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European Journal of Pharmaceutical... Jul 2021Hypertension, a form of cardiovascular diseases, is considered a major risk factor associated with deaths in type 2 diabetes patients. The current medication systems for...
Hypertension, a form of cardiovascular diseases, is considered a major risk factor associated with deaths in type 2 diabetes patients. The current medication systems for treating such chronic coexisting diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic and treatment regimen. The objective of the present study is to design and optimize pioglitazone (PIO) and eprosartan mesylate (EM)-loaded nano-transferosomes (NTs) using Design-Expert software, aiming its transdermal delivery as a novel combination therapy for concomitant treatment of hypertensive diabetic patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities. NTs were prepared using PIO and EM as the two model drugs and optimized using Box-Behnken design by considering phospholipid (X1), surfactant (X2), ratio of solvents (X3), and sonication time (X4), as independent variables, each at three levels. Entrapment efficiency (Y1 and Y2) and flux (Y3 and Y4) of PIO and EM, respectively, were selected as dependent variables. Among all the prepared formulations, one optimized formulation was chosen by the point prediction method and evaluated for drug-polymer compatibility, particle size, and surface charge analysis, followed by skin permeation and pharmacodynamic studies. The optimized nano-transferosomal gel (ONTF) showed all responses which confirm with the values predicted by the design. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats after the ONTF was applied, compared to oral and drug-loaded NT formulations. Results of the current study suggest that the development of such combinational delivery system can result in a rational therapeutic regimen for effective treatment of concomitant disease conditions of diabetic hypertensive patients.
Topics: Acrylates; Animals; Diabetes Mellitus, Type 2; Drug Carriers; Drug Delivery Systems; Humans; Hypertension; Imidazoles; Liposomes; Mesylates; Particle Size; Pioglitazone; Rats; Rats, Wistar; Thiophenes
PubMed: 33757828
DOI: 10.1016/j.ejps.2021.105811 -
BMC Plant Biology Jul 2022Metals such as Zn or Cd are toxic to plant and humans when they are exposed in high quantities through contaminated soil or food. Noccaea caerulescens, an extraordinary...
BACKGROUND
Metals such as Zn or Cd are toxic to plant and humans when they are exposed in high quantities through contaminated soil or food. Noccaea caerulescens, an extraordinary Zn/Cd/Ni hyperaccumulating species, is used as a model plant for metal hyperaccumulation and phytoremediation studies. Current reverse genetic techniques to generate mutants based on transgenesis is cumbersome due to the low transformation efficiency of this species. We aimed to establish a mutant library for functional genomics by a non-transgenic approach, to identify mutants with an altered mineral profiling, and to screen for mutations in bZIP19, a regulator of Zn homeostasis in N. caerulescens.
RESULTS
To generate the N. caerulescens mutant library, 3000 and 5000 seeds from two sister plants of a single-seed recurrent inbred descendant of the southern French accession Saint-Félix-de-Pallières (SF) were mutagenized respectively by 0.3 or 0.4% ethyl methane sulfonate (EMS). Two subpopulations of 5000 and 7000 M2 plants were obtained after 0.3 or 0.4% EMS treatment. The 0.4% EMS treatment population had a higher mutant frequency and was used for TILLING. A High Resolution Melting curve analysis (HRM) mutation screening platform was optimized and successfully applied to detect mutations for NcbZIP19, encoding a transcription factor controlling Zn homeostasis. Of four identified point mutations in NcbZIP19, two caused non-synonymous substitutions, however, these two mutations did not alter the ionome profile compared to the wild type. Forward screening of the 0.4% EMS treatment population by mineral concentration analysis (ionomics) in leaf material of each M2 plant revealed putative mutants affected in the concentration of one or more of the 20 trace elements tested. Several of the low-Zn mutants identified in the ionomic screen did not give progeny, illustrating the importance of Zn for the species. The mutant frequency of the population was evaluated based on an average of 2.3 knockout mutants per tested monogenic locus.
CONCLUSIONS
The 0.4% EMS treatment population is effectively mutagenized suitable for forward mutant screens and TILLING. Difficulties in seed production in low Zn mutants, obtained by both forward and reverse genetic approach, hampered further analysis of the nature of the low Zn phenotypes.
Topics: Biodegradation, Environmental; Brassicaceae; Cadmium; Ethyl Methanesulfonate; Humans; Metals; Zinc
PubMed: 35869423
DOI: 10.1186/s12870-022-03739-x -
Chemistry (Weinheim An Der Bergstrasse,... Nov 2015The total synthesis of (-)-isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson-Claisen rearrangement in...
The total synthesis of (-)-isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson-Claisen rearrangement in basic media and the facile assembly of the key tetracyclic quinolone intermediate through a cascade cyclization. The characteristic cyclic aminal was constructed by late-stage C-H functionalization at the position adjacent to the lactam nitrogen using a combination of CrO3 and nBu4 NIO4 and subsequent Bi(OTf)3 -mediated cyclization.
Topics: Cyclization; Hydrogen Bonding; Indole Alkaloids; Mesylates; Onium Compounds; Stereoisomerism
PubMed: 26424406
DOI: 10.1002/chem.201503606 -
Journal of Integrative Plant Biology Apr 2021Pre-mRNA (messenger RNA) splicing participates in the regulation of numerous biological processes in plants. For example, alternative splicing shapes transcriptomic...
Pre-mRNA (messenger RNA) splicing participates in the regulation of numerous biological processes in plants. For example, alternative splicing shapes transcriptomic responses to abiotic and biotic stress, and controls developmental programs. However, no study has revealed a role for splicing in maintaining the root stem cell niche. Here, a screen for defects in root growth in Arabidopsis thaliana identified an ethyl methane sulfonate mutant defective in pre-mRNA splicing (rdm16-4). The rdm16-4 mutant displays a short-root phenotype resulting from fewer cells in the root apical meristem. The PLETHORA1 (PLT1) and PLT2 transcription factor genes are important for root development and were alternatively spliced in rdm16-4 mutants, resulting in a disordered root stem cell niche and retarded root growth. The root cap of rdm16-4 contained reduced levels of cytokinins, which promote differentiation in the developing root. This reduction was associated with the alternative splicing of genes encoding cytokinin signaling factors, such as ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN5 and ARABIDOPSIS RESPONSE REGULATORS (ARR1, ARR2, and ARR11). Furthermore, expression of the full-length coding sequence of ARR1 or exogenous cytokinin application partially rescued the short-root phenotype of rdm16-4. This reveals that the RDM16-mediated alternative splicing of cytokinin signaling components contributes to root growth.
Topics: Arabidopsis Proteins; Cytokinins; Ethyl Methanesulfonate; Gene Expression Regulation, Plant; Meristem; Nuclear Proteins; RNA Precursors; RNA Splicing Factors; Stem Cells; Transcription Factors
PubMed: 32790237
DOI: 10.1111/jipb.13006 -
BMC Genetics Aug 2020Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527)...
BACKGROUND
Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527) background. To reveal the genetic basis of lmpa1 mutant, phenotypic observations and analyses of chlorophyll content and photosynthesis were carried out in lmpa1, KD527 and their F and F derivatives. Further, bulked segregation analysis (BSA) in combination with a 660 K SNP array were conducted on the F segregation population of lmpa1/Chinese spring (CS) to locate the lmpa1 gene.
RESULTS
Most agronomic traits of lmpa1 were similar to those of KD527 before lesion-like spots appeared. Genetic analysis indicated that the F plants from the crossing of lmpa1 and KD527 exhibited the lmpa phenotype and the F progenies showed a segregation of normal (wild type, WT) and lmpa, with the ratios of lmpa: WT = 124:36(χ = 1.008 < =3.841), indicating that lmpa is a dominant mutation. The combination of BSA and the SNP array analysis of CS, lmpa1 and lmpa1/CS F WT pool (50 plants) and lmpa pool (50 plants) showed that polymorphic SNPs were enriched on chromosome 5A, within a region of 30-40 Mb, indicating that the wheat premature aging gene Lmpa1 was probably located on the short arm of chromosome 5A.
CONCLUSIONS
EMS-mutagenized mutant lmpa1 deriving from elite wheat line KD527 conferred lmpa. Lmpa phenotype of lmpa1 mutant is controlled by a single dominant allele designated as Lmpa1, which affected wheat growth and development and reduced the thousand grain weight (tgw) of single plant in wheat. The gene Lmpa1 was tentatively located within the region of 30-40 Mb near to the short arm of chromosome 5A.
Topics: Alleles; Chlorophyll; Chromosome Mapping; Ethyl Methanesulfonate; Genes, Plant; Mutagens; Phenotype; Photosynthesis; Polymorphism, Single Nucleotide; Triticum
PubMed: 32807077
DOI: 10.1186/s12863-020-00891-x -
Archives of Razi Institute Jun 2023Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant...
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant and anti-apoptotic activity in experimental models. Moreover, it has low permeability and its oral bioavailability is weak and highly variable due to extensive first-pass hepatic metabolism (35%). This study aimed to formulate rasagiline mesylate (RM) as a lipid-polymer hybrid nanoparticle in order to enhance its permeation and increase its chance to be absorbed by lymphatic circulation to avoid metabolism and control its release. Successful formulation (PCL-2) was reached by the nanoprecipitation method using polycaprolactone with RM in the organic phase and lecithin in the aqueous phase DSPE-PEG. The lipid:polymer ratio of 24% and DSPE: lecithin of 50% resulted in stable nanoparticles having a particle size of 132±4.58 nm, polydispersity index of 0.273±0.02, zeta potential of -25.6±3.3, entrapment efficiency of 46±3.9%, and drug loading of 51.93±6.5. Results showed that the diffusion was more effective on the release profile than the degradation and resulted in a Fickian diffusion mechanism.
Topics: Animals; Monoamine Oxidase Inhibitors; Lecithins; Neuroprotective Agents; Mesylates
PubMed: 38028832
DOI: 10.22092/ARI.2022.360193.2563 -
Journal of Aerosol Medicine and... Dec 2022Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is... (Review)
Review
Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.
Topics: Humans; Dihydroergotamine; Administration, Intranasal; Administration, Inhalation; Migraine Disorders; Technology; Mesylates
PubMed: 36108289
DOI: 10.1089/jamp.2022.0005 -
The Journal of Prevention of... 2022Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.
BACKGROUND
Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD).
OBJECTIVES
The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY).
DESIGN
The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase.
SETTING
76 clinical research sites in North America and Europe.
PARTICIPANTS
545 patients with probable AD or MCI-AD in the final version of the protocol.
INTERVENTION
Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose.
MEASUREMENTS
Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography.
RESULTS
446 participants are expected to complete the 12-month placebo-controlled phase in March 2022.
CONCLUSIONS
If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.
Topics: Humans; Alzheimer Disease; Activities of Daily Living; Fluorodeoxyglucose F18; Atrophy; Mesylates
PubMed: 36281683
DOI: 10.14283/jpad.2022.63 -
Journal of Hazardous Materials Mar 2017Triketones, derived chemically from a natural phytotoxin (leptospermone), are a good example of allelochemicals as lead molecules for the development of new herbicides.... (Review)
Review
Triketones, derived chemically from a natural phytotoxin (leptospermone), are a good example of allelochemicals as lead molecules for the development of new herbicides. Targeting a new and key enzyme involved in carotenoid biosynthesis, these latest-generation herbicides (sulcotrione, mesotrione and tembotrione) were designed to be eco-friendly and commercialized fifteen-twenty years ago. The mechanisms controlling their fate in different ecological niches as well as their toxicity and impact on different organisms or ecosystems are still under investigation. This review combines an overview of the results published in the literature on β-triketones and more specifically, on the commercially-available herbicides and includes new results obtained in our interdisciplinary study aiming to understand all the processes involved (i) in their transfer from the soil to the connected aquatic compartments, (ii) in their transformation by photochemical and biological mechanisms but also to evaluate (iii) the impacts of the parent molecules and their transformation products on various target and non-target organisms (aquatic microorganisms, plants, soil microbial communities). Analysis of all the data on the fate and impact of these molecules, used pure, as formulation or in cocktails, give an overall guide for the assessment of their environmental risks.
Topics: Cyclohexanones; Ecosystem; Ecotoxicology; Environment; Herbicides; Hydrogen-Ion Concentration; Ketones; Mesylates; Photochemistry; Plants; Risk Assessment; Soil; Soil Microbiology; Sulfones; Temperature; Water; Water Pollutants, Chemical
PubMed: 27930998
DOI: 10.1016/j.jhazmat.2016.11.059 -
Drug Discovery Today Oct 2014Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are... (Review)
Review
Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are alkylating agents, their mechanisms of action, pharmacokinetics (PK) and toxicity profiles are different. Experience with busulfan in pediatric HSCT is broad and the knowledge on the pharmacodynamics (PD), PK and, to a lesser extent, pharmacogenetics (PG) has resulted in a more effective therapy. Treosulfan has only recently been introduced in pediatric HSCT and is considered a promising new therapy because of its beneficial toxicity profile. However, knowledge of the PK and PG of treosulfan is limited. In this review, we describe the pharmacology of both agents and discuss factors causing variability in PK in relation to therapeutic outcome in HSCT.
Topics: Animals; Antineoplastic Agents, Alkylating; Busulfan; Child; Drug Monitoring; Hematopoietic Stem Cell Transplantation; Humans; Polymorphism, Genetic; Precision Medicine
PubMed: 24747172
DOI: 10.1016/j.drudis.2014.04.005