scholarly journals The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

2020 ◽  
Vol 22 (3) ◽  
pp. 259-269 ◽  
Keyword(s):  
Molecular Targets ◽  
Neuropsychiatric Disorders ◽  
Lipid Mediators ◽  
Therapeutic Window ◽  
Signaling System ◽  
Catabolic Enzymes ◽  
Therapeutic Drugs ◽  
Wide Range ◽  
Cb2 Receptors ◽  
Complex Signaling

The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB1 and CB2 receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome). This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids. These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations.

Bioprospecting Cryptogams as Potential Source of Unique Biodynamic Phytochemicals with Diverse Pharmaceutical Applications

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Brahma N. Singh ◽  
Garima Pandey ◽  
Prateeksha ◽  
J. Kumar
Keyword(s):  
Secondary Metabolites ◽  
Higher Plants ◽  
New Drugs ◽  
Terrestrial Plants ◽  
Pharmacological Activities ◽  
Therapeutic Drugs ◽  
Potential Source ◽  
Therapeutic Value ◽  
Wide Range ◽  
Novel Structures

With the advent of green pharmaceuticals, the secondary metabolites derived from plants have provided numerous leads for the development of a wide range of therapeutic drugs; however the discovery of new drugs with novel structures has declined in the past few years. Cryptogams including lichens, bryophytes, and pteridophytes represent a group of small terrestrial plants that remain relatively untouched in the drug discovery process though some have been used as ethnomedicines by various tribes worldwide. Studies of their secondary metabolites are recent but reveal unique secondary metabolites which are not synthesized by higher plants. These compounds can have the potential to develop more potential herbal drugs for prevention and treatment of diseases The present article . deals with the secondary metabolites and pharmacological activities of cryptogams with an objective to bring them forth as potential source of biodynamic compounds of therapeutic value.

scholarly journals Anodic Titanium Dioxide Nanotubes for Magnetically Guided Therapeutic Delivery

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Morteza Hasanzadeh Kafshgari ◽  
Delf Kah ◽  
Anca Mazare ◽  
Nhat Truong Nguyen ◽  
Monica Distaso ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Iron Oxide ◽  
Iron Oxide Nanoparticles ◽  
Hela Cells ◽  
Release Kinetics ◽  
Drug Loading ◽  
Oxide Nanoparticles ◽  
Site Specific ◽  
Therapeutic Drugs ◽  
Wide Range

Abstract Hollow titanium dioxide (TiO2) nanotubes offer substantially higher drug loading capacity and slower drug release kinetics compared to solid drug nanocarriers of comparable size. In this report, we load TiO2 nanotubes with iron oxide nanoparticles to facilitate site-specific magnetic guidance and drug delivery. We generate magnetic TiO2 nanotubes (TiO2NTs) by incorporating a ferrofluid containing Ø ≈ 10 nm iron oxide nanoparticles in planar sheets of weakly connected TiO2 nanotubes. After thermal annealing, the magnetic tubular arrays are loaded with therapeutic drugs and then sonicated to separate the nanotubes. We demonstrate that magnetic TiO2NTs are non-toxic for HeLa cells at therapeutic concentrations (≤200 µg/mL). Adhesion and endocytosis of magnetic nanotubes to a layer of HeLa cells are increased in the presence of a magnetic gradient field. As a proof-of-concept, we load the nanotubes with the topoisomerase inhibitor camptothecin and achieve a 90% killing efficiency. We also load the nanotubes with oligonucleotides for cell transfection and achieve 100% cellular uptake efficiency. Our results demonstrate the potential of magnetic TiO2NTs for a wide range of biomedical applications, including site-specific delivery of therapeutic drugs.

scholarly journals WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 484
Author(s):  
Dongchen An ◽  
Steve Peigneur ◽  
Jan Tytgat
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
G Protein ◽  
Cannabinoid Receptors ◽  
Inward Rectifier ◽  
Xenopus Laevis Oocyte ◽  
Inward Rectifier Potassium Channels ◽  
Wide Range ◽  
Cb2 Receptors ◽  
G Protein Coupled

The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2-GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

scholarly journals Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion

2021 ◽  
pp. 1-8
Author(s):  
Matthew Rosebraugh ◽  
Wei Liu ◽  
Melina Neenan ◽  
Maurizio F. Facheris
Keyword(s):  
Steady State ◽  
Phase 1 ◽  
The United States ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Advanced Parkinson’S Disease ◽  
Subcutaneous Infusion ◽  
Study Results ◽  
Wide Range ◽  
Favorable Safety

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

scholarly journals An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

2021 ◽  
Author(s):  
Darcy S.O. Mora ◽  
Madeline Cox ◽  
Forgivemore Magunda ◽  
Ashley B. Williams ◽  
Lyndsey Linke
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Nucleic Acids ◽  
Endosomal Escape ◽  
Therapeutic Window ◽  
Target Cells ◽  
Full Potential ◽  
Wide Range ◽  
Delivery Platform

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza- targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

scholarly journals SPECIFIC MARKERS OF NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS WITH MENTAL DISORDERS – REVIEW OF THE LITERATURE

2019 ◽  
Vol 72 (7) ◽  
pp. 1359-1363
Author(s):  
Marcin Zarzycki ◽  
Magdalena Flaga-Łuczkiewicz ◽  
Joanna Czuwara ◽  
Lidia Rudnicka
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Psychiatric Disorders ◽  
Lupus Erythematosus ◽  
Neuropsychiatric Disorders ◽  
Systemic Lupus ◽  
Medical Specialties ◽  
Potential Association ◽  
Neuropsychiatric Sle ◽  
Neuropsychiatric Diseases ◽  
Wide Range

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease belonging to spectrum of interest of many medical specialties. Wide range of patients 14−75% with SLE suffers from neuropsychiatric disorders. The problematic diagnosis of neuropsychiatric SLE has generated many studies focusing on etiology of the disease with the presence of specific autoantibodies, abnormalities which can be detected by imaging examinations or correlation with catecholamine levels. The aim of this review paper is to discuss the frequency of neuropsychiatric disturbances in patients with SLE and their potential association with immunological abnormalities and specific disease markers. So far published literature regarding this topic indicates the usefulness of autoantibodies specificity. The use of the specific antibodies may be helpful in targeting diagnostics towards psychiatric disorders, especially depressive ones. Imaging scanning techniques such as computed tomography (CT) have limited value in psychiatric disorders diagnosis but can be useful in neurological symptoms and complains. Therapeutic use of systemic glucocorticosteroids due to anti-inflammatory properties with multidirectional action, may also significantly influence the course of neuropsychiatric diseases, especially in patients with SLE. Awareness of the morbidity of neuropsychiatric disorders and the possibilities of their diagnosis are important in the management of patients with systemic lupus erythematosus, which significantly affects the quality of life of patients, treatment efficacy and psyche.

scholarly journals GLP-1: Molecular mechanisms and outcomes of a complex signaling system

2019 ◽  
Vol 128 ◽  
pp. 94-105 ◽  
Author(s):  
Nicholas K. Smith ◽  
Troy A. Hackett ◽  
Aurelio Galli ◽  
Charles R. Flynn
Keyword(s):  
Molecular Mechanisms ◽  
Signaling System ◽  
Complex Signaling

Does a plasma level of chlorpromazine help?

1981 ◽  
Vol 11 (4) ◽  
pp. 729-734 ◽  
Author(s):  
Theodore van Putten ◽  
Philip R. A. May ◽  
Donald J. Jenden
Keyword(s):  
Plasma Level ◽  
Plasma Levels ◽  
Internal Standard ◽  
Gas Chromatography Mass Spectrometry ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Speed Of Response ◽  
Wide Range ◽  
Dose Period ◽  
Schizophrenic Patients

SynopsisForty-eight newly admitted schizophrenic patients were treated with a fixed, conservative (6·6 mg/kg) dose of chlorpromazine (CPZ) for 28 days. CPZ plasma levels were measured by a gas chromatography mass spectrometry method (GCMS) using 2H6-chlorpromazine as an internal standard. At the end of the fixed-dose period, ‘responders’ had the same plasma levels as ‘non-responders’, suggesting that lack of response is primarily a matter of the illness' sensitivity to CPZ, not to a plasma level below some therapeutic window. After the fixed-dose period, the dosage of CPZ was increased in the ‘non-responders’ by physician's choice. Improvement occurred over a wide range of 10–225 picomoles (3–72 ng)/ml. Above 300 picomoles (95 ng/ml) 4 inaccessible patients eventually became much worse, suggesting psychotoxicity. It is in the inaccessible patient whose illness is only minimally, or not at all, sensitive to CPZ that a plasma level might be especially useful.Interpretation of plasma levels is complicated by the speed of response: some initial non-responders improved by the 56th day of treatment on very conservative plasma levels.

scholarly journals Molecular Targets Involved in the Neuroprotection Mediated by Terpenoids

Planta Medica ◽  
2019 ◽  
Vol 85 (17) ◽  
pp. 1304-1315 ◽  
Author(s):  
Laura González-Cofrade ◽  
Beatriz de las Heras ◽  
Luis Apaza Ticona ◽  
Olga M. Palomino
Keyword(s):  
Therapeutic Potential ◽  
Cell Damage ◽  
Biological Activities ◽  
Neuronal Cell ◽  
Molecular Targets ◽  
Research Activity ◽  
Neuroprotective Effects ◽  
Therapeutic Value ◽  
Wide Range ◽  
Drug Leads

AbstractNatural products and their derivatives represent the most consistently successful source of drug leads. Terpenoids, a structurally diverse group, are secondary metabolites widely distributed in nature, endowed with a wide range of biological activities such as antibacterial, anti-inflammatory, antitumoral, or neuroprotective effects, which consolidate their therapeutic value. During the last decades, and taking into consideration the prevalence of aging-related diseases, research activity into the neuroprotective effects of these types of compounds has increased enormously. Several signaling pathways involved in neuroprotection are targets of their mechanism of action and mediate their pleiotropic protective activity in neuronal cell damage. In the present review, molecular basis of the neuroprotection exerted by terpenoids is presented, focusing on preclinical evidence of the therapeutic potential of diterpenoids and triterpenoids on neurodegenerative disorders. By acting on diverse mechanisms simultaneously, terpenoids have been emphasized as promising multitarget agents.

Biobased Spiroimides from Itaconic Acid and Formamides: Molecular Targets for a Novel Synthetic Application of Renewable Chemicals

Synthesis ◽  
2020 ◽  
Vol 53 (02) ◽  
pp. 296-308
Author(s):  
Leandro Helgueira Andrade ◽  
Milene Macedo Hornink ◽  
Alice Uva Lopes
Keyword(s):  
Itaconic Acid ◽  
Biological Activities ◽  
Molecular Targets ◽  
Synthetic Approach ◽  
Renewable Chemicals ◽  
Wide Range ◽  
Synthetic Application

AbstractSpiroimides exhibit a wide range of biological activities, such as anticonvulsant, antiarrhythmic, and antihyperglycemic activities. Herein, a novel synthetic application of renewable chemicals, itaconic acid and formamides, is described. Proper exploitation of the reactivity of itaconic acid and formamide allows for the development of an efficient synthetic approach for the production of several new biobased spiroimides, spiro[dihydroquinolin-2-one-succinimides] and spiro[indolin-2-one-glutarimides], in excellent overall yields (up to 98%).

Sign in / Sign up

Export Citation Format

Share Document