Search Results (301)

Background/Objectives: Covalent conjugation of an antibiotic vancomycin (VCM) moiety and a photosensitizing mesochlorin (mChl_Pd) unit into one molecular entity may present the potential to produce the combinatorial effect of both antibacterial photodynamic therapeutic (aPDT) and antibiotic activities. Our recent study indicated that a short linkage of <4 (C−C/or C−N) bond distances between these two moieties resulted in significant steric hindrance due to the bulky VCM, which greatly reduces the accessibility of the agent to the cell surface of methicillin-resistant Staphylococcus aureus (MRSA). The observed aPDT efficacy was found to be minimal. Here, we report that the revision of this linkage, via an EG₁₀ unit using identical synthetic procedures, was able to resolve the issue. Methods: Accordingly, the corresponding combinatorial aPDT−antibiotic compound, consisting of two covalently bonded quaternary ammonium pentacationic arms on the mesochlorin chromophore core, designated as VCMe-mChl_Pd-N₁₀⁺ (LC40e⁺), was prepared for applications in antibacterial photodynamic inactivation (aPDI) activity. It was selected to investigate its enhanced binding and targeting ability to the surface of Gram-positive MRSA cells. Subsequent antibacterial photodynamic therapeutic (aPDT) activity to inactivate MRSA was investigated to substantiate the corresponding cell-surface binding effect on the efficacy of aPDT. Results: We found that the covalent combination of 10 positive charges and an MRSA-targeting vancomycin (VCM) moiety in a conjugated structure, functioning as an antibiotic–decacationic photosensitizing agent (Abx-dcPS), was capable of largely improving the MRSA cell-targeting efficiency. Importantly, variation in the chain length of the oligo(ethylene glycol) linker of VCMe-mChl_Pd-N₁₀⁺, which was sufficiently long enough to properly separate the photoactive mesochlorin ring moiety from the VCM moiety within the molecular structure, resulted in significantly enhanced aPDT activity. The new conjugate provided nearly complete eradication (>6.5-log₁₀ colony-forming units (CFU) reduction) of MRSA cells in vitro. The aPDT efficacy followed the order Abx-dcPS (combinatorial decacationic) > dcPS (decacationic) >> nPS (nonionic). This order was also verified by the relative physical binding trend of these PSs using either nPS-, dcPS-, or Abx-dcPS-pretreated and pre-fixed MRSA cells in investigations of fluorescent confocal microscopy, UV–vis fluorescence spectroscopy, and transmission electron microscopy (TEM). Conclusions: Furthermore, the molecular conjugate of Abx-dcPS may provide covalent co-delivery of two drug components concurrently, which might also serve as an effective antibiotic agent after aPDT and potentially prevent the reoccurrence of MRSA-induced infection. Full article

Chimeric compounds represent a promising strategy in cancer therapy by simultaneously targeting multiple pathways responsible for tumour growth and survival. Their structure comprises two or more pharmacophores connected through suitable chemical linker. These dual or multi-functional drugs can interact with several biological targets for a more pronounced pharmacological effect. In order to identify new multi-targeting agents with anticancer efficacy, we designed and synthesised a series of novel multi-functional molecules by covalently linking antitumor compounds dichloroacetate (DCA) and Nutlin-3a. The design was aimed at addressing two critical events in cancer: (1) the Warburg effect and (2) the dysregulations of protein p53 pathway, both of which are directly linked to the predominant survival and aggressive proliferation of malignant cells. DCA reactivate oxidative phosphorylation by inhibiting mitochondria pyruvate dehydrogenase kinase (PDK), thereby unlocking the Warburg metabolism of cancer cells and its antiapoptosis state. Concurrently, Nutlin-3a restores the protective function of the “genome guardian” p53 protein, by blocking its antagonist oncoprotein E3 ligase MDM2. Chimeric compounds were obtained using a chemoenzymatic multi-step procedure that included a key lipase-catalysed asymmetric reaction. Biological evaluation of the synthesised Nutlin-DCA chimeras in a panel of three cancer cell lines demonstrated promising results in vitro. Specifically, compounds rac-19a, rac-19b, rac-20a, rac-20b and enantioenriched 20a caused a statistically significant reduction in cell viability at micromolar concentrations. These findings suggest that targeting both the Warburg effect and the p53 pathway with a single molecule is a viable approach for future cancer therapeutic development. Full article

Background and Objectives: Infectious keratitis (IK) is typically managed in an outpatient setting, but patients with severe infections or significant social barriers may require hospital admission. In safety-net hospital systems, these admissions to the intensive care unit (ICU) occur due to hospital protocols for frequent topical antibiotic administration. This study aims to characterize the ocular and social risk factors, visual outcomes, and financial costs associated with ICU admission for IK in an underserved population. Materials and Methods: We conducted a retrospective case series of all patients admitted to the ICU for primary treatment of IK at the Denver Health Medical Center between 1 January 2017 and 31 December 2022. Patients admitted for other medical issues with concurrent IK were excluded. Demographic data, ocular and social risk factors, microbiological culture results, reasons for admission, length of stay, hospital charges, and clinical outcomes were obtained via chart review. Results: Fourteen patients with 16 ICU admissions were included. The average age was 51.7 years, and 79% were male. Most patients endorsed current illicit drug use (71%), and 36% were unhoused. The most common ocular risk factor was trauma (43%). Mean length of stay was 7.43 days, with a mean hospital charge of $48,535.90 per admission. Most ulcers were large (88%) and presented with poor vision (only 19% had better than hand motion vision). The most common reason for ICU admission was concern about outpatient compliance (63%). At last follow-up, 40% of patients had stable vision and 40% had improved vision compared to admission. Conclusions: ICU admission for IK in patients with significant social barriers may preserve vision, but it comes with substantial financial and societal cost. Alternative care strategies and preventative interventions should be considered to reduce reliance on ICU resources while maintaining effective treatment. Full article

Background/Objectives: Hepatoblastoma (HB), the most common pediatric liver cancer, often bears mutations in and/or otherwise deregulates the oncogenic transcription factors β-catenin (B), YAP (Y) and NRF2 (N). HB research is hampered by a paucity of established cell lines, particularly those possessing these molecular drivers. All combinations of B, Y and N (BY, BN, YN and BYN) are tumorigenic when overexpressed in murine livers, but it has not been possible to establish cell lines from primary tumors. Recently, we found that concurrent, in vivo Crispr-mediated targeting of the Cdkn2a tumor suppressor locus allows for immortalized cell lines to be efficiently generated. Methods: We derived and characterized five immortalized cell lines from Cdkn2a-targeted BN and YN HBs. Results: Four of the above five cell lines retained their ability to grow as subcutaneous or “pseudo-metastatic” pulmonary tumors in the immunocompetent mice from which they originated. Most notably, when maintained under hypoxic conditions for as little as 2 days, BN cells transiently upregulated the expression of numerous endothelial cell (EC)-specific genes and acquired EC-like properties that benefited tumor growth. These lines and those from previously derived BY and BYN HBs also possessed similar sensitivities to four commonly employed chemotherapeutic drugs. Conclusions: The above-described approach is currently the only means to generate HB cell lines with pre-selected and clinically relevant oncogenic drivers. Its generic nature should also allow bespoke HB cell lines with other oncogenic drivers to be readily produced. A collection of such cell lines will be useful for studying tumor cell-to-EC trans-differentiation, interactions with the immune environment and drug sensitivities. Full article

Background/Objectives: Inflammatory processes, both acute and chronic, encompass a wide range of autoimmune, metabolic, and neurodegenerative conditions. Conventional treatments, primarily anti-inflammatories and immunosuppressants, provide partial relief but are often hampered by adverse effects and limited durability. Mesenchymal stem cells (MSCs) have emerged as a powerful new treatment due to their immunomodulatory and anti-inflammatory properties, primarily mediated through their secretome, which is a complex mixture of bioactive factors. Secretome-based therapeutic strategies show strong potential for controlling inflammation, mitigating oxidative stress, and supporting tissue regeneration and repair. However, the therapeutic efficacy of MSCs’ secretome is subject to modification by concurrent anti-inflammatory drug regimens used in clinical settings. Methods: To evaluate the effect of combinatorial treatment strategies on the secretome of the MSCs, we employed an in vitro retinal inflammation model to investigate whether the exposure of the MSCs to five representative anti-inflammatory drugs (ketorolac, diclofenac, α-lipoic acid, N-acetyl-L-cysteine, and nicotinamide) impacts the functionality of the resulting secretome. Specifically, we evaluated the effect of the above-mentioned drugs on the anti-inflammatory properties of the secretome in relation to the secreted levels of two main MSC secretome factors—the Brain-Derived Neurotrophic Factor (BDNF) and the Vascular Endothelial Growth Factor (VEGF)—and on the secretome’s pro-metabolic activity. Results: Our findings provide evidence that the presence of any of the tested drugs during MSC secretome production does not compromise its anti-inflammatory activity; BDNF and VEGF levels remain stable, and the secretome retains a high degree of its pro-metabolic effect. Conclusions: These results underscore the robustness and clinical resilience of MSC-based therapies, even when administered alongside pharmacological agents. This work advances the translational viability of MSC therapies for inflammatory diseases and supports the development of safe, combinatorial treatment strategies. Full article

Interest in ketamine as a novel treatment for substance use disorders (SUDs) has been increasing due to its N-methyl-D-aspartate (NMDA) glutamate receptor antagonism and mounting evidence that glutamate neurotransmission is involved in the pathogenesis of both depression and addictions. This narrative review provides an outline of clinical evidence reported in the literature from the 1970s to 2025 that examines the efficacy of ketamine for the treatment of SUDs, focusing primarily on randomized blinded controlled trials (RBCTs). Key cohort studies, retrospective studies, secondary analyses, case reports, and relevant basic neuroscience studies are reviewed to complement the more rigorous human controlled trial data. Thus far, ketamine has been tested in nine RBCTs targeting cocaine (three studies), alcohol (three studies), opioid use disorder (two studies), and nicotine (one study), suggesting efficacy for addiction in combination with psychotherapies, and often when doses produce subjectively reported mystical or psychedelic experiences. This review highlights promising preliminary evidence, and the need for more rigorous studies to elucidate the scope of drug addictions ketamine may target, its optimal dosing or route of administration, the importance of concurrent psychotherapies, professional supervision and safety monitoring, and which psychiatric comorbidities or contexts may contraindicate its use for SUDs. Full article

We present a dual biosensing strategy integrating Quartz Crystal Microbalance (QCM) and Surface-Enhanced Raman Spectroscopy (SERS) for the quantitative and molecular-specific detection of FKBP12. Silver nanodendritic arrays were electrodeposited onto QCM sensors, optimized for SERS enhancement using Rhodamine 6G, and functionalized with a custom-designed receptor to selectively capture FKBP12. QCM measurements revealed a two-step Langmuir adsorption behavior, enabling sensitive mass quantification with a low limit of detection. Concurrently, in situ SERS analysis on the same sensor provided vibrational fingerprints of FKBP12, resolved through comparative studies of the free protein, surface-bound receptor, and surface-bound receptor–protein complex. Ethanol-induced denaturation confirmed protein-specific peaks, while shifts in receptor vibrational modes—linked to FKBP12 binding—demonstrated dynamic molecular interactions. A ratiometric parameter, derived from key peak intensities, served as a robust, concentration-dependent signature of complex formation. This platform bridges quantitative (QCM) and structural (SERS) biosensing, offering real-time mass tracking and conformational insights. The nanodendritic substrate’s dual functionality, combined with the receptor’s selectivity, advances label-free protein detection for applications in drug diagnostics, with potential adaptability to other target analytes. Full article

Caffeine is a widely consumed psychoactive compound known to influence drug metabolism and efficacy through interactions with key enzymes such as cytochrome P450 3A4 (CYP3A4). This study investigates the molecular impact of caffeine on the binding behavior of imatinib, a first-line BCR-ABL tyrosine kinase inhibitor, using molecular docking simulations. Structural optimization and lipophilicity analyses were conducted using HyperChem, while docking was performed with HEX software (Version 8.0.0) against the CYP3A4 receptor (PDB ID: 1W0E). Two administration scenarios were evaluated: concurrent caffeine–imatinib complex formation and sequential administration with caffeine pre-bound to CYP3A4. The caffeine–imatinib complex exhibited a predicted increase in lipophilicity (logP = 3.09) compared to imatinib alone (logP = −1.29), which may indicate the potential for enhanced membrane permeability and tissue distribution. Docking simulations revealed stronger binding affinity of the complex to CYP3A4 (−350.53 kcal/mol) compared to individual compounds, and improved imatinib binding when CYP3A4 was pre-complexed with caffeine (−294.14 kcal/mol vs. −288.19 kcal/mol). Frontier molecular orbital analysis indicated increased reactivity of the complex (ΔE = 7.74 eV), supporting the hypothesis of altered pharmacodynamic behavior. These findings suggest that caffeine may modulate imatinib’s metabolic profile and therapeutic efficacy by enhancing receptor binding and altering drug distribution. The study underscores the importance of evaluating dietary components during drug development and therapeutic planning, particularly for agents metabolized by CYP3A4. Full article

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide, characterized by remarkable molecular heterogeneity and poor clinical outcomes. Despite advancements in diagnosis and treatment, the prognosis for HCC remains dismal, largely due to late-stage diagnosis and limited therapeutic efficacy. Therefore, there is a critical need to identify novel therapeutic targets and explore alternative strategies, such as drug repurposing, to improve patient outcomes. Methods: In this study, we employed network pharmacology, molecular docking, and molecular dynamics (MD) simulations to explore the potential therapeutic targets of Nirmatrelvir in HCC. Results: Nirmatrelvir targets were predicted through SwissTarget (101 targets), SuperPred (1111 targets), and Way2Drug (38 targets). Concurrently, HCC-associated genes (5726) were retrieved from DisGeNet. Cross-referencing the two datasets identified 29 overlapping proteins. A protein–protein interaction (PPI) network constructed from the overlapping proteins was analyzed using CytoHubba, identifying 10 hub genes, with HDAC1, HDAC3, and STAT3 achieving the highest degree scores. Molecular docking revealed a strong binding affinity of Nirmatrelvir to HDAC1 (docking score = −7.319 kcal/mol), HDAC3 (−6.026 kcal/mol), and STAT3 (−6.304 kcal/mol). Moreover, Nirmatrelvir displayed stable dynamic behavior in repeated 200 ns simulation analyses. Binding free energy calculations using MM/GBSA showed values of −23.692 kcal/mol for the HDAC1–Nirmatrelvir complex, −33.360 kcal/mol for HDAC3, and −21.167 kcal/mol for STAT3. MM/PBSA analysis yielded −17.987 kcal/mol for HDAC1, −27.767 kcal/mol for HDAC3, and −16.986 kcal/mol for STAT3. Conclusions: The findings demonstrate Nirmatrelvir’s strong binding affinity towards HDAC3, underscoring its potential for future drug development. Collectively, the data provide computational evidence for repurposing Nirmatrelvir as a multi-target inhibitor in HCC therapy, warranting in vitro and in vivo studies to confirm its clinical efficacy and safety and elucidate its mechanisms of action in HCC. Full article

Background/Objectives: The novel compound 221s (2,9), derived from danshensu and ACEI-active proline, exhibits antihypertensive effects (50/35 mmHg SBP/DBP reduction in SHRs) with potential cough mitigation. However, its excretion kinetics remain unstudied. This study investigates 221s (2,9) elimination in rats to bridge this knowledge gap. Methods: Excretion of unchanged 221s (2,9) was quantified in urine, feces, and bile of Sprague-Dawley rats after oral administration (30 mg/kg). Concentrations of unchanged 221s (2,9) in all matrices were quantified using developed UPLC-MS/MS that underwent methodological validation. Excretion amount, excretion velocity, and accumulative excretion rate of 221s (2,9) were calculated. Results: Urinary excretion exhibited rapid elimination kinetics, reaching peak cumulative excretion rates (138.81 ± 15.56 ng/h) at 8 h post-dosing and plateauing by 48 h (cumulative excretion: 1479.81 ± 155.7 ng). Fecal excretion displayed an accelerated elimination phase between 4 and 8 h (excretion rate: 7994.29 ± 953.75 ng/h), followed by a sustained slow-release phase, culminating in a cumulative output of 36,726.31 ± 5507 ng at 48 h. Biliary excretion was minimal and ceased entirely by 24 h. Notably, total recovery of unchanged drug across all matrices remained below 1% (urine: 0.020 ± 0.021%; feces: 0.73 ± 0.069%; bile: 0.00044 ± 0.00002%) at 72 h. Conclusions: This study provides the first definitive excretion data for 221s (2,9). Quantitative analysis via a validated UPLC-MS/MS method revealed that fecal excretion is the principal elimination pathway for unchanged 221s (2,9) in rats, with direct excretion of the parent compound accounting for <1% of the administered dose over 72 h. Future studies will employ extended pharmacokinetic monitoring and concurrent UPLC-MS/MS analysis of the parent drug and phase II conjugates to resolve the observed mass imbalance and elucidate contributions to total elimination. Full article

Background/objectives: In some cases of concomitant use of direct oral anticoagulants (DOAC) and certain anticancer medications, pharmacokinetic interactions are expected; however, clinical data is scarce. This report reviews the recommendations on the use of DOAC concurrently with anticancer drugs according to different clinical decision support systems and sources, with a focus on discrepancies. Methods: We reviewed the recommendations from the American Heart Association (AHA), European Heart Rhythm Association (EHRA), summary of product characteristics (SPC) in FASS (Swedish medicine information portal), the Swedish clinical decision support system Janusmed, and information from the Food and Drug Administration (FDA) on the concomitant use of apixaban, edoxaban, and rivaroxaban (activated factor X (FXa) inhibitors) and 80 anticancer drugs from 11 categories (240 drug pairs). Results: No warnings of expected pharmacokinetic drug interactions between FXa inhibitors and anticancer drugs were found for 155 drug pairs (65%) across all sources. The remaining 35% of drug pairs were flagged as having possible interactions with FXa inhibitors according to at least one source. Discrepancies in the recommendations from the different sources were reported. The reported discrepancies were, for the most part, associated with different assessments of the mechanism and the extent of pharmacokinetic interactions of each anticancer medication. Also, knowledge sources have different approaches to reporting potential interactions, in some cases reporting clinically relevant strictly pharmacokinetic interactions, whereas others include even patient-specific factors. Conclusions: The lack of clinical data and different recommendations can make clinical decisions on the concomitant use of DOAC and anticancer drugs difficult. Our compilation is meant to assist clinicians in making decisions based on the available evidence, even if it is scarce. Full article

Background and Purpose: Glioblastoma remains a therapeutic challenge with a poor prognosis despite multimodal treatments. Reporter-based magnetic resonance imaging (MRI) offers a promising approach for tumor visualization, but its efficacy depends on sufficient reporter gene expression. This study aimed to develop a chimeric element-regulated ferritin heavy chain 1 (FTH1) reporter system to enhance MRI-based glioma detection while enabling targeted therapy via transferrin receptor (TfR)-mediated drug delivery. Methods: Using gene cloning techniques, we constructed a chimeric FTH1 expression system comprising tumor-specific PEG3 promoter (transcriptional control), bFGF-2 5′UTR (translational enhancement), and WPRE (mRNA stabilization). Lentiviral vectors delivered constructs to U251 glioblastoma cells and xenografts. FTH1/TfR expression was validated by Western blot and immunofluorescence. Iron accumulation was assessed via Prussian blue staining and TEM. MRI evaluated T2 signal changes. Transferrin-modified doxorubicin liposomes (Tf-LPD) were characterized for size and drug loading and tested for cellular uptake and cytotoxicity in vitro. In vivo therapeutic efficacy was assessed in nude mouse models through tumor volume measurement, MR imaging, and histopathology. Results: The chimeric system increased FTH1 expression significantly over PEG3-only controls (p < 0.01), with an increase of nearly 1.5-fold compared to the negative and blank groups and approximately a two-fold increase relative to the single promoter group, with corresponding TfR upregulation. Enhanced iron accumulation reduced T2 relaxation times significantly (p < 0.01), improving MR contrast. Tf-LPD (115 nm, 70% encapsulation) showed TfR-dependent uptake, inducing obvious apoptosis in high-TfR cells compared with that in controls. In vivo, Tf-LPD reduced tumor growth markedly in chimeric-system xenografts versus controls, with concurrent MR signal attenuation. Conclusions: The chimeric regulatory strategy overcomes limitations of single-element systems, demonstrating significant potential for integrated glioma theranostics. Its modular design may be adaptable to other reporter genes and malignancies. Full article

Background and Objectives: The worldwide shift toward psychiatric deinstitutionalization has aimed to enhance patient autonomy, social integration, and overall quality of life. However, limited studies have examined how concurrent substance use—particularly alcohol, marijuana, and inhalable drugs—affects clinical outcomes in these populations. This study aimed to evaluate psychiatric patients with varying degrees of institutionalization and investigate whether substance use complicates or exacerbates treatment outcomes. We hypothesized that individuals using substances would demonstrate worse psychosocial functioning, higher healthcare costs, and increased readmission rates. Methods: We performed a cross-sectional study of 95 participants recruited from long-term care facilities. Participants completed the SF-36 survey validated in Romanian. Financial data were collected to gauge direct and indirect healthcare expenditures. Results: Results indicated that 34.7% of participants reported alcohol use, 12.6% used marijuana, and 9.5% used inhalable substances. Substance-using patients experienced higher mean hospitalization costs of approximately USD 3251.8, compared to non-users (USD 2743.6, p = 0.032). Quality-of-life scores were significantly lower among substance users (mean SF-36 score 58.4 vs. 66.7, p = 0.027). Rates of relapse and readmission were also notably higher in the substance-using cohort (42.1%) relative to non-users (29.8%, p = 0.041). Conclusions: To our knowledge, this is the first Romanian study—and one of only a handful in Europe—to quantify how specific substance-use profiles simultaneously alter quality of life and direct healthcare costs in a deinstitutionalized psychiatric population. Our findings highlight the need for integrated interventions targeting both mental health and substance abuse. Full article

Background/Objectives: Inter-individual metabolic responses to caffeine are shaped by CYP1A2 clearance rate and by concurrent lipid- or glucose-lowering drugs. We investigated how habitual caffeine intake relates to serum cholesterol and fasting glucose under different CYP1A2 rs762551 genotypes and statin or oral antidiabetic (OAD) use. Methods: A prospective cross-sectional analysis was performed on 358 adults (AA = 65, AC = 163, CC = 130) with recorded genotype, daily caffeine intake, total cholesterol, fasting glucose, and medication status. Multivariable linear regression tested the main and interaction effects of caffeine (mg day⁻¹), genotype, and therapy. Results: Caffeine intake was positively associated with cholesterol levels (β = 0.30; p < 0.001). A significant genotype × caffeine interaction (β = 0.27; p < 0.001) revealed the steepest rise in fast metabolisers (AA) not on statins, an effect largely blunted by statin therapy. For glucose, the genotype × caffeine term was also significant (β = 0.30; p < 0.001). Among slow metabolisers (CC) without OADs, caffeine correlated positively with glycaemia (r = 0.34; p = 0.028), whereas in fast metabolisers on OADs the association reversed (r = −0.36; p = 0.015). No meaningful associations occurred in AC carriers. Conclusions: Caffeine’s metabolic impact depends jointly on CYP1A2 genotype and medication. It raises cholesterol in fast metabolisers lacking statins and elevates glucose in slow metabolisers without OADs, yet may lower glucose when rapid metabolisation coincides with antidiabetic therapy. Accounting for this gene–diet–drug interplay could refine caffeine guidance within precision nutrition frameworks. Full article

Introduction: Methadone, a synthetic opioid used for opioid substitution therapy (OST), is typically associated with arrhythmias rather than direct myocardial depression. Neurological complications, especially with concurrent antipsychotic use, have also been reported. Acute left ventricular failure in young adults is uncommon and often linked to genetic or infectious causes. We present a rare case of reversible cardiogenic shock and cerebellar insult due to methadone toxicity. Case Presentation: A 37-year-old man with a history of drug abuse on OST with methadone (130 mg/day) was admitted to the ICU with hemodynamic instability, seizures, and focal neurological deficits. Diagnostic workup revealed low cardiac output syndrome and a right cerebellar insult, attributed to methadone toxicity. The patient received individualized catecholamine support. After 10 days in the ICU, he was transferred to a general ward for ongoing cardiac and neurological rehabilitation and discharged in stable condition seven days later. Conclusions: Methadone-induced reversible left ventricular failure, particularly when accompanied by cerebellar insult, is rare but potentially life-threatening. Early recognition and multidisciplinary management are essential for full recovery in such complex toxicological presentations. Full article