Esterase Inhibitor Research Articles

Multi-Target Quinoxaline Derivatives for Alzheimer’s Disease: Inhibitory Activities Against AChE and BACE-1 Enzymes

New choline esterase inhibitors and B-secretase inhibitors present promising treatment options for the treatment of Alzheimer's disease (AD). In this study, molecular docking was performed using our chemistry library to discover lead compounds. Molecular docking was employed to predict binding affinities, while molecular dynamics (MD) simulations provided insights into the stability of the ligand–enzyme interactions. To improve the activity, 12 new derivatives were designed and synthesized based on the lead compound obtained. The structures of the synthesized compounds were identified by 1H-NMR,13C-NMR, and HRMS techniques. Their activities on choline esterase enzymes and Beta-secretase 1 enzyme were elucidated through in vitro studies. Compound 4f had an IC50 = 0.026 ± 0.001 µ. value against the acetylcholinesterase (AChE) enzyme and an IC50 = 0.125 ± 0.005 µ. value against the BACE-1 enzyme. The excellent activity of compound 4f was supported by molecular docking and MD simulation studies.

Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines.

Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly. Subsequent post hoc analyses of clinical trial data alongside real-world evidence led to a paradigm shift. In 2013, the US HAE Association guidelines recommended that all attacks, irrespective of location or severity, be considered for treatment as early as possible after onset to minimize morbidity and mortality. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance.

Exploring New Structures of Kinase Inhibitors and Multitarget Strategies in Alzheimer's Disease Treatment

Alzheimer's disease (AD) treatments currently available have ineffective results. Previously employed Acetylcholine esterase inhibitors and memantine, an NMDA receptor antagonist, target a single target structure that plays a complex role in the multifactorial progression of disease. Memantine moderates the toxic effects of excessive glutamate activity by blocking NMDA receptors, which decreases neurotoxicity in AD, while acetylcholine esterase inhibitors function by blocking cholinergic receptors (muscarinic and nicotinic), preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission, thus improving cognitive functions in mild to moderate stages of AD. Every drug class targets a distinct facet of the intricate pathophysiology of AD, indicating the diverse strategy required to counteract the advancement of this neurodegenerative disorder. Thus, patients are currently not getting much benefit from current drugs. A closer look at the course of AD revealed several potential target structures for future drug discovery. AD drug development strategies focus on developing new target structures in addition to well-established ones for combination treatment regimens, ideally with a single drug that can target two different target structures. Because of their roles in AD progression pathways like pathologic tau protein phosphorylations as well as amyloid β toxicity, protein kinases have been identified as potential targets. This review will give a quick rundown of the first inhibitors of single protein kinases, such as glycogen synthase kinase (gsk3) β, along with cyclin-dependent kinase 5. We will also look into novel inhibitors that target recently identified protein kinases in Alzheimer's disease, such as dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Additionally, multitargeting inhibitors, which target multiple protein kinases as well as those thought to be involved in other processes related to AD will be discussed. This kind of multitargeting offers prospective hope for improved patient outcomes down the road since it is the most effective way to impede multifactorial disease development.

Study of Urinary Protein Biomarkers in Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease, and diagnosis is often missed or delayed. We aimed to identify noninvasive urinary protein biomarkers and to evaluate their potential roles in diagnosis and evaluation of disease severity. Using data-independent acquisition (DIA)-based urinary proteomics, we identified proteins that were differentially expressed between patients with HAE and healthy control (HC) groups. Then, the parallel reaction monitoring (PRM)-targeted proteomics method was used to validate promising biomarker candidates in other HAE patients and HCs. Furthermore, enzyme-linked immunosorbent assay (ELISA) was conducted to verify levels of several key proteins in HAE, histamine-mediated angioedema, and HCs. Differential expression between HAE patients and HCs was observed in 269 of the 2562 urinary proteins identified. In the biofunction analysis, these differentially expressed proteins were significantly enriched in leukocyte migration, adhesion of immune cells, endothelial cell development, permeability of the vascular system, and death of immune cells. Moreover, a biomarker panel (C1 esterase inhibitor, pro-epidermal growth factor, and kininogen-1) was validated in 2 independent clinical cohorts with area under the curve values of 0.910 and 0.949 for a diagnosis of HAE. Additionally, the urinary clusterin level was found to be significantly correlated with HAE severity scores (R=-0.758, P<.01). This study describes the first application of a DIA-PRM-ELISA workflow to identify noninvasive urine biomarkers of HAE. The results will contribute to our understanding of the pathogenesis of HAE and may also provide a potential alternative method for diagnosis and evaluation of disease severity.

Cell Wall Dynamics in the parasitic plant (Striga) and rice pathosystem.

In the plant-plant pathosystem of rice (Oryza sativa) and the parasitic plant Striga hermonthica, cell walls from either plant are important defensive and offensive structures. Here we reveal cell wall dynamics in both Striga and rice using simultaneous RNA sequencing. We used weighted gene co-expression network analysis (WGCNA) to home in on cell wall modification processes occurring in interactions with a resistant rice cultivar (Nipponbare) compared to a susceptible one (IAC 165). Likewise, we compared the cell wall dynamics in Striga infecting resistant and susceptible rice. Our study revealed an intense battlement at the Striga-rice cell walls involving both parasite (offense) and host (defense) factors; the outcome of which makes the difference between successful or failed parasitism. Striga activates genes encoding cell wall degrading enzymes (CWDEs) to gain access to the host; expansins to allow cell elongation and pectin methyl esterase inhibitors for rigidity during infection. In the susceptible host, immune response processes are not induced and Striga derived CWDEs easily breach the host cell wall resulting in successful parasitism. In contrast, the resistant host invokes immune responses modulated by phytohormones to fortify the cell wall through polysaccharides and lignin deposition. Through these processes, the cell wall of the resistant host successfully obstructs parasite entry. We discuss the implications of these findings in the context of practical agriculture in which cell wall modification can be used to manage parasitic plants.

Advances in the Pathogenesis of Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.

Validating and utilizing dried blood spots for family screening: Screening Programme Providing Outreach for Testing Hereditary Angioedema (SPPOT-HAE).

Hereditary angioedema (HAE) is a rare genetic disorder with potentially life-threatening consequences, traditionally diagnosed by conventional laboratory methods that can be resource intensive and inconvenient. Incorporating dried blood spot (DBS) tests may be a promising alternative for diagnosing HAE and family screening. This study aimed to validate DBS with conventional laboratory assays among confirmed C1 esterase inhibitor (C1-INH) HAE patients and assess the utility of DBS in a Screening Programme Providing Outreach for Testing Hereditary Angioedema (SPPOT-HAE). In part 1, 16 Chinese C1-INH-HAE patients from 7 families participated in the validation of DBS for detecting C4, C1-INH, and functional C1-INH (fC1-INH). The results were compared with conventional laboratory assays. In part 2, DBS was utilized in family screening for HAE in a large Chinese family with relatives previously refusing testing. The study found strong correlation between conventional assays and DBS in measuring C4 (r= 0.870, P< .0001), C1-INH (r= 0.978, P< .0001), and fC1-INH (r= 0.756, P< .0001). There were no false-negative results from the DBS for C4, C1-INH or fC1-INH. SPPOT-HAE successfully recruited 9 additional relatives for family screening, of whom 22% were confirmed to have HAE. The use of DBS in an outreach program overcame barriers of prior family screening initiatives. This is the first study to validate measurement of fC1-INH using DBS in C1-INH-HAE with conventional assays. An outreach program using DBS is a promising strategy overcoming previous barriers of family screening. Further large-scale, multicenter studies are required to establish the role of DBS, compare cost-effectiveness with prior strategies, and maximize diagnosis in resource-constrained countries.

Functionalized Graphene Quantum Dots as an Eco-Friendly Fluorescent Probe for Galantamine Analysis: Greenness Evaluation With Application to Pharmacokinetics Monitoring.

In this study, the use of functionalized graphene quantum dots (GQDs) as a fluorescent probe has been investigated for the quantitative determination of galantamine, a choline esterase inhibitor used for the treatment of Alzheimer's disease. The GQDs exhibit a significant quenching in their fluorescence intensity upon interaction with galantamine allowing for sensitive and selective detection of the drug. This quenching process follows a dynamic pattern with a linear relationship between fluorescence intensity and the concentration of galantamine. Several factors affecting the quenching process were investigated and optimized, including the concentration of GQDs, the pH of the solution, and the incubation time. The proposed probe exhibited excellent analytical performance with a linear range of 10-500 ng/mL, a limit of detection of 15 ng/mL, accuracy of 100.78 ± 0.698%, and intraday and interday precision of 0.742 and 1.369%, respectively. Furthermore, the GQDs-based sensor exhibited good selectivity towards galantamine in the presence of potentially interfering substances. Another advantage of the GQDs-based sensor is its greenness evaluation, as it offers a more environmentally friendly alternative compared to traditional methods. In addition, the GQDs-based sensor was successfully applied to analyze galantamine in pharmaceutical samples and invivo samples, demonstrating its potential for pharmacokinetics monitoring.

Clinical Utility and Safety of an Ultrasonic Head Stimulator in Dementia With Lewy Bodies.

The potential of Ultra-Ma, an ultrasonic head stimulator, for the supplementary treatment of dementia with Lewy bodies (DLB) was evaluated in patients with various symptoms under poor control by drug therapy. Patients with DLB treated with choline esterase inhibitor or L-DOPA, either alone or in combination, and who met inclusion criteria were enrolled. Four weeks of placebo stimulation was followed by 8 weeks of active ultrasonic stimulation and a 4-week follow-up. Primary endpoints were the effects of ultrasonic head stimulation on both cognitive dysfunction and behavioral and psychological symptoms of dementia (BPSD). Cognitive dysfunction was evaluated using the Japanese versions of the Mini-Mental State Examination and Montreal Cognitive Assessment, and BPSD was assessed using the Neuropsychiatric Inventory Brief Questionnaire Form. For cognitive fluctuations, the Cognitive Fluctuation Inventory served as an index. Improvements in parkinsonism, activities of daily living, and caregiver burden were examined as secondary endpoints. Twelve patients were enrolled. The primary endpoint was significantly improved during the active stimulation period, as were secondary endpoint ratings for parkinsonism and caregiver burden. No notable adverse events occurred. The findings suggest that ultrasonic head stimulation has supplementary potential when combined with drug treatment in DLB.

Managing Hereditary Angioedema in a Three-Generation Family: Danazol's Promise in Resource-Limited Settings.

Background Hereditary angioedema (HAE) is a rare disorder in India, and while prevalence data is limited, it is believed that a significant number of individuals may be affected. Due to restricted access to first-line treatments, older therapies like danazol are commonly used despite associated risks in resource-constrained settings. This study aimed to assess the efficacy of danazol as an affordable long-term prophylaxis (LTP) for HAE in a three-generation family. Methods In this retrospective study, we analyzed demographic and clinical data from 22 HAE patients within a three-generation family, assessing serum C4 and C1 esterase inhibitor levels to confirm diagnosis. Patients were treated with danazol for LTP, and the effectiveness of treatment was evaluated using the angioedema control test (AECT), alongside monitoring for adverse effects. A paired-sample t-test was used to compare AECT scores before and after treatment. Results The participants had a mean age of 33.5 years and a male predominance (63.63%). The mean age of symptom onset was 20.4 years, and six died due to laryngeal edema episodes. Nearly all patients exhibited low serum C1-INH levels, confirming the diagnosis. Among the nine patients treated with danazol for LTP, AECT scores significantly improved from a mean of 7.9 to 9.8 (p = 0.003), with 90% experiencing reduced attack frequency. Mild adverse effects, such as weight gain and menstrual irregularities, were observed in 44.4% of treated patients. Conclusions This retrospective study demonstrated that danazol reduced attack frequency and severity in HAE patients in a resource-limited setting, with mild adverse effects observed in some individuals. While these findings support danazol as a cost-effective option for managing HAE, the results should be interpreted with caution due to the study's design limitations. The AECT proves to be a useful tool for evaluating the control of angioedema attacks. Because the risk of adverse effects is high, close monitoring of patients is mandatory. However, many patients accept the adverse effects of prophylactic treatment to avoid the distressing and sometimes life-threatening attacks of this condition. Regular monitoring remains essential to mitigate adverse effects, and prospective clinical trials are necessary to further validate the efficacy and safety of danazol for LTP.

Inheritance and Resistance Mechanisms of Field-Evolved Resistance to Pyrethroids in a Fall Armyworm (Spodoptera frugiperda J.E. Smith) (Lepidoptera: Noctuidae) Strain from Puerto Rico.

This study examines resistance inheritance to the pyrethroid insecticides esfenvalerate and deltamethrin in a Puerto Rican strain of fall armyworm (FAW), Spodoptera frugiperda, a major global pest of corn. The resistant strain (PPR) showed significantly higher resistance compared to a susceptible strain (SUS), with a 62-fold X-linked and 15-fold autosomal-linked resistance ratio (RR50) for esfenvalerate and deltamethrin, respectively. Resistance was incompletely dominant for both insecticides. Synergist bioassays revealed that detoxification enzymes play a key role in resistance, with PPR exhibiting increased toxicity across all tested synergists, especially with a 12-fold increase when all were combined. Deltamethrin assays confirmed the importance of these enzymes, with a 17-fold increase in PPR toxicity when combined with esterase inhibitors. These findings highlight the complexity of pyrethroid resistance, involving multiple non-target site mechanisms, and suggest that heterozygous individuals could survive in treated crops due to incomplete dominance. The results emphasize the need for diversified pest management strategies, including insecticide rotation, to effectively control FAW populations.

Patterns of C1-Inhibitor Plasma Levels and Kinin-Kallikrein System Activation in Relation to COVID-19 Severity.

Although more than four years have passed since the pandemic began, SARS-CoV-2 continues to be of concern. Therefore, research into the underlying mechanisms that contribute to the development of the disease, especially in more severe forms, remains a priority. Sustained activation of the complement (CS), contact (CAS), and fibrinolytic and kinin-kallikrein systems (KKS) has been shown to play a central role in the pathogenesis of the disease. Since the C1 esterase inhibitor (C1-INH) is a potent inhibitor of all these systems, its role in the disease has been investigated, but some issues remained unresolved. We evaluated the impact of C1-INH and KKS on disease progression in a cohort of 45 COVID-19 patients divided into groups according to disease severity. We measured plasma levels of total and functional C1-INH and its complexes with kallikrein (PKa), reflecting KKS activation and kallikrein spontaneous activity. We observed increased total and functional plasma concentrations of C1-INH in COVID-19 patients. A direct correlation (positive Spearman's r) was observed between C1-INH levels, especially functional C1-INH, and the severity of the disease. Moreover, a significant reduction in the ratio of functional over total C1-INH was evident in patients exhibiting mild to intermediate clinical severity but not in critically ill patients. Accordingly, activation of the KKS, assessed as an increase in PKa:C1-INH complexes, was explicitly observed in the mild categories. Our study's findings on the consumption of C1-INH and the activation of the KKS in the less severe stages of COVID-19 but not in the critical stage suggest a potential role for C1-INH in containing disease severity. These results underscore the importance of C1-INH in the early phases of the disease and its potential implications in COVID-19 progression and/or long-term effects.

Association between coagulation activity and clinical and imaging outcomes in acute ischemic stroke patients - A sub-study of the MR CLEAN NO-IV trial

BackgroundThe MR CLEAN NO-IV trial showed neither superiority nor noninferiority of endovascular treatment (EVT) alone compared to intravenous thrombolysis (IVT; Alteplase) before EVT in acute ischemic stroke (AIS) patients with large vessel occlusion of the anterior circulation. Although the treatment effect is largely attributable to EVT, IVT may affect hypercoagulability during AIS. AimsTo investigate the association between activated coagulation and final infarct volume and clinical outcomes (modified Rankin Scale 3–6 and mortality 90 days post-EVT), and whether this effect is modified by IVT administration. MethodsEnzyme-linked immunosorbent assays were used to quantify activated coagulation markers (activated coagulation factor (F) XIIa-C1 esterase inhibitor (C1inh); FXIIa-antithrombin (AT), FXIa-C1inh, FXIa-AT, FIXa-AT, FXa-AT, T-AT, FVIIa-AT) in plasma samples obtained on admission (T0), 1 h post-EVT (T1) and 24 h post-EVT (T2). Multivariable regressions were performed to investigate the associations and effect modification. ResultsIn the total cohort of 116 patients, a significant increase at T1 was seen in FIXa-AT (p = .001), FXa-AT (p < .001), T-AT (p < .001), and FVIIa-AT (p = .012), while there was a significant increase at T2 in FXIIa-C1inh (p < .001). Similar results were seen in the IVT+EVT subgroup. The EVT alone subgroup showed a significant temporary increase at T1 in FXa-AT (p < .001) and T-AT (p = .014). Neither the enzyme:inhibitor complexes nor the interaction with IVT were significantly associated with the outcome measures. ConclusionDespite temporary significant increases in enzyme:inhibitor complexes in the IVT+EVT group, but not in the EVT alone group, there were no significant associations with final infarct volume and clinical outcomes.

A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors.

The kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders. Here, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors. The model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production. Our mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation. The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.

De-Methyl Esterification Modification of Root Pectin Mediates Cd Accumulation of Lactuca sativa.

Cadmium (Cd) contamination in agricultural soil brings severe health risks through the dietary intake of Cd-polluted crops. The comprehensive role of pectin in lowering Cd accumulation is investigated through low Cd accumulated (L) and high Cd accumulated (H) cultivars of L. sativa. The significantly different Cd contents in the edible parts of two L. sativa cultivars are accomplished by different Cd transportations. The pectin is the dominant responsive cell wall component according to significantly increased uronic acid contents and the differential Cd absorption between unmodified and modified cell wall. The chemical structure characterization revealed the decreased methyl esterification in pectin under Cd treatment compared with control. Significantly brighter LM19 relative fluorescence density and 40.82% decreased methanol in the root pectin of L cultivar under Cd treatment (p < 0.05) supported that the de-methyl esterification of root pectin is more significant in L cultivar than in H cultivar. The pectin de-methyl esterification of L cultivar is achieved by the upregulation of pectin esterases and the downregulation of pectin esterase inhibitors under Cd treatments, which has facilitated the higher Cd-binding of pectin. Our findings provide deep insight into the differential Cd accumulation of L. sativa cultivars and contribute to the understanding the pollutant behaviors in plants.

Comparative Post-Marketing Surveillance of Memantine and Cholinesterase Inhibitors: Cardiovascular Adverse Events With a Focus on Sex Differences Using the FDA Adverse Event Reporting System Database.

The aim of this study was to conduct a comparative analysis of the proportion of cardiovascular adverse events (AEs) associated with the utilization of memantine and cholinesterase inhibitors and to highlight the potential impact of sex differences in these AEs. Cardiac and vascular disorders AEs with antidementia medications were obtained from the FDA Adverse Event Reporting System database. The reporting odds ratio and its corresponding 95% confidence intervals were calculated. The chi-squared test was used to evaluate differences in categorical variables, and a two-way ANOVA followed by a Bonferroni post-test was used to compare the AEs reported for antidementia medications. Memantine was associated with 544 selected cardiac and vascular disorder AEs. A signal for bradycardia, myocardial infarction, atrial fibrillation and cardiac arrest has been observed in patients receiving choline esterase inhibitors compared to those receiving memantine. On the other hand, cardiac failure and deep vein thrombosis AEs were found to be more common in patients receiving memantine. The majority of reported cardiac and vascular AEs were reported more frequently in female patients. More cases of cardiac failure, cardiac arrest, and deep vein thrombosis were reported in females than males taking memantine, but bradycardia was more common in males than females. Healthcare professionals should be aware of the potential for cardiovascular AEs during treatment with antidementia medications and the possibility of sex differences in this regard. Memantine differs from cholinesterase inhibitors in terms of cardiovascular AEs, and there may be sex-related differences in the proportion of these AEs.

A QTL on chromosome 17 identified by Genome-Wide Association Mapping controls postharvest cold tolerance of Cucurbita pepo L.

The worldwide cultivated Cucurbita pepo L. is one of the most diverse species in the plant kingdom. In this study, chilling tolerance over a wide range of cultivars was characterized to discover the allelic variants to improving the postharvest quality of the immature fruit during cold storage. For this purpose, fruits from 126 accessions of worldwide origin have been evaluated for weight loss and chilling injury after 3, 7 and 14 days of cold storage, classifying them into tolerant, partially tolerant, and sensitive accessions. To verify this classification, antioxidant capacity and lipid peroxidation (MDA) of contrasting accessions (tolerant vs. sensitive) were assessed. The antioxidant capacity significantly decreased during cold storage in the sensitive accessions, while it was maintained in tolerant accessions. Additionally, the sensitive accessions presented a higher accumulation of MDA during this period. Finally, a GWAS analysis using GBS data available in CuGenDBv2, combined with weight loss percentage data, led to the identification of a candidate QTL located on chromosome 17 that regulates postharvest cold tolerance in zucchini. The region contains four SNPs whose alternative alleles were significantly associated with lower weight loss percentage and chilling injury indices during cold storage. Two SNPs are located in the 3' UTR region of the gene CpERS1, a gene involved in ethylene perception. The other two SNPs generate missense mutations in the coding region of a Pectin methyl esterase inhibitor gene (CpPMI). The role of this QTL and these variants in chilling tolerance is discussed.

Study the effect of Convolvulus pilosellifolius Desr. as antialzheimer and identification of its active compounds

The phenolic pattern of the plant using chromatographic and spectroscopic methods. Three flavonoid and two phenolic compounds were isolated for first time from the alcoholic plant extract which identified as; Quercetin-3’-galactoside, Quercetin-7-glucoside, Quercetin −3-glucoside and two phenolic compounds identified as Methyl-trans-dihydroxy cinnamic acid and Methyl-cis-dihydroxy cinnamic acid, they were isolated and purified using classical and modern chromatographic methods; (PC, TLC, CC and HPLC); identified by Rf, UV,1H NMR,13C NMR and 2D NMR (HMQC) spectroscopy. The activity of total alcoholic extract of Convolvulus pilosellifolius as antialzheimer was investigated concerning its activity as acetylcholine esterase inhibitor. The recorded IC50 was 0.391 and 0.131 µg/mL for the extract and donepezil respectively. The activity of isolated compounds as acetylcholine esterase inhibitor were evaluated by Autodock Vina software to perform the docking protocol. This revealed that the most active compound was Quercetin-3Ì· galactoside.

In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge. Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites. The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives. The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

Omics analysis reveals galectin-3 to be a potential key regulator of allergic inflammation in hereditary angioedema

Hereditary angioedema (HAE) is a rare inherited disorder that predisposes an individual to develop vasogenic edema. Bradykinin release, which increases vascular permeability, results in angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes involved in bradykinin generation and mutations in genes that encode the C1 inhibitor of complement factor 1, which prevent its synthesis (type I HAE), form a dysfunctional protein (type II HAE), or have normal functioning C1-INH (type III HAE, aka HAE-III). The goals of this study were to use a systems biology analysis to identify novel biomarkers to aid in the diagnosis of HAE-III and to elucidate its underlying pathogenic mechanisms. Blood samples were obtained from HAE-III subjects and age- and sex-matched healthy controls. DNA, RNA, and protein purified from the samples were subjected to multiomics analysis using a 1-shot liquid chromatography-mass spectrometry-based multiomics platform (Omni-MS, Dalton Bioanalytics) to profile proteins, lipids, electrolytes, and metabolites enabling concurrent analysis of diverse analyte classes. A total of 1647 novel identifications that included genes, proteins, and metabolites were made when comparing HAE-III samples to control samples. Our identification library included MSFragger for protein identification, LipiDex for lipid identification, and Compound Discoverer for metabolite identification, enabling differential expression analysis. Key findings included a significant increase in the expression levels of galectin-3, lysosomal α-glucosidase, platelet factor 4, and platelet-derived growth factor subunit Ain HAE-III subjects compared to controls, all of which generate an immunomodulatory response. Galectin-3 plays a critical role in eosinophil recruitment and airway allergic inflammation. It may contribute to chronic inflammation and fibrosis resulting in leaky vasculature, and it could be a potential therapeutic target in HAE-III.