Search Results (28,684)

Patients with cerebrovascular disease frequently require concomitant antiplatelet and antiseizure therapy. However, experimental evidence regarding potential pharmacodynamic interactions between these medications remains limited. The present study investigated whether clopidogrel affects the anticonvulsant effects of valproic acid (VPA) or levetiracetam (LEV) in a pentylenetetrazol (PTZ)-induced seizure model. Forty-two male Wistar rats were randomly allocated to seven groups (n = 6/group): Control, PTZ, clopidogrel (CLP), VPA, LEV, VPA + CLP + PTZ, and LEV + CLP + PTZ. Electroencephalographic recordings, passive avoidance testing, histopathological examination, and glial fibrillary acidic protein (GFAP) immunohistochemistry were performed to evaluate seizure activity, behavioral performance, neuronal injury, and astroglial activation. Both VPA and LEV significantly reduced spike–wave discharge frequency and duration compared with the PTZ group (p < 0.05). Clopidogrel alone did not exhibit anticonvulsant activity, and co-administration with either VPA or LEV did not significantly alter electrophysiological, behavioral, histopathological, or GFAP-associated immunohistochemical outcomes. Overall, these findings indicate that clopidogrel did not significantly affect the anticonvulsant efficacy of VPA or LEV under the experimental conditions of this acute PTZ-induced seizure model. Full article

Hippodamia variegata is a key natural enemy of various aphid pests in agricultural ecosystems, and its foraging and oviposition behaviors are strongly dependent on chemical signals from prey aphids and host plants. In this study, we functionally characterized the chemosensory protein HvarCSP8 to elucidate its potential role in mediating olfactory responses to aphid-induced plant volatiles. The expression profiles of HvarCSP8 were examined by quantitative real-time PCR (qRT-PCR) across developmental stages and sexes; the recombinant HvarCSP8 was purified; the potential ligands specificity and affinity were studied using fluorescence-based competitive binding assays; and structural characteristics were obtained via homology modeling and molecular docking simulations. The results demonstrated that HvarCSP8 exhibits pronounced sex- and tissue-specific expression, with significant upregulation in adult antennae, particularly in females. The purified protein exhibited selective binding affinity to multiple aphid-induced plant volatiles, such as α-Farnesene, α-Terpinene, and 2-Ethyl-1-hexanol. Molecular docking revealed that HvarCSP8 interacts with these ligands through multiple amino acid binding sites, among which hydrophobic residues such as VAL29, LEU61, ILE64, and LEU65 frequently occur in binding sites for multiple ligands, suggesting that these residues play important roles in binding. These findings indicate that HvarCSP8 may be involved in the olfactory detection of aphid-induced plant volatiles in H. variegata, providing a candidate target for the development of behavior-based biological control strategies against aphid pests. Full article

Background/Objectives: Abnormal blood pressure (BP) in youth is strongly linked to genetic predisposition, particularly involving lipid metabolism genes. However, little is known about whether such polymorphisms affect ambulatory BP (ABP) parameters and whether other factors modify the associations in youth populations. Methods: A total of 510 medical students from a university in Changsha were included. Multivariable linear regression and logistic regression models were used to analyze the association between sterol regulatory element-binding protein cleavage-activating protein (SCAP) gene polymorphisms and ABP parameters among youth. Results: After adjusting for age, sex, BMI, ethnicity, monthly household income per capita, salt intake habits, fruit and vegetable intake frequency, smoking, drinking, history of hypertension and waist circumference, carriers of the A allele of rs76558868 had higher daytime systolic blood pressure (SBP) than G allele carriers (β = 1.55, SE = 0.77, p = 0.046, corrected p =0.092). A significant interaction between rs12487736 and sex on 24 h SBP (p_interaction = 0.023) and daytime SBP (p_interaction = 0.048) levels was found. In males, the CC genotype carriers had elevated 24 h SBP (β = 3.53, SE = 1.36, p = 0.010, corrected p =0.020) and daytime SBP (β = 3.18, SE = 1.53, p = 0.040, corrected p = 0.080) levels compared to TC/TT genotype carriers, whereas no significant association was found in females. In addition, we also noted an interaction between rs76558868 and sex on 24 h SBP (p_interaction = 0.016), nighttime SBP (p_interaction = 0.027) and nighttime diastolic blood pressure (DBP) (p_interaction = 0.025) levels; the A allele carriers had significantly higher 24 h SBP (β = 2.02, SE = 0.84, p = 0.018, corrected p =0.036), nighttime SBP (β = 2.64, SE = 0.98, p = 0.008, corrected p =0.016) and DBP levels (β = 1.65, SE = 0.63, p = 0.009, corrected p =0.018) compared to G allele carriers among males, but not in females. Conclusions: An interaction between SCAP gene polymorphisms and sex was observed for ABP parameters among college students. These findings provide insights for future targeted early hypertension prevention and personalized health management strategies. Full article

The synuclein family, comprising α-, β-, and γ-synucleins, consists of highly conserved, intrinsically disordered proteins sharing substantial structural homology and exhibiting multifunctional roles in membrane interactions, vesicle trafficking, lipid homeostasis, and cellular signalling. Synucleins are enriched at presynaptic terminals, where they regulate synaptic vesicle dynamics and neurotransmission by contributing to vesicle clustering, trafficking, and the availability of vesicles for release. Aberrant expression, misfolding, and aggregation of synucleins are associated with several human diseases, particularly neurodegenerative disorders and certain cancers, highlighting their biological and clinical relevance. The primary aim of this review was to provide a focused overview of current knowledge regarding the physiological presynaptic functions of synucleins. By concentrating on this relatively underexplored aspect of synuclein biology, we sought to highlight their roles in synaptic transmission and presynaptic regulation, thereby complementing the extensive literature devoted to their pathological significance. Here, the recent findings on the contributions of α-, β-, and γ-synucleins to synaptic vesicle organization, trafficking and neurotransmitter release were summarized, and their emerging roles in maintaining presynaptic homeostasis were discussed. In addition, we consider how disruption of these physiological functions may contribute to synaptic dysfunction and the development of disease. Full article

This study aimed to investigate the effects of cysteamine zinc (CS-Zn) supplementation on blood biochemical indices, blood hormones, fecal fermentation, fecal microbial diversity, and blood metabolites in lactating mares. Blood samples were collected via jugular venipuncture, and fecal samples were collected via rectal sampling before morning tethering on days 30, 60, and 90 of the trial. Fecal samples were analyzed for volatile fatty acids (VFAs) and microbial diversity, while changes in blood biochemical indices, blood hormones, and blood non-targeted metabolomics were also analyzed. The results showed that compared with the control group, the test group exhibited significant increases in total protein, globulin, urea, and glucose in the blood (p < 0.05); growth hormone (GH) levels significantly increased, while somatostatin levels significantly decreased (p < 0.05); and concentrations of all VFAs in feces significantly increased (p < 0.05). Simultaneously, CS-Zn supplementation significantly reduced the relative abundance of Family_XIII_UCG-001, Monoglobus, and UCG-007 at the genus level. Metabolomics analysis revealed that differentially expressed metabolites were enriched in pathways such as neuroactive ligand–receptor interaction, phenylalanine, tyrosine and tryptophan biosynthesis, and dopaminergic synapse, with significant upregulation of L-tyrosine and dopamine in the blood. These findings indicate that CS-Zn supplementation, on the one hand, can enhance pathways such as glucose metabolism, tyrosine metabolism, and bile secretion by depleting somatostatin and increasing growth hormone levels, and on the other hand, it can improve energy metabolism in mares by altering intestinal microbiota structure and enhancing fiber fermentation efficiency. Full article

The human APOBEC3 (A3) family of cytidine deaminases, including A3G, A3F, and A3H, participates in cellular anti-retroviral immunity. In contrast, to antagonize the anti-retroviral activities of these A3 family proteins, HIV-1 produces its gene product called viral infectivity factor (Vif) in infected cells. Vif is a pleiotropic hub protein that specifically binds to various A3 proteins with the aid of host core-binding factor subunit β (CBF-β) and mediates their proteasomal degradation. To date, numerous biological and structural studies have been performed to understand the arms race between A3 and Vif. Previous extensive mutagenesis and structural analyses have suggested that there are three distinct types of Vif-binding interfaces among human A3s and three largely nonoverlapping interfaces on Vif for binding with these A3s. Moreover, recent cryo-electron microscopy (cryo-EM) structural analyses have clarified further details of the different intermolecular interactions of Vif with each of three human A3s (A3G, A3F, and A3H) and have proposed a possible mechanism by which one Vif molecule can recognize all three types of A3s. In this review, we summarize the current understanding of the structural basis of the interaction between A3 and Vif. This information may be helpful for developing drugs targeting these interfaces. Full article

Background: Thyroid carcinoma (THCA), especially papillary thyroid carcinoma (PTC), remains clinically challenging because recurrence and metastasis occur in a subset of patients. SMDT1 is an essential regulator of the mitochondrial calcium uniporter complex that may influence tumor progression, but its role in thyroid carcinoma is unclear. This study investigated the expression, clinical significance, and biological functions of SMDT1 in thyroid carcinoma. Methods: Public databases were used to analyze SMDT1 expression, diagnostic value, prognostic relevance, co-expression networks, functional enrichment, protein interactions, and immune infiltration. SMDT1 expression was validated in 50 paired PTC and adjacent non-tumorous tissues. In vitro SMDT1 overexpression was performed in PTC cell lines, followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB), CCK-8, colony formation, wound healing, and transwell assays. Results:SMDT1 was significantly downregulated in thyroid carcinoma tissues, PTC tissues, and PTC cell lines. Low SMDT1 expression was associated with lymph node metastasis and shorter disease-free survival. Functional analyses linked SMDT1 with mitochondrial calcium transport, oxidative phosphorylation, apoptosis, cellular senescence, and immune infiltration, including CD8⁺ T cells and activated NK cells. SMDT1 overexpression significantly suppressed PTC cell proliferation, colony formation, migration, and invasion. Conclusions:SMDT1 may function as a tumor suppressor in thyroid carcinoma and has potential diagnostic and prognostic value. Its effects may involve mitochondrial calcium homeostasis, metabolic regulation, and immune microenvironment remodeling. Full article

Biolayer Interferometry (BLI) has traditionally been used for characterization of protein–protein interactions (PPI) with proteins, such as antibodies and their antigens, through kinetic and quantitation assays. Limitations, for example in sensitivity and the availability of established assay formats, have restricted its adoption across other analytical applications. This article highlights three case studies which demonstrate the expansion of BLI into novel applications, spanning the areas of protein detection and viral vector characterization. The first case study details the use of a multi-step signal amplification assay to enable the detection of low abundant molecules, such as cytokines, at lower concentrations than can be detected using the standard one-step binding approach. Cytokines are sandwiched between biotinylated and HRP-conjugated antibodies, then dipped into 3-amino-9-ethylcarbazole (AEC) reagent, resulting in an enhancement of the cytokine detection sensitivity. The second case study uses BLI for the quantitation of mixed populations of a bispecific antibody (bsAb). Bridging and dual binding assay formats are evaluated for their assessment of bsAb antigen binding kinetics and ability to determine the ratio of correctly assembled bsAb within a sample. In the third case study, BLI detection principles are used to estimate the percentage full capsids in a mixed population of AAV particles. Collectively, these case studies demonstrate the versatility of Octet^® BLI and highlight its potential to support an increasing range of analytical workflows beyond its traditional applications. Full article

The rapid emergence of carbapenem-resistant Acinetobacter baumannii has become a major health concern, primarily driven by the dissemination of class D β-lactamases, particularly OXA-23, which compromise the efficacy of last-line β-lactam antibiotics. Drug repurposing combined with structure-based computational approaches provides a promising strategy for accelerating the discovery of novel therapeutic candidates against multidrug-resistant pathogens. This study aimed to identify FDA-approved non-steroidal anti-inflammatory drugs (NSAIDS) with potential inhibitory activity against OXA-23 β-lactamase by using a comprehensive computational drug discovery workflow. Twenty-six FDA-approved NSAIDs were evaluated using an integrated computational pipeline comprising network pharmacology, KEGG pathway analysis, molecular docking, molecular dynamics simulations and ADMET profiling. KEGG pathway analysis confirmed the central role of OXA-23 in β-lactam resistance, while network pharmacology prioritized nine candidates NSAIDS for subsequent structure-based investigation. Molecular docking was performed using the crystal structure of OXA-23 β-lactamase (PDB ID: 4K0X), followed by molecular dynamics simulations to assess the stability of the protein–ligand complexes. Among the prioritized compounds, sulfasalazine demonstrated the most favorable predicted binding affinity (−8.3 kcal/mol), forming stable interactions with key catalytic residues, including SER126, VAL128, and LEU166 and exhibiting a more favorable docking profile than the reference drug imipenem (−5.7 kcal/mol). Molecular dynamics simulations supported the structural stability of the sulfasalazine OXA-23 complex throughout the simulation period. Furthermore, ADMET analysis indicated favorable pharmacokinetic characteristics including good oral bioavailability, high gastrointestinal absorption, low central nervous system penetration, and an acceptable predicted safety profile. This integrated computational study identifies sulfasalazine as a promising repurposing candidate for targeting OXA-23 β-lactamase in carbapenem-resistant A. baumannii. The findings demonstrate the utility of combining network pharmacology with molecular modeling to prioritize candidate therapeutics and provide a computational framework for accelerating antimicrobial drug discovery. Experimental validation is warranted to confirm the inhibitory activity and therapeutic potential of sulfasalazine against multidrug-resistant A. baumannii. Full article

SARS-CoV-2 nucleocapsid protein (N protein) binds nucleic acids and packages viral RNA. DNA aptamers that specifically bind the N protein have been used in antigen-based COVID-19 detection and have potential clinical applications for preventing SARS-CoV-2 infection. However, the complex structures of the N protein with DNA aptamers and the mechanisms by which aptamers recognize the N protein remain unclear. Here, we report the NMR-derived complex structure of the N-terminal domain of the N protein (N-NTD) with a 58 nt DNA aptamer, A48. The complex structure reveals a distinct topology with a large contact area between A48 and N-NTD. The N-terminal intrinsically disordered region (IDR) of N-NTD forms close contact with A48, primarily stabilized by hydrophilic interactions. Deletion of the N-terminal IDR or substitution of positively charged arginine residues with negatively charged glutamate residues in the IDR region substantially reduced the binding affinity for A48. Because most previously determined N protein structures were obtained using constructs lacking the N-terminal IDR, this study reveals a topology of the N protein-nucleic acid complex and highlights the importance of the N-terminal IDR in nucleic acid binding. Full article

Aberrant self-assembly of ataxin-3 (ATX3) into amyloid aggregates is a key pathological event in spinocerebellar ataxia type 3 (SCA3). Bioactive nutraceutical compounds, particularly polyphenols, have emerged as promising candidates for targeting protein aggregation and cellular stress responses associated with neurodegenerative disorders. Here, we investigated cinnamon bud extract as a natural source of neuroprotective molecules, focusing on its total extract (Etot) and two bioactive fractions: a polyphenol-enriched fraction (Fr. B) and a cinnamaldehyde-rich fraction (Fr. C). By integrating biochemical and biophysical techniques, we demonstrate that cinnamon-derived compounds modulate ATX3 aggregation by reducing the formation of β-sheet-rich amyloid assemblies and promoting the generation of SDS-resistant, soluble, structurally distinct, non-fibrillar species. NMR profiling identified flavonoids, cinnamaldehyde, and cinnamic acid as key ATX3-interacting molecules, supporting their contribution to the anti-amyloidogenic activity of the extract. Moreover, in a Caenorhabditis elegans SCA3 model, Etot and Fr. B improved locomotor defects and enhanced resistance to oxidative and thermal stress, indicating broader cytoprotective effects beyond direct aggregation modulation. Overall, these findings highlight cinnamon bud extract, particularly its polyphenol-rich fraction, as a promising nutraceutical source of bioactive compounds with potential neuroprotective properties and provide a basis for further investigation of nutraceutical strategies targeting polyglutamine-related neurodegenerative diseases. Full article

Objectives: Thiocarbohydrazones represent an important class of Schiff base derivatives with versatile chemical and biological properties. Methods: Herein, we present a combined in silico spectroscopic and molecular docking investigation of N′-benzylidenehydrazinecarbothiohydrazide (1). Results: Conformational docking studies were conducted against cathepsin B, acetylcholinesterase, HER2, protein kinase C, and protein kinase A. The compound displayed favorable binding affinities and key interactions within the catalytic sites of all targets, with the strongest predicted binding observed for acetylcholinesterase. Notably, all conformers exhibited higher affinity for protein kinase C than the reference inhibitor balanol, and hydroxylation led to an approximately 10% enhancement in docking performance. Density functional theory (DFT) calculations were employed to analyze vibrational properties, and IR and Raman spectra were computed to elucidate structural features and conformational behavior. Conclusions: The integrated spectroscopic and docking analyses provide mechanistic insights into ligand–target interactions and support rational drug design. These findings identify thiocarbohydrazone derivatives as promising multi-target candidates for the development of enzyme inhibitors relevant to neurodegenerative, oncological, and inflammatory diseases. Full article

Preserving high-quality forage through silage is essential for continuous livestock production, yet protein degradation during fermentation remains a major challenge. To mitigate this nutrient loss, probiotics and phytobiotics are utilized as protective additives. This study investigated the synergistic application of lactic acid bacteria (LAB) and plant-derived bioactive compounds as deamination inhibitors to improve the fermentation quality and amino acid profiles of tropical forage silages. The experiment followed a 2 × 4 × 4 completely randomized factorial design with five replications. Factor A tested the inclusion of lactic acid bacteria (LAB) inoculum (Lactiplantibacillus plantarum). Factor B compared different plant extracts as additives (Acacia mangium, Swietenia macrophylla, and cumin essential oil), while Factor C evaluated various forage types (Pennisetum purpureum, Indigofera zollingeriana, Gliricidia sepium, and Stylosanthes guianensis). Statistical analysis revealed that LAB inoculation significantly reduced the pH level, suppressed fungal contamination, and improved physical traits (p < 0.05). Both the additive sources and forage types also exerted strong influences across all measured variables (p < 0.05). The interaction between microbes and plant extracts enhances protein preservation during ensiling. Among all the treatments tested, Indigofera zollingeriana showed the best response. The specific combination of L. plantarum and A. mangium extracts in Indigofera silage produced the best fermentation characteristics and a high ability to retain essential amino acids, particularly histidine, lysine, tryptophan, and valine. Lower NH₃-N concentrations and better amino acid preservation in this treatment indicate reduced protein loss due to proteolysis and deamination during fermentation. These findings confirm that the combination of probiotics and certain plant extracts is a highly effective strategy for maintaining the nutritional integrity of tropical forage preserved in silage form. Full article

Background/Objectives: The lack of effective antiviral therapies for many viral infections highlights the need for the development of new antiviral agents. The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the in vitro viral inhibitory activity of newly synthesized GPA derivatives against Zika virus (ZIKV), chikungunya virus (CHIKV), o’nyong-nyong virus (ONNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Antiviral activity (EC50) and cytotoxicity (CC50) of the active compounds were determined using cell-based assays. The mechanism of action of the lead compound was investigated using binding and entry assays, cell-free virion pre-incubation, a virion destabilization assay, a liposome-based capsid protection assay, and molecular docking analysis. Results: Seven of the compounds were able to inhibit ZIKV and two compounds inhibited all four tested viruses. Among them, a teicoplanin pseudoaglycone derivative, compound 7, showed the strongest antiviral activity, inhibiting all four viruses at low micromolar concentrations. Mechanistic studies demonstrated that compound 7 acts during an early stage of ZIKV infection and inhibits low-pH-triggered virus–liposome fusion. Molecular docking analysis suggested potential interactions between compound 7 and the viral envelope protein that could interfere with the conformational rearrangements required for membrane fusion. Conclusions: The present findings demonstrate that hydrophobic GPA derivatives, particularly compound 7, exhibit promising broad-spectrum antiviral activity in vitro. Whether similar mechanisms contribute to the antiviral activity against other viruses remains unknown. The studied GPA derivatives are promising candidates for further pre-clinical and clinical development as broad-spectrum antivirals. Full article

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1’s role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors. Full article