Current Medicinal Chemistry - Online First

The incidence of psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety, and depression, has been steadily increasing, while current treatment approaches remain limited in efficacy. As a result, there is an urgent need to explore more effective therapeutic interventions. In recent years, MDMA (3,4-methylenedioxymethamphetamine)-assisted therapy (MDMA-AT) has emerged as a promising and innovative approach, demonstrating favorable clinical potential in the treatment of these disorders. Although preliminary studies have confirmed its therapeutic efficacy, a comprehensive and systematic analysis of the research trends and current limitations of MDMA-AT remains lacking.

This study employed a bibliometric approach to systematically retrieve and analyze research literature published between 1994 and 2023 on the application of MDMA in the treatment of PTSD, anxiety, and depression. Relevant data were obtained from three prominent databases: Web of Science Core Collection, PubMed, and Scopus. VOSviewer and Microsoft Excel were used to perform visual and quantitative analyses, focusing on publication trends, research hotspots, prolific authors, leading institutions, and international collaboration networks.

The findings indicated a substantial increase in MDMA-related research over the past decade. The United States has led the field in publication output, with the Multidisciplinary Association for Psychedelic Studies (MAPS) identified as the most productive institution. Key figures, such as Rick Doblin, have demonstrated high influence and centrality within the global research network. The research focus has gradually shifted from investigations of the neurotoxic properties of MDMA to explorations of its therapeutic mechanisms, safety profiles, and clinical applications.

This study provides a comprehensive synthesis of the past thirty years of research on MDMA-AT in the treatment of PTSD, anxiety, and depression, identifying major research trajectories and critical challenges in the field. While current findings highlight the therapeutic promise of MDMA and its translational potential, further research is needed to improve trial design, enhance sample diversity, and evaluate long-term effects in order to support the standardization and evidence-based integration of MDMA-assisted therapy into clinical practice.

Fructose, like other sugars and sugar metabolites, is capable of glycating protein. Insulin's fructosylation leads to the generation of Advanced Glycation End Products (AGEs). Reducing sugars reaction with proteins to form Schiff’s bases, which are characterized by the presence of an imine (C=N) bond. The Schiff bases then undergo irreversible rearrangements, followed by the production of much more stable compounds called Amadori products. These Amadori products can further undergo oxidation, dehydration, cyclization, and condensation to form highly toxic advanced glycation end-products (AGEs). These processes are accompanied by oxidative stress, secondary structural perturbations, and altered morphology, progressing toward amyloidogenesis. Metformin, a biguanide, is the most common drug used to treat type 2 Diabetes Mellitus (T2DM).

The aim of this study was to evaluate the protective effect of metformin against fructosylation-induced cross-β structures and amyloid aggregations of human insulin.

UV-absorbance and fluorescence spectroscopy, determination of carbonyl content, free lysine and arginine residues, determination of fructosamine content, SDS-PAGE, circular dichroism (CD) spectroscopy, dynamic light scattering, and scanning and transmission electron microscopy.

Physicochemical studies in the presence or absence of metformin revealed a concentration-dependent structural restoration of fructosylated insulin. Results from the thioflavin-T fluorescence assay suggested that metformin limited the transition of insulin from native to fibrillar state, which was validated by scanning and transmission electron microscopy. Metformin lowered the ThT fluorescence intensity in a concentration-dependent manner. The ThT-specific fluorescence intensity was reduced to 114 and 112.5%. The fluorescence intensity at 2.5 mM metformin was close to native insulin. Electron microscopy revealed that insulin fructosylated by 25 mM fructose in the presence of 2.5 mM metformin suppressed the formation of fibrillar structures. Dynamic light scattering data revealed the potential of metformin to conserve and reinstate the increased hydrodynamic radii (Rh) of fructosylated insulin close to the native conformer. The Rh values of native, fructosylated insulin and insulin incubated with fructose and metformin were found to be 2.65 ± 0.28, 307.6 ± 24.19 nm, and 110.1 ± 4.08 nm, respectively. This study also identified metformin as an antioxidant by protecting critical amino acid residues of the insulin domain.

The study reports the protective effects of metformin on insulin structure, conformation, and function. The findings suggest a potential role for metformin in improving the risk profile associated with insulin resistance due to altered structure or the accumulation of protein aggregates. Interaction studies between insulin and metformin presented here are due to the chemical effect; hence, further in-depth studies are required to identify the molecular mechanism of insulin sensitivity and changes in cellular processes and pathways.

The results suggest that metformin safeguards against fructosylation-induced structural, conformational, morphological, and amyloidogenic aggregating tendencies of insulin. Protein aggregation has been linked to several neurological and metabolic diseases. Hence, metformin may be crucial in preserving the biological activity of insulin by maintaining and protecting its structural integrity and minimizing the associated comorbidities. The study may further be extended to identify the role of metformin in controlling the gradual insulin resistance in T2DM at the molecular level.

Negative emotional states, such as nervousness, anxiety, depression, and tension, exert profound detrimental effects on an individual's quality of life and overall health. Although certain widely prescribed medications have been observed to modulate these emotional states, the existing body of research in this domain remains insufficient. To address this gap, Mendelian randomization (MR) methodologies, leveraging large-scale datasets, were employed to investigate the causal relationships between 21 commonly utilized medications and the manifestation of negative emotions.

The inverse variance weighting (IVW) method was employed as the primary analytical strategy to analyze causal relationships. MR-Egger, weighted mode, and weighted median approaches were utilized to enhance the robustness of the results. Sensitivity analyses were conducted to assess the stability of the data.

Agents acting on the renin-angiotensin system, β-blocking agents, antithrombotic agents, and salicylic acid and derivatives could reduce the risk of nervousness, anxiety, tension, or depression (OR = 0.61, 95% CI 0.37 to 0.99, p = 0.047; OR = 0.59, 95% CI 0.36 to 0.98, p = 0.041; OR = 0.55, 95% CI 0.34 to 0.88, p = 0.013; OR = 0.61, 95% CI 0.40 to 0.95, p = 0.030), with no heterogeneity, horizontal pleiotropy, or reverse causation (p > 0.05).

This study revealed four medications associated with reducing the risk of negative emotions, providing clinicians with a scientific basis for medication selection to better assist patients in alleviating psychological issues and improving their quality of life.

Highly sensitive, accurate, and low-cost detection systems are gaining interest for early intervention in the progression of Alzheimer's disease (AD). Amyloid-beta (Aβ), a peptide highly involved in the progression of AD, is found in abundance in patients with severe AD.

This research focused on developing an Aβ oligomer (AβO) biosensor using a single-walled carbon nanotube-modified (SWCN) interdigitated electrode (IDE) sensor.

The SWCN was functionalized onto the sensor surface through an amine linker, followed by the attachment of an aptamer-gold nanoparticle (GNP) complex, which was used to capture the AβO.

The GNP-aptamer was saturated at 500 nM on the SWCN surface, and AβO was detected using a sandwich consisting of aptamer-AβO-antibody. The SWCN modification increased the number of aptamer attachment sites on the IDE, while the aptamer and antibody conjugation with GNP enhanced AβO interaction. This sandwich assay detected AβO at concentrations as low as 10 fM, with a linear regression coefficient (y = 2.9189x - 2.076; R² = 0.9544). Furthermore, AβO-spiked artificial CSF was detected without interference, as confirmed by the increased current responses. No significant changes were recorded with control proteins, including α-synuclein, IgG antibody, and a complementary aptamer, indicating specific AβO detection.

This SWCN modified IDE-based sandwich detects AβO at its lower level and contributes to the early diagnosis of AD.

Anophthalmia/microphthalmia (A/M) and anterior segment dysgenesis (ASD) are severe ocular anomalies impacting eye morphology, occurring in 30 per 100,000 live births. Genetic research has identified over 30 genes linked to A/M anomalies, with their products mainly involved in eye organogenesis.

This study examined two consanguineous A/M families to identify disease-associated pathogenic mutations and predict their functional impact.

Patients were clinically examined using A-scan and ophthalmic ultrasonography. Whole exome sequencing (WES) identified candidate pathogenic variants validated through Sanger sequencing. Computational analyses assessed the impact of these mutations on protein structure and function.

The clinical diagnosis of family A revealed microphthalmia with ASD, while family B presented with an A/M phenotype. Exome analysis of family A identified a novel missense variant, NM_012293:c.A3742G [p.(Arg1248Gly)], in the peroxidasin (PXDN) gene (ClinVar ID: VCV001333267.1). At the cellular level, PXDN is involved in establishing sulfilimine bonds in collagen IV, a component of the basement membrane, suggesting that ocular defects may result from impaired integrity of the basement membrane in the developing eye. In contrast, Family B exhibited a nonsense variant NM _012186:c.720C>A (p.Cys240*) in the FOXE3 gene. This variant has been previously reported in other South Asian populations, suggesting a founder effect in subcontinent populations. Structural modeling and simulation analysis of mutant proteins revealed altered properties, thus corroborating the pathogenicity of the identified mutation.

Our findings may contribute to the elucidation of genotype-phenotype correlations, potentially facilitating the molecular diagnosis of microphthalmia and ASD.