and related compounds are described.     

Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)—From insights into human memory to therapy of its dysfunction

Noninvasive stimulation of the brain by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) has driven important discoveries in the field of human memory functions. Stand-alone or in combination with other brain mapping techniques noninvasive brain stimulation can assess issues such as location and timing of brain activity, connectivity and plasticity of neural circuits and functional relevance of a circumscribed brain area to a given cognitive task. In this emerging field, major advances in technology have been made in a relatively short period. New stimulation protocols and, especially, the progress in the application of tDCS have made it possible to obtain longer and much clearer inhibitory or facilitatory effects even after the stimulation has ceased. In this introductory review, we outline the basic principles, discuss technical limitations and describe how noninvasive brain stimulation can be used to study human memory functions in vivo. Though improvement of cognitive functions through noninvasive brain stimulation is promising, it still remains an exciting challenge to extend the use of TMS and tDCS from research tools in neuroscience to the treatment of neurological and psychiatric patients.     

Chemokine receptor binding and signal transduction in native cells of the central nervous system

Chemokine receptors belong to the superfamily of seven-transmembrane-spanning, G-protein-coupled receptors, and their expression by central nervous system cells is clearly documented. As this gene family has become the target of novel therapeutic development, the analysis of these receptors requires radioligand binding techniques as well as methods that entail assessing receptor stimulation of signal transduction pathways. Herein, we describe specific protocols for measuring radiolabeled chemokine binding to their cognate receptors on cultured glial cells as well as to receptors expressed in heterologous cell systems. Multiple downstream signaling pathways, including intracellular calcium influx and receptor-dependent kinase activation, are associated with chemokine receptor stimulation. Protocols for measuring these signaling events in chemokine-receptor-expressing cells are also presented.     

Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)-From insights into human memory to therapy of its dysfunction

Noninvasive stimulation of the brain by means of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) has driven important discoveries in the field of human memory functions. Stand-alone or in combination with other brain mapping techniques noninvasive brain stimulation can assess issues such as location and timing of brain activity, connectivity and plasticity of neural circuits and functional relevance of a circumscribed brain area to a given cognitive task. In this emerging field, major advances in technology have been made in a relatively short period. New stimulation protocols and, especially, the progress in the application of tDCS have made it possible to obtain longer and much clearer inhibitory or facilitatory effects even after the stimulation has ceased. In this introductory review, we outline the basic principles, discuss technical limitations and describe how noninvasive brain stimulation can be used to study human memory functions in vivo. Though improvement of cognitive functions through noninvasive brain stimulation is promising, it still remains an exciting challenge to extend the use of TMS and tDCS from research tools in neuroscience to the treatment of neurological and psychiatric patients.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest

Background  

Histone deacetylase inhibitors have been proposed as potential enhancers of the cytotoxic effect of cisplatin and other anticancer drugs. Their application would permit the use of lower therapeutic doses and reduction of the adverse side effects of the drugs. However, the molecular mechanisms by which they sensitize the cells towards anticancer drugs are not known in details, which is an obstacle in developing effective therapeutic protocols.     

Magnetic stimulation of one-dimensional neuronal cultures

Transcranial magnetic stimulation is a remarkable tool for neuroscience research, with a multitude of diagnostic and therapeutic applications. Surprisingly, application of the same magnetic stimulation directly to neurons that are dissected from the brain and grown in vitro was not reported to activate them to date. Here we report that central nervous system neurons patterned on large enough one-dimensional rings can be magnetically stimulated in vitro. In contrast, two-dimensional cultures with comparable size do not respond to excitation. This happens because the one-dimensional pattern enforces an ordering of the axons along the ring, which is designed to follow the lines of the magnetically induced electric field. A small group of sensitive (i.e., initiating) neurons respond even when the network is disconnected, and are presumed to excite the entire network when it is connected. This implies that morphological and electrophysiological properties of single neurons are crucial for magnetic stimulation. We conjecture that the existence of a select group of neurons with higher sensitivity may occur in the brain in vivo as well, with consequences for transcranial magnetic stimulation.     

Increased oxidative stress induces apoptosis in human cystic fibrosis cells

Oxidative stress results in deleterious cell function in pathologies associated with inflammation. Here, we investigated the generation of superoxide anion as well as the anti-oxidant defense systems related to the isoforms of superoxide dismutases (SOD) in cystic fibrosis (CF) cells. Pro-apoptotic agents induced apoptosis in CF but not in control cells that was reduced by treatment with SOD mimetic. These effects were associated with increased superoxide anion production, sensitive to the inhibition of IκB-α phosphorylation, in pancreatic but not tracheal CF cells, and reduced upon inhibition of either mitochondrial complex I or NADPH oxidase. CF cells exhibited reduced expression, but not activity, of both Mn-SOD and Cu/Zn-SOD when compared to control cells. Although, expression of EC-SOD was similar in normal and CF cells, its activity was reduced in CF cells. We provide evidence that high levels of oxidative stress are associated with increased apoptosis in CFTR-mutated cells, the sources being different depending on the cell type. These observations underscore a reduced anti-oxidant defense mechanism, at least in part, via diminished EC-SOD activity and regulation of Cu/Zn-SOD and Mn-SOD expressions. These data point to new therapeutic possibilities in targeting anti-oxidant pathways to reduce oxidative stress and apoptosis in CF cells.     

Improvement and impairment of visually guided behavior through LTP- and LTD-like exposure-based visual learning

Cellular studies have focused on long-term potentiation (LTP) and long-term depression (LTD) to understand requirements for persistent changes in synaptic connections. Whereas LTP is induced through high-frequency intermittent stimulation, low-frequency stimulation evokes LTD. Because of the ubiquitous efficacy of these protocols, they are considered fundamental mechanisms underlying learning. Here we adapted LTP/LTD-like protocols to visual stimulation to alter human visually guided behavior. In a change-detection task, participants reported luminance changes against distracting orientation changes. Subsequently, they were exposed to passive visual high- or low-frequency stimulation of either the relevant luminance or irrelevant orientation feature. LTP-like high-frequency protocols using luminance improved ability to detect luminance changes, whereas low-frequency LTD-like stimulation impaired performance. In contrast, LTP-like exposure of the irrelevant orientation feature impaired performance, whereas LTD-like orientation stimulation improved it. LTP-like effects were present for 10 days, whereas LTD-like effects lasted for a shorter period of time. Our data demonstrate that instead of electrically stimulating synapses, selective behavioral changes are evoked in humans by using equivalently timed visual stimulation, suggesting that both LTD- and LTP-like protocols control human behavior but that the direction of changes is determined by the feature incorporated into the stimulation protocol.     

Anti-atherosclerotic and anti-diabetic properties of probucol and related compounds

Abstract

Probucol is a diphenolic compound with anti-oxidant and anti-inflammatory properties that reduces atherosclerosis and restenosis. Unfortunately, adverse effects on blood lipoproteins and cardiac electrophysiology have curtailed its use as a drug. Compounds related to probucol that have improved efficacy without the adverse effects offer promise as novel therapies of cardiovascular disease. Recent results suggest that these compounds may be used for the prevention of type 2 diabetes, a disease that is increasing in prevalence and importance world-wide. In this review, the molecular mechanisms underlying the beneficial activities of probucol and related compounds are described.     

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Because of the complex cascade of molecular events that can occur in the brain of an Alzheimer's disease (AD) patient, the therapy of this neurodegenerative disease seems more likely to be achieved by multifunctional drugs. Herein, a new series of dual-targeting ligands have been developed and in vitro bioevaluated. Their architecture is based on conjugating the acetylcholinesterase inhibition and anti-oxidant properties in one molecular entity. Specifically, a series of naturally occurring phenolic acids with recognized anti-oxidant properties (derivatives of caffeic acid, rosmarinic acid, and trolox) have been conjugated with choline to account for the recognition by acetylcholinesterase (AChE). The synthesized hybrid compounds evidenced AChE inhibitory capacity of micromolar range (rationalized by molecular modeling studies) and good antioxidant properties. Their effects on human neuroblastoma cells, previously treated with beta-amyloid peptides and 1-methyl-4-phenylpyridinium ion neurotoxins (to simulate AD and Parkinson's disease, respectively), also demonstrated a considerable capacity for protection against the cytotoxicity of these stressors.     

Acute exposure to high‐induction electromagnetic field affects activity of model peripheral sensory neurons

Exposure to repetitive low‐frequency electromagnetic field (LF‐EMF) shows promise as a non‐invasive approach to treat various sensory and neurological disorders. Despite considerable progress in the development of modern stimulation devices, there is a limited understanding of the mechanisms underlying their biological effects and potential targets at the cellular level. A significant impact of electromagnetic field on voltage‐gated calcium channels and downstream signalling pathways has been convincingly demonstrated in many distinct cell types. However, evidence for clear effects on primary sensory neurons that particularly may be responsible for the analgesic actions of LF‐EMF is still lacking. Here, we used F11 cells derived from dorsal root ganglia neurons as an in vitro model of peripheral sensory neurons and three different protocols of high‐induction magnetic stimulation to determine the effects on chemical responsiveness and spontaneous activity. We show that short‐term (<180 sec.) exposure of F11 cells to LF‐EMF reduces calcium transients in response to bradykinin, a potent pain‐producing inflammatory agent formed at sites of injury. Moreover, we characterize an immediate and reversible potentiating effect of LF‐EMF on neuronal spontaneous activity. Our results provide new evidence that electromagnetic field may directly modulate the activity of sensory neurons and highlight the potential of sensory neuron‐derived cell line as a tool for studying the underlying mechanisms at the cellular and molecular level.