Search Results (332)

Coumarin derivatives, whether natural or synthetic, have attracted considerable interest from medicinal chemists due to their versatile biological properties. Their appealing pharmacological activities—such as anticancer, anti-inflammatory, neuroprotective, anticoagulant, and antioxidant effects—combined with the ease of their synthesis and the ability to introduce chemical modifications at multiple positions have made them a widely explored class of compounds. In the scientific literature, there are many examples. On the other hand, dithiocarbamates, originally employed as pesticides and fungicides in agriculture, have recently emerged as potential therapeutic agents for the treatment of serious diseases such as cancer and microbial infections. Moreover, dithiocarbamates bearing diverse organic functionalities have demonstrated significant antifungal properties against resistant phytopathogenic fungi, presenting a promising approach to combat the growing global issue of fungal resistance. Dithiocarbamates linked to coumarin derivatives have been shown to exhibit cytotoxic activity against various human cancer cell lines, including MGC-803 (gastric), MCF-7 (breast), PC-3 (prostate), EC-109 (esophageal), H460 (non-small cell lung), HCCLM-7 (hepatocellular carcinoma), HeLa (cervical carcinoma), MDA-MB-435S (mammary adenocarcinoma), SW480 (colon carcinoma), and Hep-2 (laryngeal carcinoma). Numerous studies have revealed that the inclusion of a dithiocarbamate moiety can provide central nervous system (CNS) activity, particularly through inhibitory potency and selectivity toward acetylcholinesterase (AChE) and monoamine oxidases (MAO-A and MAO-B). Recently, it has been reported that coumarin–dithiocarbamate derivatives exhibit α-glucosidase inhibitory effects and also possess promising antimicrobial activity. This study presents an overview of recent progress in the chemistry of coumarin–dithiocarbamate derivatives, with a focus on their biological activity. Previous review papers focused on coumarin derivatives as multitarget compounds for neurodegenerative diseases and described various types of compounds, with dithiocarbamate derivatives representing only a small part of them. Our work deals exclusively with coumarin dithiocarbamates and their biological activity. Full article

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article

It has been shown previously that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior, with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main neurotransmitter events in some brain regions of aggressive male mice. Fighting deprivation (a no-fight period of 2 weeks) causes a significant increase in their aggressiveness. This paper is aimed at studying—after a period of fighting deprivation—the involvement of genes (associated with neurotransmitter systems within the nucleus accumbens) in the above phenomena. The nucleus accumbens is known to participate in reward-related mechanisms of aggression. We found the following differentially expressed genes (DEGs), whose expression significantly differed from that in controls and/or mice with positive fighting experience in daily agonistic interactions followed by fighting deprivation: catecholaminergic genes Th, Drd1, Drd2, Adra2c, Ppp1r1b, and Maoa; serotonergic genes Maoa, Htr1a, Htr1f, and Htr3a; opioidergic genes Oprk1, Pdyn, and Penk; and glutamatergic genes Grid1, Grik4, Grik5, Grin3a, Grm2, Grm5, Grm7, and Gad1. The expression of DEGs encoding proteins of the GABAergic system in experienced aggressive male mice mostly returned to control levels after fighting deprivation, except for Gabra5. In light of the conceptual paradigm for analyzing data that was chosen in our study, the aforementioned DEGs associated with the behavioral pathology can be considered responsible for consequences of aggression followed by fighting deprivation, including mechanisms of an aggression relapse. Full article

Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved compared to those of single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including “benzimidazole”, “pyrimidine”, “Biginelli”, “benzimidazole-pyrimidine hybrids”, “anticancer”, “antiviral”, “antimicrobial”, and “anti-inflammatory”. Results: In this review, benzimidazole–pyrimidine hybrids are reported as anticancer, antimicrobial, antiviral, anti-inflammatory, analgesic, antiulcer, antidepressant, anti-Alzheimer’s, or antioxidant agents, with activities even better than those of existing drugs. The IC₅₀ values for these anticancer hybrids are in the nanomolar range, which signifies potent anticancer agents. It can be mentioned here that the anticancer hybrid Abemaciclib, as a CDK4/6 inhibitor for the treatment of certain types of breast cancer, was approved in 2017. The antimicrobial activity of these hybrids proved especially potent against a broad variety of infections, with MIC values in the range of µM or even nM. Moreover, these hybrids exhibited good antiviral properties against SARS-CoV-2, HIV-1, and the hepatitis C virus. The hybrids also functioned as JAK3 inhibitors, COX-1 inhibitors, and MAO-A inhibitors. Conclusions: This review presents synthesis methods of benzimidazole–pyrimidine hybrids, their medicinal properties, and SAR studies reported in the last 20 years. For almost every therapeutic activity, SAR studies have revealed the essential presence of a substituent on the aromatic rings or between the two benzimidazole and pyrimidine nuclei. Full article

Isoliquiritigenin (ISL) is a type of chalcone that widely exists in medicinal plants of the Leguminosae family and exhibits a remarkable anti-ischemic stroke (IS) effect. However, the anti-IS mechanisms of ISL remain to be systematically elucidated. In this study, network pharmacology was used to predict potential targets related to the anti-IS effect of ISL. The binding ability of ISL to potential core targets was further analyzed by molecular docking and molecular dynamics (MD) simulations. By establishing an oxygen–glucose deprivation/reoxygenation (OGD/R)-induced HT22 cell model, the anti-IS mechanisms of ISL were investigated via RT-qPCR and Western Blot (WB). As a result, network pharmacology analysis revealed that APP, ESR1, MAO-A, PTGS2, and EGFR may be potential core targets of ISL for anti-IS treatment. Molecular docking and molecular dynamics simulation results revealed that ISL can stably bind to the five potential core targets and form stable complex systems with them. The results of the cell experiments revealed a significant anti-IS effect of ISL. Additionally, mRNA and protein expression levels of APP, MAO-A and PTGS2 or ESR1 in the ISL treatment group were significantly lower or higher than those in the OGD/R group In conclusion, ISL may improve IS by regulating the protein expression levels of APP, ESR1, MAO-A, and PTGS2. Full article

Heavy metals are a major toxicological concern due to their adverse effects on human health, particularly in children exposed to contaminated areas. This study evaluated biomarkers of exposure in 253 children aged 6 to 12 from Magangue, Achi, and Arjona (Bolivar, Colombia), analyzing their relationship with neurotoxicity and hematological markers. The mean Pb concentrations at the study sites were 1.98 µg/g (Magangue) > 1.51 µg/g (Achi) > 1.24 µg/g (Arjona). A similar pattern was observed for Cd concentrations for Magangue (0.39 µg/g) > Achi (0.36 µg/g) > Arjona (0.14 µg/g). In contrast, Se concentrations followed a different trend for Arjona (0.29 µg/g) > Magangue (0.21 µg/g) > Achi (0.16 µg/g). The proportion of Se/Pb molar ratios > 1 was higher in Arjona (3.8%) than in Magangue (0.9%) and Achi (2.0%). For Se/Cd ratios, values > 1 were also more frequent in Arjona (70.7%), exceeding 20% in the other two locations. Significant differences were found among locations in red and white blood cell parameters and platelet indices. Neurotransmitter-related biomarkers, including serotonin, monoamine oxidase A (MAO-A), and acetylcholinesterase levels, also varied by location. Principal component analysis showed that Pb and Cd had high loadings on the same component as PLT, WBC, and RDW, and while Se loaded together with HGB, PDW, MCHC, MCH, and MCV, suggesting distinct hematological patterns associated with each element. Multiple linear regression analysis demonstrated a statistically significant inverse association between hair Pb levels and serotonin concentrations. Although MAO-A and Cd showed negative β coefficients, these associations were not statistically significant after adjustment. These findings highlight the potential impact of toxic element exposure on key hematological and neurochemical parameters in children, suggesting early biological alterations that may compromise health and neurodevelopment. Full article

Some studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cyclization approach is applied to synthesize the basic hydrazine used for the formation of the designed series of hydrazones (15a–15g). The potential neurotoxic and neuroprotective effects of the newly synthesized derivatives were investigated in vitro using different models of induced oxidative stress at three subcellular levels (rat brain synaptosomes, mitochondria, and microsomes). The results identified as the least neurotoxic molecules, 15a, 15d, and 15f applied at a concentration of 100 µM to the isolated fractions. In addition, the highest statistically significant neuroprotection was observed for 15a and 15d at a concentration of 100 µM using three different injury models on subcellular fractions, including 6-hydroxydopamine in rat brain synaptosomes, tert-butyl hydroperoxide in brain mitochondria, and non-enzyme-induced lipid peroxidation in brain microsomes. The hMAOA/MAOB inhibitory activity of the new compounds was studied at a concentration of 1 µM. The lack of a statistically significant hMAOA inhibitory effect was observed for all tested compounds, except for 15f, which showed 40% inhibitory activity. The most prominent statistically significant hMAOB inhibitory effect was determined for 15a, 15d, and 15f, comparable to that of selegiline. The corresponding selectivity index defined 15f as a non-selective MAO inhibitor and all other new hydrazones as selective hMAOB inhibitors, with 15d indicating the highest selectivity index of >471. The most active and least toxic representative (15d) was evaluated in vivo on Rotenone based model of Parkinson’s disease. The results revealed no microscopically visible alterations in the ganglion and glial cells in the animals treated with rotenone in combination with 15d. Full article

Background: Constipation is a common gastrointestinal disorder with a significant impact on quality of life. Methods: Constipation was induced in male ICR mice via 25% cotrimoxazole gavage (20 mL/kg/day for 7 days). Mice were divided into prevention (pre-MBSFL), treatment (MBSFL), and control groups. MBSFL was prepared by fermenting mung bean starch with Lactobacillus plantarum (1:3 w/v ratio, 37 °C for 48 h), and administered via daily oral gavage (250 mg/kg bw) for 14 days. Fecal parameters (water content and first black stool latency), gastrointestinal motility (gastric emptying and small intestinal propulsion), serum biomarkers (NO, VIP, SP, and 5-HT), and intestinal gene expression (5HTR₄, SERT, and MAO_A) were analyzed. Results: MBSFL intervention restored fecal water content by 38%, reduced first black stool latency from 6.2 h to 3.1 h, and improved small intestinal propulsion by 64%. Additionally, it downregulated serum NO (25%) and VIP (32%) while upregulating SP (49%) and 5-HT (78%) levels. Intestinal 5HTR4 and SERT expression increased by 78% and 71%, respectively, with MAOA suppression (25%). Microbial analysis revealed a 140% increase in Dubosiella and 49% in Lactobacillus abundance, alongside a 62% reduction in Mucispirillum. MBSFL contained polysaccharides (12.3% w/w) and organic acids, including hydroxy butyric acid (4.2 mg/mL). Conclusions: MBSFL alleviates constipation through dual mechanisms: modulating 5-HT pathway activity and restoring gut microbiota homeostasis. Full article

Owing to the need for a brain supplement targeting neuroprotection against age-related brain disorders and the known effect of carotenoids on brain function, we aimed to assess the effect of consuming carotenoid-rich functional congee for 8 weeks on cognitive function and age-related serum biomarkers. Both males and females (60–70 years old) were randomly assigned to consume either placebo or carotenoid-rich functional congee containing dried tomato powder at doses of 200 and 400 mg per day. Cognitive function, working memory, and serum biomarkers including alpha-synuclein and PARK7, together with serum oxidative stress parameters and neurotransmitters, were assessed prior to consumption and every 4 weeks throughout the study period. The contents of Lactobacillus and Bifidobacterium spp. in feces were also determined. Both doses of carotenoid-enriched congee enhanced cognitive function (P300), but only low doses improved working memory and decreased the activity of MAO-A and serum alpha-synuclein. The high-dose congee-treated group exhibited an increase in the density of Lactobacillus spp. in feces. Taking all data together, the carotenoid-enriched congee enhances cognitive function and working memory. The mechanisms may partly involve the increase in monoaminergic function, while the modulation of the gut–brain axis may require further confirmation. Full article

The synthesis method of the Pr-doped CeO₂ catalyst support in Ni/Pr-CeO₂ CO₂ methanation catalysts is varied by changing the type/basicity of the precipitating solution and the hydrothermal treatment temperature. The use of highly basic NaOH as the precipitating agent and elevated hydrothermal treatment temperature (100 or 180 °C) leads to the formation of structured Pr-doped CeO₂ nanorods and nanocubes, respectively, whereas the use of a mildly basic NH₃-based buffer in the absence of hydrothermal treatment (i.e., co-precipitation) leads to an unstructured mesoporous morphology with medium-sized supported Ni nanoparticles. The latter catalyst (Ni/CP_NH3) displays a high surface area, high population of moderately strong basic sites, high oxygen vacancy population, and favorable Ni dispersion. These properties lead to a higher catalytic activity for CO₂ methanation (75% CO₂ conversion and 99% CH₄ selectivity at 350 °C) compared to the catalysts with structured nanorod and nanocube support morphologies, which are found to contain a significant amount of leftover Na from the synthesis procedure that can act as a catalyst inhibitor. In addition, the best-performing Ni/CP_NH3 catalyst is shown to be highly stable, with minimal deactivation during time-on-stream operation. Full article

Background/Objectives: Kyphoplasty and vertebroplasty are minimally invasive approaches for spinal fractures aiming to reduce pain, increase mobilization, and prevent further vertebral height loss. Their efficacy in treating burst fractures has been questioned due to fragment mobility and concerns for cement leakage. We aim to report outcomes in patients who underwent kyphoplasty for spinal burst fractures. Methods: We conducted a retrospective review of patients with burst fractures treated from 2018 to 2023. Those who underwent kyphoplasty or vertebroplasty and had follow-up imaging were included. Clinical characteristics and follow-up outcomes were obtained through chart review. The primary outcome was the need for surgical intervention after kyphoplasty. Results: We identified ten patients (mean age 67.9 years, range 36–93 years) with burst fractures who underwent kyphoplasty/vertebroplasty. Six received kyphoplasty/vertebroplasty within 1 week of injury and four between 1 and 4 months post-injury. Nine patients had a TLICS score of 2, and one had a TLICS score of 5. Kyphoplasty/vertebroplasty was performed for pain management in seven patients and significant/worsening vertebral height loss in three patients. At follow-up, 70% of patients reported an improvement in pain and 75% of patients reported improved mobility. One patient experienced progression of an L2 burst fracture but improved with conservative management. No patient required additional surgical fixation. Conclusions: In this series of ten patients with spinal burst fractures, standalone kyphoplasty was a safe and effective treatment. Our findings suggest kyphoplasty may be a viable treatment option for select spinal traumatic burst fractures, offering potential pain relief and mobility improvement in the short term. Full article

Epigenetic modifications play a crucial role in gene regulation and have been implicated in various physiological processes and disease conditions. DNA methylation (DNAm) has been implicated in the etiology and progression of many stress-related psychiatric behaviors, such as depression. The ability to manipulate DNAm may provide a means to reverse and treat such disorders. Although CRISPR-based technologies have enabled locus-specific DNAm editing, their clinical applicability may be limited due to immunogenicity concerns and off-target effects. In this study, we introduce a novel approach for targeted DNAm manipulation using single-stranded methylated DNA probes. The probes were designed against the GRE of FKBP5 and the promoter region of MAOA. In both human embryonic kidney HEK293 and mouse pituitary AtT-20 cells, transfection with their respective methylated probes significantly increased DNAm at targeted CpG sites in a persistent and dose-dependent manner. Importantly, the induced methylation effectively attenuated glucocorticoid-induced upregulation of FKBP5 gene expression. Alteration of methylation was specific to single-stranded probes, as double-stranded methylated probes and unmethylated probes showed no significant effects. Some limitations include the need to further characterize factors that influence probe efficiency, such as probe length and CpG density; develop an efficient in vivo probe delivery system; and perform a more extensive consideration of possible off-target effects. Despite these limitations, our findings suggest that methylated DNA probes have the potential to function as a simple tool for targeted epigenetic manipulation and serve as a safer alternative to CRISPR-based epigenome editing tools for the treatment of stress-related disorders such as depression. Full article

Background/Objectives: Mixed martial arts (MMA) is a combat sport which heavily involves upper limb strength, mobility, and stability. Shoulder injuries, given their impact on striking and grappling, may significantly hinder performance and career longevity. However, their specific effects on competitive outcomes remain poorly defined. This study evaluates return-to-sport rates, fight performance, and long-term success in professional MMA athletes following shoulder injuries. Methods: A retrospective cohort study was conducted using publicly available databases to identify professional MMA fighters from the UFC, Bellator, and Strikeforce who sustained shoulder injuries requiring withdrawal from scheduled bouts. Fighter demographics, injury characteristics, and treatment approaches were recorded. Performance metrics—including winning percentage, takedown (TD), knockdown (KD), and significant strike (SS) rates—were compared before and after injury. Independent t-tests were used, and significance was set at p < 0.05. Results: A total of 27 fighters with 34 documented shoulder injuries were included. The most common injury was a torn labrum (41.2%), with 76.5% requiring surgical intervention. Aggregate winning rates significantly declined from 81.96% pre-injury to 54.7% post-injury (p < 0.001). Aggregate KD rates also dropped significantly (p < 0.001), while TD rates trended downward without reaching statistical significance. SS rates remained stable, suggesting potential compensatory mechanisms. Injury recurrence was observed in 22.2% of cases. Conclusions: Shoulder injuries in MMA are associated with a substantial decline in competitive success, particularly in knockout capability, emphasizing the critical role of shoulder integrity in fight performance. The high recurrence rate suggests the need for optimized rehabilitation protocols and stricter return-to-sport guidelines to enhance fighter longevity. Full article

This paper presents the modified arithmetic optimization algorithm (MAOA), a swift and effective optimization algorithm specifically designed for electromagnetic applications. Its primary advantage is its ability to avoid local minima by striking a balance between global exploration and local exploitation searches. This equilibrium is maintained through three key improvements: an enhanced initialization process, a distinctive guidance mechanism for steering searches, and an additional learning phase to refine newly found solutions. This process innovation significantly boosts MAOA’s performance in addressing both constrained and unconstrained optimization challenges. In this study, MAOA is applied to optimize the spacing and current amplitude of linear antenna array (LAA) elements, with the goal of minimizing peak side lobe level (PSLL), close-in side lobe level (CSLL), and overall side lobe level (SLL), both with and without constraints on first null beamwidth (FNBW), as well as null positioning with SLL minimization. Ten designs, comprising 10 and 20 antenna elements of LAA and one 14-element circular antenna array (CAA), showcase MAOA’s proficiency in antenna array pattern synthesis. Optimizing element positions results in a PSLL of −21.28 dB, a CSLL of −34.50 dB, and a null depth of −89.00 dB, while optimizing current amplitude achieves a PSLL of −24.32 dB, a CSLL of −29.73 dB, and a null depth of −77.60 dB across various antenna designs. Simulation results reveal that MAOA significantly surpasses traditional uniform linear arrays (ULA) and established optimization techniques. Its superiority is further confirmed through a Wilcoxon rank-sum and Friedman test. Full article

Nuclear receptor coactivator 6 is a gene that produces a protein that regulates transcriptional activity. It is also involved in many processes like cell survival, metabolism, homeostasis, and embryonic development. This study focused on studying the genetic influence of single-nucleotide polymorphisms (SNPs) within the NCOA6 gene on lactation performance characteristics. The objective of this study was to determine the genetic impact of SNPs of the NCOA6 gene on milk production traits. After the random selection of twenty cows, PCR amplification and sequencing were performed from their blood samples to find the SNPs present in the bovine NCOA6 gene. As a result, two SNPs, g.71544C > T and g.87310A > G, were found. Then, the genotyping of the cows (n = 985) was conducted using a Sequenom MassARRAY based on previously identified SNP information. The least-square method was applied to study the links between lactation traits, somatic cell score (SSC), and 305-day milk output. The results indicated that the SNP g.87310A > G was strongly associated with g.71544C > T in linkage disequilibrium. The single-nucleotide polymorphism g.87310A > G showed a very strong association with daily milk yield and 305-day milk production. Individuals with the AA genotype exhibited a notable increase in daily milk production by 1.64 kg, and their 305-day milk yield was approximately 500 kg higher. This variation demonstrated a significant genetic effect on milk output. In brief, the pleiotropic influence of the cattle NCOA6 gene on lactation traits was revealed in this study. However, additional research will provide a basis for further exploring the underlying correlation and theoretical framework of the molecular genetics of milk composition and the production attributes of Holstein cows. Full article