-
Biomedicine & Pharmacotherapy =... Feb 2024Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational...
Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational and type 2 diabetes in pregnancy are still limited. Empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) are three sodium glucose co-transporter 2 (SGLT2) inhibitors, a newer group of oral antidiabetics that are well established in the treatment of type 2 diabetes mellitus in non-pregnant patients. To date, no data regarding their placental transfer and safety in pregnant women are available. We performed ex vivo human placental perfusions (n = 4, term placentas, creatinine and antipyrine as connectivity controls) to evaluate the transplacental transfer of EMPA, DAPA and CANA across the placental barrier and assessed their influence on the secretion of two placental peptide hormones, leptin and β-human chorionic gonadotropin (β-hCG). We discovered that all three SGLT2 inhibitors cross the placental barrier and attained maximal foetal to maternal concentration ratios of 0.38 ± 0.09 (EMPA), 0.67 ± 0.05 (DAPA) and 0.62 ± 0.05 (CANA) within the tested 360 min. A moderate but statistically significant decrease in placental leptin - but not β-hCG - secretion was observed during perfusions with SGLT2 inhibitors, which was confirmed in experiments performed with human placental BeWo cells. SGLT2 inhibitors are able to cross the human placental barrier and seem to interfere with placental leptin production. These observations should be considered in the ongoing discussion on the optimal treatment for gestational diabetes and type 2 diabetes mellitus in pregnancy.
Topics: Humans; Female; Pregnancy; Canagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Leptin; Placenta; Benzhydryl Compounds; Hypoglycemic Agents; Perfusion; Glucosides
PubMed: 38262151
DOI: 10.1016/j.biopha.2024.116177 -
Molecules (Basel, Switzerland) Nov 2023In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate...
In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate derivative is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (-) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative () which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against β-carbonic anhydrase. The amount of cellular protein released by is directly correlated to the concentration of compound , which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound . This finding supports compound 's antibacterial properties and explains how the formation of holes in the cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against β-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound () declared a greater activity than the other synthesized compounds.
Topics: Escherichia coli; Antipyrine; Carbonic Anhydrases; Anti-Infective Agents; Molecular Docking Simulation; Structure-Activity Relationship; Molecular Structure; Carbonic Anhydrase Inhibitors
PubMed: 38005213
DOI: 10.3390/molecules28227491 -
Analytical Chemistry Aug 2023Glycogen is a highly branched biomacromolecule that functions as a glucose buffer. It is involved in multiple diseases such as glycogen storage disorders, diabetes, and...
Glycogen is a highly branched biomacromolecule that functions as a glucose buffer. It is involved in multiple diseases such as glycogen storage disorders, diabetes, and even liver cancer, where the imbalance between biosynthetic and catabolic enzymes results in structural alterations and abnormal accumulation of glycogen that can be toxic to cells. Accurate and sensitive glycogen quantification and structural determination are prerequisites for understanding the phenotypes and biological functions of glycogen under these conditions. In this research, we furthered cell glycogen characterization by presenting a highly sensitive method to measure the glycogen content and degree of branching. The method employed a novel fructose density gradient as an alternative to the traditional sucrose gradient to fractionate glycogen from cell mixtures using ultracentrifugation. Fructose was used to avoid the large glucose background, allowing the method to be highly quantitative. The glycogen content was determined by quantifying 1-phenyl-3-methyl-5-pyrazolone (PMP)-derivatized glucose residues obtained from acid-hydrolyzed glycogen using ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC/QqQ-MS). The degree of branching was determined through linkage analysis where the glycogen underwent permethylation, hydrolysis, PMP derivatization, and UHPLC/QqQ-MS analysis. The new approach was used to study the effect of insulin on the glycogen phenotypes of human hepatocellular carcinoma (Hep G2) cells. We observed that cells produced greater amounts of glycogen with less branching under increasing insulin levels before reaching the cell's insulin-resistant state, where the trend reversed and the cells produced less but higher-branched glycogen. The advantage of this method lies in its high sensitivity in characterizing both the glycogen level and the structure of biological samples.
Topics: Humans; Glycogen; Mass Spectrometry; Chromatography, Liquid; Chromatography, High Pressure Liquid; Glucose; Edaravone; Insulins
PubMed: 37584460
DOI: 10.1021/acs.analchem.3c02230 -
Medicina (Kaunas, Lithuania) Feb 2024Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation... (Review)
Review
Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.
Topics: Humans; Edaravone; Antioxidants; Oxidative Stress; Eye Diseases; Retinal Diseases; Ophthalmic Solutions
PubMed: 38541080
DOI: 10.3390/medicina60030354 -
Molecules (Basel, Switzerland) Nov 2023Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have...
Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.
Topics: Humans; Edaravone; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Adamantane; Riluzole; Amantadine
PubMed: 38005288
DOI: 10.3390/molecules28227567 -
Doklady. Biochemistry and Biophysics Oct 2023New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized....
New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.
Topics: Memantine; Edaravone; Receptors, N-Methyl-D-Aspartate; Adamantane
PubMed: 38093132
DOI: 10.1134/S1607672923700461 -
Applied Microbiology and Biotechnology Apr 2024Water bodies are increasingly contaminated with a diversity of organic micropollutants (OMPs). This impacts the quality of ecosystems due to their recalcitrant nature....
Water bodies are increasingly contaminated with a diversity of organic micropollutants (OMPs). This impacts the quality of ecosystems due to their recalcitrant nature. In this study, we assessed the removal of OMPs by spent mushroom substrate (SMS) of the white button mushroom (Agaricus bisporus) and by its aqueous tea extract. Removal of acesulfame K, antipyrine, bentazon, caffeine, carbamazepine, chloridazon, clofibric acid, and N, N-diethyl-meta-toluamide (DEET) by SMS and its tea was between 10 and 90% and 0-26%, respectively, in a 7-day period. Sorption to SMS particles was between 0 and 29%, which can thus not explain the removal difference between SMS and its tea, the latter lacking these particles. Carbamazepine was removed most efficiently by both SMS and its tea. Removal of OMPs (except caffeine) by SMS tea was not affected by heat treatment. By contrast, heat-treatment of SMS reduced OMP removal to < 10% except for carbamazepine with a removal of 90%. These results indicate that OMP removal by SMS and its tea is mediated by both enzymatic and non-enzymatic activities. The presence of copper, manganese, and iron (0.03, 0.88, and 0.33 µg L, respectively) as well as HO (1.5 µM) in SMS tea indicated that the Fenton reaction represents (part of) the non-enzymatic activity. Indeed, the in vitro reconstituted Fenton reaction removed OMPs > 50% better than the teas. From these data it is concluded that spent mushroom substrate of the white button mushroom, which is widely available as a waste-stream, can be used to purify water from OMPs.
Topics: Ecosystem; Caffeine; Hydrogen Peroxide; Agaricus; Water; Tea; Carbamazepine
PubMed: 38639797
DOI: 10.1007/s00253-024-13132-3 -
Neuropharmacology Sep 2024Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to...
Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further in vitro investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.
Topics: Animals; Toll-Like Receptor 4; Mice; Male; Cognitive Dysfunction; Receptors, Immunologic; Membrane Glycoproteins; Edaravone; Up-Regulation; Mice, Transgenic; Neuroprotective Agents; MAP Kinase Signaling System; Hippocampus; Amyloid beta-Protein Precursor; Mice, Inbred C57BL; Alzheimer Disease; Disease Models, Animal; Presenilin-1
PubMed: 38763325
DOI: 10.1016/j.neuropharm.2024.110006 -
Scientific Reports Apr 2024The etiopathogenesis of severe acute pancreatitis (SAP) remains poorly understood. We aim to investigate the role of immune cells Infiltration Characteristics during SAP...
The etiopathogenesis of severe acute pancreatitis (SAP) remains poorly understood. We aim to investigate the role of immune cells Infiltration Characteristics during SAP progression. Gene expression profiles of the GSE194331 dataset were retrieved from the GEO. Lasso regression and random forest algorithms were employed to select feature genes from genes related to SAP progression and immune responses. CIBERSORT was utilized to estimate differences in immune cell types and proportions and the relationship between immune cells and gene expression. We performed pathway enrichment analysis using GSEA to examine disparities in KEGG signaling pathways when comparing the two groups. Additionally, CMap analysis was executed to identify prospective small molecular compounds. The three hub genes (CBLB, JADE2, RNF144A) were identified that can predict SAP progression. Analysis of CIBERSORT and TISIDB databases has shown that there are significant differences in immune cell expression levels between the normal and SAP groups, and three hub genes (CBLB, JADE2, RNF144A) were highly correlated with multiple immune cells, regulating the characteristics of immune cell infiltration in the microenvironment. Finally, drug prediction through the Connectivity Map database suggested that compounds such as Entecavir, KU-0063794, Y-27632, and Antipyrine have certain effects as potential targeted drugs for the treatment of SAP. CBLB, JADE2, and RNF144A are hub genes in SAP, potentially playing important roles in SAP progression. This finding further broadens the understanding of the etiopathogenesis of SAP and provides a feasible basis for future research on diagnostic and immunotherapeutic targets for SAP.
Topics: Humans; Acute Disease; Prospective Studies; Pancreatitis; Drug Delivery Systems; Computational Biology
PubMed: 38622245
DOI: 10.1038/s41598-024-59205-1 -
Microbiome Research Reports 2024The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report...
The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report on the added value of combining a microbiome screening model, the i-screen, with fresh intestinal tissue explants in a microfluidic gut-on-a-chip model, the Intestinal Explant Barrier Chip (IEBC). Adult human gut microbiome (fecal pool of 6 healthy donors) was cultured anaerobically in the i-screen platform for 24 h, without and with exposure to 4 mg/mL inulin. The i-screen cell-free culture supernatant was subsequently applied to the luminal side of adult human colon tissue explants ( = 3 donors), fixed in the IEBC, for 24 h and effects were evaluated. The supplementation of the media with inulin promoted the growth of , , , and in the i-screen, and triggered an elevated production of butyrate by the microbiota. Human colon tissue exposed to inulin-treated i-screen cell-free culture supernatant or control i-screen cell-free culture supernatant with added short-chain fatty acids (SCFAs) showed improved tissue barrier integrity measured by a 28.2%-34.2% reduction in FITC-dextran 4000 (FD4) leakage and 1.3 times lower transport of antipyrine. Furthermore, the release of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α was reduced under these circumstances. Gene expression profiles confirmed these findings, but showed more profound effects for inulin-treated supernatant compared to SCFA-supplemented supernatant. The combination of i-screen and IEBC facilitates the study of complex intestinal processes such as host-microbial metabolite interaction and gut health.
PubMed: 38841408
DOI: 10.20517/mrr.2023.79