Search Results (1,533)

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these drugs are safe and highly effective, there is significant variability in response among patients. This can be partly attributed to the patients’ genetic background, thus pointing to the need to identify pharmacogenetic markers for treatment response. Methods: The study involved 88 Greek patients who were treated with inhibitors of the IL-17A signaling for at least 6 months. Patients were classified as responders and non-responders according to the change in Psoriasis Area Severity Index. A total of 730,000 variants were genotyped and analyzed for association with the 3-month and 6-month responses to treatment. Results: The analysis identified 21 variants which were associated with the response, showing statistical significance after Bonferroni correction. These include variants located in protein coding genes (TP63, NRG1, SCN8A, TAF9, TMEM9, SMIM36, SYT14, BPIFC, SEZ6L2, PCARE), as well as intergenic and long non-coding RNA intronic variants. The functional significance of the variants was assessed using in silico analysis and for several variants, a link with immune processes was proposed. Notably, rs11649499 status, which was associated with complete clinical remission at 3 months, may influence key lipid mediators involved in psoriasis. Conclusions: This GWAS identified novel variants that could be utilized upon validation in larger populations as predictive markers regarding patient response to drugs targeting the IL-17A pathway. Full article

The sustainable revalorization of porcine blood is crucial due to the large volumes daily generated in slaughterhouses. The aim of this study was to obtain a novel ingredient rich in free amino acids and bioactive peptides from the sequential hydrolysis of porcine blood. Porcine blood was hydrolyzed with Alcalase 4.0 L and Protana™ Prime enzymes, followed by molecular weight fractionation (<10 kDa) and spray-drying. The antioxidant, hypoglycemic, and anti-inflammatory bioactivities of the resulting hydrolysate (PBSH) were studied in vitro. Further fractionation by reversed-phase high-performance liquid chromatography (RP-HPLC) was performed to isolate the most bioactive fraction based on polarity. Peptides from fraction 1 (F1) were identified using LC-MS/MS and analyzed in silico. Finally, some peptides were synthesized, and their bioactivity was subsequently assessed. PBSH hydrolysate showed antioxidant activity with IC₅₀ values of 2.09, 135.05, and 26.73 mg/mL for ABTS, FRAP, and DPPH assays, respectively. Additionally, PBSH exhibited hypoglycemic, anti-inflammatory, and immunomodulatory potential through the inhibition of DPP-IV (82.78%), NEP (84.72%), TACE (50.79%), and MGL (69.08%) enzymes at a concentration of 20, 20, 100, and 20 mg/mL, respectively. Peptides PDDFNPS, FPPKPKD, DNPIPK, GHLDDLPG, and GDL were identified in the most polar and bioactive fraction (F1) and proved a synergistic hypoglycemic effect at a concentration of 1 mmol/L. The peptide PDDFNPS exhibited multifunctional properties with 56.43% inhibition of DPP-IV and 83.54% inhibition of NEP. PBSH resulted in a novel functional ingredient for animal feed as it contains a variety of identified bioactive peptides and a high amount of free amino acids. Full article

Background/Objectives: Biofilm formation by Acinetobacter baumannii contributes to its persistence in clinical settings and resistance to antibiotic treatment. This study aims to identify and characterize antimicrobials from lactic acid bacteria (LAB) using molecular and in silico approaches that can prevent and disrupt A. baumannii biofilms, assess their antimicrobial host range, and define their synergy with current antibiotics. Methods: Thirteen LAB isolates from the Human Microbiome Project were screened for anti-biofilm activity against A. baumannii. Conditioned media was further tested against six ESKAPE pathogens and three skin commensals. Lentilactobacillus hilgardii was selected for detailed study and antimicrobial peptide (AMP) prediction analysis due to limited toxicity toward commensals. In silico identified peptides were synthesized and tested individually and in combination with sub-MIC doses of an antibiotic. Results: Conditioned media from five LAB species (Lentilactobacillus hilgardii, Lentilactobacillus buchneri, Ligilactobacillus ruminis, Limosilactobacillus fermentum, and Limosilactobacillus antri) significantly inhibited A. baumannii biofilm formation and reduced biomass of mature biofilms. LAB-conditioned media also exhibited broad-spectrum activity against ESKAPE pathogens, though effects on commensals varied. Bioinformatically predicted AMPs from L. hilgardii inhibited planktonic A. baumannii growth but showed no direct biofilm activity even at high doses. However, AMPs were found to synergize with sub-MIC doses of meropenem against mature biofilms leading to decolonization. Conclusions: Our study provides a comprehensive platform for the discovery and characterization of AMPs and supports using commensal bacteria to reduce, prevent, and decolonize biofilms from pathogenic bacteria in community and nosocomial settings. Full article

Background/Objectives: Gliomas are the most common tumours of the central nervous system (CNS), classified into grades I to IV based on their malignancy. Genetic and epigenetic alterations play a crucial role in glioma progression. DNA methyltransferases (DNMTs) are vital enzymes responsible for DNA methylation, with DNMT1 and DNMT3 catalysing the addition of a methyl group to the 5-carbon of cytosine in CpG dinucleotides. Targeting DNMTs with DNA methyltransferase inhibitors (DNMTi) has become a promising therapeutic approach in tumour treatment. In this study, in silico screening tools were employed to evaluate potential inhibitors of DNMT1, DNMT3A, and DNMT3B for the treatment of glioblastoma multiforme (GBM). Methods: The Gene2Drug platform was used to screen compounds and rank them based on their capacity to dysregulate DNMT genes. PRISM viability assays were performed on 68 cell lines, and DepMap data were analyzed to assess the antitumor activities of these compounds and their target genes. Candidate drug similarity was evaluated using DSEA, and compounds with p < 1 × 10⁻³ were considered statistically significant. Gene-compound interactions for DNMT1, DNMT3A, and DNMT3B were confirmed using Expression Public 24Q2, while Prism Repositioning Public data were analyzed via DepMap. Results: Glioblastoma cell lines showed sensitivity to compounds including droperidol, demeclocycline, benzthiazide, ozagrel, pizotifen, tracazolate, norcyclobenzaprine, monocrotaline, dydrogesterone, 6-benzylaminopurine, and nifedipine. SwissTargetPrediction was utilised to identify alternative molecular targets for selected compounds, revealing high-probability matches for droperidol, pizotifen, tracazolate, monocrotaline, dydrogesterone, and nifedipine. Conclusions: Integrating computational approaches with biological insights and conducting tissue-specific and experimental validations may significantly enhance the development of DNMT-targeted therapies for gliomas. Full article

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial–mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood–brain barrier (BBB) permeability was predicted using four independent in silico platforms—ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)—all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB’s translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further in vivo validation and preclinical development as a novel therapeutic candidate for GBM. Full article

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2–p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC₅₀ 6.67–8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (−10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski’s Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile. Full article

Background/Objectives: Lifitegrast is a recent therapeutic agent provoking scientific and regulatory interest due to its outstanding safety profile and high efficacy in the treatment of dry eye disease. Methods: Herein we employ NMR spectroscopy and mass spectrometry to investigate the weak spots of lifitegrast under standard to extreme stress conditions, resulting in the characterization of three known and nine new degradation products (of which DP7 presented the greatest structural challenge, but was eventually determined as C10 hydroxy derivative, warranting a revision of its previously suggested structure). Results: The first weak spot is identified as a N1–C40 amide bond, and its high susceptibility to hydrolysis is explained through computational DFT analysis. The second and third weak spots are elucidated through bond dissociation energy (BDE) calculations which highlighted the oxidative vulnerabilities of both the piperidine and benzofuran ring. Conclusions: Additionally, two degradation products, observed in initial, extended, and targeted oxidative forced degradation studies, were selected for in silico toxicity assessment and were predicted to have toxicity profiles comparable to or lower than lifitegrast. Full article

Antibody-free nucleic acid lateral flow assays (AF-NALFA) are an established approach for rapid detection of amplified pathogens DNA but can yield inconsistent signals across targets. Since AF-NALFA depends on dual hybridization of probes to single-stranded amplicons (ssDNA), site-specific thermodynamic (Gibbs free energy-ΔG) at probe-binding regions may be crucial for performance. This study investigated how site-specific-ΔG and sequence complementarity at probe-binding regions determine Test-line signal generation, comparing native and synthetic amplicons and assessing the effects of local secondary structures and mismatches. Asymmetric PCR-generated ssDNA amplicons of Listeria monocytogenes, Mycobacterium leprae, and Leishmania amazonensis were analyzed in silico and tested in AF-NALFA prototypes with gold-labeled thiol probes and biotinylated capture probes. T-line signals were photographed, quantified (ImageJ version 1.4k), and statistically correlated with site-specific-ΔG. While native ssDNA from M. leprae and L. amazonensis failed to produce AF-NALFA T-line signals, L. monocytogenes yielded strong detection. Site-specific-ΔG below −10 kcal/mol correlated with reduced hybridization. Synthetic oligos preserved signals despite structural constraints, whereas ~3–4 mismatches, especially at capture probe regions, markedly impaired T-line intensity. The performance of AF-NALFA depends on the synergism between thermodynamic accessibility, site-specific-ΔG-induced site constraints, and sequence complementarity. Because genomic context affects hybridization, target-specific thermodynamic in silico evaluation is necessary for reliable pathogen DNA detection. Full article

Background/Objectives: Erectile dysfunction (ED) is a prevalent and multifactorial condition influenced by psychological and sleep-related factors. This study aimed to evaluate the independent and combined associations of insomnia and benzodiazepine use with the risk of ED. Methods: An analytical cross-sectional study was conducted in adult men with and without ED. Logistic regression was used to estimate crude and adjusted odds ratios (ORs). Effect modification was assessed through stratified analyses. Additionally, an in silico analysis of 17 active compounds was performed using SwissADME and Molinspiration to explore physicochemical properties. Results: Insomnia (adjusted OR 2.05; 95% CI 1.13–3.74; p = 0.019) and benzodiazepine use (adjusted OR 2.14; 95% CI 1.10–4.15; p = 0.025) were each independently associated with ED. In contrast, antidepressant use was not significantly associated with ED in the sample analyzed. Participants with both insomnia and benzodiazepine use had a markedly higher risk (adjusted OR 3.96; 95% CI 1.51–10.40; p = 0.005). The joint association of insomnia and benzodiazepine use was consistent with the combined effect expected from their individual associations. The in silico analysis showed an overlapping profile, suggesting benzodiazepine properties may underline their link to ED, supporting the results of the cross-sectional study. Conclusions: Both insomnia and benzodiazepine use independently increased the odds of ED. Their co-occurrence was linked to a substantially higher likelihood of ED, highlighting the clinical importance of assessing both conditions concurrently in patients with sexual dysfunction. Full article

Background/Objectives: Allophylus edulis, known as “vacum”, is popularly used in Brazil for treating inflammatory diseases, though no scientific evidence supports the anti-inflammatory activity of its leaf infusion. This study aimed to assess the chemical composition, antioxidant and anti-inflammatory properties of the lyophilized infusion (ILAE) of A. edulis leaves, as well as the pharmacological effects of its hydromethanolic fraction (HMf) and the isolated compound vitexin 2″-O-rhamnoside (AE-1). Histochemical analyses of the leaves and in silico toxicity prediction of AE-1 were also performed. Methods: Fresh leaves were used for histochemical analysis and preparation of ILAE. The infusion was fractionated into n-hexane (Hf), ethyl acetate (EAf), and HMf fractions. Total phenols, flavonoids, flavonols, tannins, and antioxidant activity were determined by spectrophotometric methods. AE-1 was obtained from HMf through chromatographic methods and was evaluated by the ProTox model in relation to toxicity predictions (in silico). Anti-inflammatory effects of ILAE (3, 30, 100 mg/kg), HMf (3, 30 mg/kg), and AE-1 (3 mg/kg) were evaluated in carrageenan-induced paw edema, pleurisy, and CFA-induced inflammation in mice. Results: ILAE and its fractions were rich in total phenols (≤177 mg GAE/g) and showed potent antioxidant activity. Histochemical analysis revealed leaf secretory structures. AE-1 showed no hepatotoxic, carcinogenic, mutagenic, or cytotoxic effects in silico. All doses of ILAE and HMf reduced edema, hyperalgesia, and leukocyte migration. ILAE (30 mg/kg), HMf (30 mg/kg), and AE-1 (3 mg/kg) reduced CFA-induced inflammatory responses. Conclusions: ILAE contains polyphenolic compounds with antioxidant, anti-inflammatory, and antihyperalgesic properties, supporting the traditional use of A. edulis and its potential in inflammation-related therapies. Full article

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess the ability of acai berry extracts to counter L-Glu neurotoxicity using human differentiated TE671 cells. Methods: The cytotoxicity of L-Glu and acai berry extracts was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial function was examined by a quantitation of cellular ATP levels, the maintenance of the mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). Whole-cell patch-clamp recordings monitored the activation of N-methyl-D-aspartate receptors (NMDARs). Candidate phytochemicals from acai berry extracts were modeled in silico for NMDAR binding. Results: L-Glu significantly reduced cell viability, ATP levels, the MMP, and increased cellular ROS. Generally, acai berry extracts alone were not cytotoxic, although high concentrations were detrimental to ATP production, maintenance of the MMP, and elevated ROS levels. Whole-cell patch-clamp recordings revealed that the combined addition of 300 µM L-Glu and 10 µM glycine activated currents in differentiated TE671 cells, consistent with triggering NMDAR activity. Acai berry extracts ameliorated the L-Glu-induced cytotoxicity, mitochondrial dysfunction, elevated ROS levels, and limited the NMDAR-mediated excitotoxicity (p < 0.001–0.0001). Several virtual ligands from acai berry extracts exhibited high-affinity NMDAR binding (arginine, 2,5-dihydroxybenzoic acid, threonine, protocatechuic acid, and histidine) as possible candidate receptor antagonists. Conclusions: Acai berry phytochemicals could be exploited to reduce the L-Glu-induced neurotoxicity often observed in stroke and other neurodegenerative diseases. Full article

Background/Objectives: This study investigates the dosimetric impact of a 3D-printed applicator integrating multilayer catheter geometry and high-density shielding, designed for contact interventional radiotherapy (IRT) in non-melanoma skin cancer (NMSC) treatment. The aim is to assess its potential to enhance target coverage and reduce doses in organs at risk (OARs). Methods: A virtual prototype of a multilayer applicator was designed using 3D modeling software and realized through fused deposition modeling. Dosimetric simulations were performed using both TG-43 and TG-186 formalisms on CT scans of a water-equivalent phantom. A five-catheter array was reconstructed, and lead-cadmium-based alloy shielding of varying thicknesses (3–15 mm) was contoured. CTVs of 5 mm and 8 mm thickness were analyzed along with a neighboring OAR. Dosimetric endpoints included V95%, V100%, V150% (CTV), D_2cc (OAR), and therapeutic window (TW). Results: Compared to TG-43, the TG-186 algorithm yielded lower OAR doses while maintaining comparable CTV coverage. Progressive increase in shielding thickness led to improved V95% and V100% values and a notable reduction in OAR dose, with an optimal trade-off observed between 6 and 9 mm of shielding. The TW remained above 7 mm across all configurations, supporting its use in lesions thicker than conventional guidelines recommend. Conclusions: The integration of multilayer catheter geometry with high-density shielding in a customizable 3D-printed applicator enables enhanced dose modulation and OAR sparing in superficial IRT. This approach represents a step toward personalized brachytherapy, aligning with the broader movement in radiation oncology toward patient-specific solutions, adaptive planning, and precision medicine. Future directions should include prototyping and mechanical testing of the applicator, experimental dosimetric validation in phantoms, and pilot clinical feasibility studies to translate these promising in silico results into clinical practice. Full article

Background: Dilated cardiomyopathy (DCM) and long QT syndrome (LQTS) are genetically heterogeneous cardiac disorders that contribute significantly to morbidity and sudden cardiac death. Although they are typically considered distinct entities, co-occurrence within families has been increasingly recognized, complicating diagnosis and genetic counseling. Identifying shared genetic determinants may provide insights into overlapping disease mechanisms. Methods: We investigated a multi-generational family in which several members presented with features of both DCM and LQTS. Exome sequencing was performed to identify potential disease-causing variants, and candidate findings were validated by Sanger sequencing. In silico prediction tools and evolutionary conservation analysis were used to assess the pathogenic potential of the identified variant. Results: We identified a novel heterozygous missense variant in the CRYAB gene, c.368G>A (p.Arg123Gln). This variant is located in a highly conserved region critical for protein function and was consistently predicted to be deleterious across multiple computational algorithms. Segregation analysis demonstrated co-occurrence of the variant with disease phenotypes in affected family members. Clinically, several carriers exhibited overlapping features of both DCM and prolonged QT interval, suggesting a dual cardiac phenotype associated with this mutation. Conclusions: Our findings expand the phenotypic spectrum associated with CRYAB mutations, linking them to a combined presentation of dilated cardiomyopathy and long QT syndrome. This underscores the importance of including CRYAB in comprehensive gene panels for inherited cardiac disorders and highlights the need for integrated clinical and genetic evaluation in families presenting with complex cardiac phenotypes. Full article

Background: Derivatives of Pyrido[2,3-d]pyrimidine-6-carboxylate are promising multi-target scaffolds. This study focused on synthesizing 16 amino-functionalized derivatives and evaluating their dual anticancer and antibacterial activities, supported by mechanistic and computational analyses. Objectives: Design and synthesize derivatives, evaluate cytotoxicity against HeLa, HepG-2, and MCF-7 (selectivity against WI-38), investigate EGFR^WT and EGFR^T790M inhibition, assess cell cycle, apoptosis, and migration effects, antibacterial efficacy against E. coli and P. aeruginosa, and perform in silico ADMET, docking, molecular dynamics, DFT, and antiviral predictions. Methods: Synthesized 16 derivatives; tested for cytotoxicity, EGFR inhibition, cell cycle, apoptosis, migration; assessed antibacterial activity; performed ADMET profiling, molecular docking, molecular dynamics, and DFT calculations. Results: Derivatives 1, 2, and 7 showed highest cytotoxicity (IC₅₀ = 3.98–17.52 μM; WI-38 IC₅₀ = 64.07–81.65 μM). Compound 1 potently inhibited EGFRWT (IC₅₀ = 0.093 μM) and EGFRT790M (IC₅₀ = 0.174 μM), induced G0/G1 arrest (74.86%) and apoptosis (26.37%), and reduced MCF-7 migration (69.63%). Moderate antibacterial activity observed (MIC = 50 μg/mL). ADMET indicated favorable pharmacokinetics, low CYP inhibition, negative mutagenicity, and oral toxicity class III. Molecular dynamics confirmed stable binding (EGFRWT RMSD 3 Å; EGFRT790M 3.5–4.6 Å) with persistent hydrogen bonds. In silico antiviral evaluation suggested strong binding to HCV NS5A (–9.36 kcal/mol), SARS-CoV-2 Mpro (–9.82 kcal/mol), and E.coli DNA gyrase (–10.25 kcal/mol). Conclusions: Compound 1 exhibits dual anticancer and antibacterial activity, supported by mechanistic and computational analyses, highlighting pyrido[2,3-d]pyrimidines as promising multi-target therapeutic scaffolds. Full article

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole-genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA isolated from saliva and buccal swab samples underwent WGS, and subsequent WGS data were analyzed through extensive bioinformatics analyses. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wildtype and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa. Full article