Protonophore properties of hyperforin are essential for its pharmacological activity.
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ABSTRACT:
SUBMITTER: Sell TS
PROVIDER: S-EPMC4266863 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:Although locomotion is known to be generated by networks of spinal neurons, knowledge of the properties of these neurons is limited. Using neonatal transgenic mice that express enhanced green fluorescent protein (EGFP) driven by the c-fos promoter, we visualized EGFP-positive neurons in spinal cord slices from animals that were subjected to a locomotor task or drug cocktail [N-methyl-D-aspartate, serotonin (5-HT), dopamine, and acetylcholine (ACh)]. The activity-dependent expression of EGFP was also induced in dorsal root ganglion neurons with electrical stimulation of the neurons. Following 60-90 min of swimming, whole cell patch-clamp recordings were made from EGFP+ neurons in laminae VII, VIII, and X from slices of segments T(12) to L(4). The EGFP+ neurons (n = 55) could be classified into three types based on their responses to depolarizing step currents: single spike, phasic firing, and tonic firing. Membrane properties observed in these neurons include hyperpolarization-activated inward currents (29/55), postinhibitory rebound (11/55), and persistent-inward currents (31/55). Bath application of 10-40 microM 5-HT and/or ACh increased neuronal excitability or output with hyperpolarization of voltage threshold and changes in membrane potential. 5-HT also increased input resistance, reduced the afterhyperpolarization (AHP), and induced membrane oscillations, whereas ACh reduced the input resistance and increased the AHP. In this study, we demonstrate a new way of identifying neurons active in locomotion. Our results suggest that the EGFP+ neurons are a heterogeneous population of interneurons. The actions of 5-HT and ACh on these neurons provide insights into the neuronal properties modulated by these transmitters for generation of locomotion.
| S-EPMC2804412 | biostudies-literature
Project description:The existence of functional K(v)7 channels in thalamocortical (TC) relay neurons and the effects of the K(+)-current termed M-current (I(M)) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore, we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB).Characterization of K(v)7 channels was performed by combining in vitro, in vivo and in silico techniques with a pharmacological approach. Retigabine (30 ?M) and XE991 (20 ?M), a specific K(v)7 channel enhancer and blocker, respectively, were applied in acute brain slices during electrophysiological recordings. The effects of intrathalamic injection of retigabine (3 mM, 300 nL) and/or XE991 (2 mM, 300 nL) were investigated in freely moving animals during hot-plate tests by recording behaviour and neuronal activity.K(v)7.2 and K(v)7.3 subunits were found to be abundantly expressed in TC neurons of mouse VB. A slow K(+)-current with properties of IM was activated by retigabine and inhibited by XE991. K(v)7 channel activation evoked membrane hyperpolarization, a reduction in tonic action potential firing, and increased burst firing in vitro and in computational models. Single-unit recordings and pharmacological intervention demonstrated a specific burst-firing increase upon I(M) activation in vivo. A K(v)7 channel-mediated increase in pain threshold was associated with fewer VB units responding to noxious stimuli, and increased burst firing in responsive neurons.K(v)7 channel enhancement alters somatosensory activity and may reflect an anti-nociceptive mechanism during acute pain processing.
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Project description:Flavonoids are a class of natural substances present in plants, fruits, vegetables, wine, bulbs, bark, stems, roots, and tea. Several attempts are being made to isolate such natural products, which are popular for their health benefits. Flavonoids are now seen as an essential component in a number of cosmetic, pharmaceutical, and medicinal formulations. Quercetin is the major polyphenolic flavonoid found in food products, including berries, apples, cauliflower, tea, cabbage, nuts, and onions that have traditionally been treated as anticancer and antiviral, and used for the treatment of allergic, metabolic, and inflammatory disorders, eye and cardiovascular diseases, and arthritis. Pharmacologically, quercetin has been examined against various microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium, Babesia, and Theileria parasites. Additionally, it has shown beneficial effects against Alzheimer's disease (AD), and this activity is due to its inhibitory effect against acetylcholinesterase. It has also been documented to possess antioxidant, antifungal, anti-carcinogenic, hepatoprotective, and cytotoxic activity. Quercetin has been documented to accumulate in the lungs, liver, kidneys, and small intestines, with lower levels seen in the brain, heart, and spleen, and it is extracted through the renal, fecal, and respiratory systems. The current review examines the pharmacokinetics, as well as the toxic and biological activities of quercetin.
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Project description:Essential oils of oregano are widely recognized for their antimicrobial activity, as well as their antiviral and antifungal properties. Nevertheless, recent investigations have demonstrated that these compounds are also potent antioxidant, anti-inflammatory, antidiabetic and cancer suppressor agents. These properties of oregano essential oils are of potential interest to the food, cosmetic and pharmaceutical industries. The aim of this manuscript is to review the latest evidence regarding essential oils of oregano and their beneficial effects on health.
| S-EPMC6152729 | biostudies-other
Project description:Lactoferrin is an iron-binding protein present in large quantities in colostrum and in breast milk, in external secretions and in polymorphonuclear leukocytes. Lactoferrin's main function is non-immune protection. Among several protective activities shown by lactoferrin, those displayed by orally administered lactoferrin are: (i) antimicrobial activity, which has been presumed due to iron deprivation, but more recently attributed also to a specific interaction with the bacterial cell wall and extended to viruses and parasites; (ii) immunomodulatory activity, with a direct effect on the development of the immune system in the newborn, together with a specific antinflammatory effects; (iii) a more recently discovered anticancer activity. It is worth noting that most of the protective activities of lactoferrin have been found, sometimes to a greater extent, also in peptides derived from limited proteolysis of lactoferrin that could be generated after lactoferrin ingestion. Lactoferrin could therefore be considered an ideal nutraceutic product because of its relatively cheap production from bovine milk and of its widely recognized tolerance after ingestion, along with its well demonstrated protective activities. The most important protective activities shown by orally administered bovine lactoferrin are reviewed in this article.
| S-EPMC5198036 | biostudies-literature
Project description:The research aim was to use orange essential oil and trehalose in a carrageenan matrix to form edible packaging. The edible packaging experimentally produced by casting from an aqueous solution were evaluated by the following analysis: UV-Vis spectrum, transparency value, transmittance, attenuated total reflectance Fourier-Transform spectroscopy (FTIR), scanning electron microscopy (SEM) and antimicrobial activity. The obtained results showed that the combination of orange essential oil with trehalose decreases the transmittance value in the UV and Vis regions (up to 0.14% ± 0.02% at 356 nm), meaning that produced films can act as a UV protector. Most produced films in the research were resistant to Gram-positive bacteria (Staphylococcus aureus subsp. aureus), though most films did not show antibacterial properties against Gram-negative bacteria and yeasts. FTIR and SEM confirmed that both the amount of carrageenan used and the combination with orange essential oil influenced the compatibility of trehalose with the film matrix. The research showed how different combinations of trehalose, orange essential oils and carrageenan can affect edible film properties. These changes represent important information for further research and the possible practical application of these edible matrices.
| S-EPMC7864528 | biostudies-literature
Project description:Isofraxidin (7-hydroxy-6, 8-dimethoxy coumarin) (IF) is a hydroxy coumarin with several biological and pharmacological activities. The plant kingdom is of the most prominent sources of IF, which, among them, Eleutherococcus and Fraxinus are the well-known genera in which IF could be isolated/extracted from their species. Considering the complex pathophysiological mechanisms behind some diseases (e.g., cancer, neurodegenerative diseases, and heart diseases), introducing IF as a potent multi-target agent, which possesses several herbal sources and the multiple methods for isolation/purification/synthesis, along with the unique pharmacokinetic profile and low levels of side effects, could be of great importance. Accordingly, a comprehensive review was done without time limitations until February 2020. IF extraction methods include microwave, mechanochemical, and ultrasound, along with other conventional methods in the presence of semi-polar solvents such as ethyl acetate (EtOAc). In addition to the isolation methods, related synthesis protocols of IF is also of great importance. From the synthesis point of view, benzaldehyde derivatives are widely used as precursors for IF synthesis. Along with the methods of isolation and biosynthesis, IF pharmacokinetic studies showed hopeful in vivo results of its rapid absorption after oral uses, leading to different pharmacological effects. In this regard, IF targets varieties of inflammatory mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B), tumor necrosis factor-? (TNF-?), and matrix metalloproteinases (MMPs). thereby indicating anticancer, cardioprotective, and neuroprotective effects. This is the first review on the synthesis, biosynthesis, isolation, and pharmacokinetic and pharmacological properties of IF in combating different diseases.
| S-EPMC7248759 | biostudies-literature
Project description:Psoralen is the principal bioactive component in the dried fruits of Cullen corylifolium (L.) Medik (syn. Psoralea corylifolia L), termed “Buguzhi” in traditional Chinese medicine (TCM). Recent studies have demonstrated that psoralen displays multiple bioactive properties, beneficial for the treatment of osteoporosis, tumors, viruses, bacteria, and inflammation. The present review focuses on the research evidence relating to the properties of psoralen gathered over recent years. Firstly, multiple studies have demonstrated that psoralen exerts strong anti-osteoporotic effects via regulation of osteoblast/osteoclast/chondrocyte differentiation or activation due to the participation in multiple molecular mechanisms of the wnt/?-catenin, bone morphogenetic protein (BMP), inositol-requiring enzyme 1 (IRE1)/apoptosis signaling kinase 1 (ASK1)/c-jun N-terminal kinase (JNK) and the Protein Kinase B(AKT)/activator protein-1 (AP-1) axis, and the expression of miR-488, peroxisome proliferators-activated receptor-gamma (PPAR?), and matrix metalloproteinases (MMPs). In addition, the antitumor properties of psoralen are associated with the induction of ER stress-related cell death via enhancement of PERK: Pancreatic Endoplasmic Reticulum Kinase (PERK)/activating transcription factor (ATF), 78kD glucose-regulated protein (GRP78)/C/EBP homologous protein (CHOP), and 94kD glucose-regulated protein (GRP94)/CHOP signaling, and inhibition of P-glycoprotein (P-gp) or ATPase that overcomes multidrug resistance. Furthermore, multiple articles have shown that the antibacterial, anti-inflammatory and neuroprotective effects of psoralen are a result of its interaction with viral polymerase (Pol), destroying the formation of biofilm, and regulating the activation of tumor necrosis factor alpha (TNF-?), transforming growth factor beta (TGF-?), interleukin 4/5/6/8/12/13 (IL-4/5/6/8/12/13), GATA-3, acetylcholinesterase (AChE), and the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the toxic effects and mechanisms of action of psoralen have also been reviewed.
| S-EPMC7500444 | biostudies-literature
Project description:FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-?-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [(35)S]GTP?S-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues.
| S-EPMC4492757 | biostudies-literature
Project description:Background and purposeThe sigma-1 (σ(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing.Experimental approachThe pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data.Key resultsFormalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ(1) receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation.Conclusions and implicationsThese findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.
| S-EPMC3448894 | biostudies-literature