Search Results (1,239)

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

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. Full article

Skin dullness contributes to a fatigued and aged appearance, often exceeding one’s biological age. It is a common dermatological concern influenced by aging and poor lifestyle habits, regardless of ethnicity or age. This study aimed to examine advanced glycation end products (AGEs) and their receptor (receptor for AGEs [RAGE]) as contributing factors to skin dullness. AGEs themselves have a yellowish hue, contributing to “yellow dullness.” Additionally, AGE–RAGE signaling promotes melanin production in melanocytes and impairs keratinocyte differentiation as a result of inflammation. Therefore, regulating the AGE–RAGE interaction may help reduce skin dullness. Through screening various natural ingredients, we found that peony root extract (PRE) inhibits AGE formation and blocks AGE–RAGE binding. Furthermore, the presence of PRE leads to the suppression of AGE-induced melanin production in melanocytes and the restoration of impaired keratinocyte differentiation in glycated basement membrane components. In a human clinical study, topical application of a 1% PRE-containing lotion for 2 weeks significantly reduced melanin content, with a trend toward decreased AGE accumulation and visible spots on the cheeks. These findings support the potential of PRE as a multifunctional cosmetic ingredient that comprehensively addresses skin dullness by modulating the AGE–RAGE interaction. Full article

The covalent cross-linking of caseins by the enzyme transglutaminase (Tgase) stabilizes the structure of casein micelles. In our study, the effects of a pretreatment of skim milk (SM) by Tgase on milk protein fractionation by microfiltration were tested. Tgase was found to induce amount-dependent modifications of all milk proteins in SM and a reduction in deposit resistance for laboratory dead-end filtrations of up to 20%. This improvement in process performance could partially be confirmed in pilot-scale cross-flow filtrations of Tgase-pretreated SM and micellar casein solutions (MCC). These comparative trials with untreated retentates under a variation of ΔpTM (0.5–2 bar) at 10 and 50° revealed distinct differences in deposit behavior and achieved the reduction in deposit resistance in a range of 0–20%. The possibility of pre-fouling with enzymatically pretreated MCC prior to SM filtration was also investigated. Under different pre-fouling conditions, practical modes of retentate change, and pre-foulant compositions, a switch to untreated SM consistently resulted in an immediate and major increase in deposit resistance by 50–150%. This was partially related to the change in the ionic environment and the protein fraction. Nevertheless, our results underline the potential of Tgase pretreatment and pre-fouling approaches to alter filtration performance for different applications. Full article

Changes in lifestyles, as well as the growing attention to healthy nutrition, led to the increasing demand for wines with reduced alcohol content. The reduction in fermentable sugars in the pre-fermentation stage of wine is one of the common methods for the production of wines with lower alcohol content. Viticultural practices such as early harvesting, use of growth regulators, reducing leaf area to limit photosynthetic rate, and pre-harvest irrigation are utilized. Additionally, techniques such as juice dilution, juice filtration with membranes, and the use of enzymes (e.g., glucose oxidase) are also employed in the pre-fermentation stage. This review summarizes and describes the classic and innovative viticultural and pre-fermentation techniques used to reduce the alcohol content and their main impact on the compositional characteristics of wine. Full article

Transcranial direct current stimulation (tDCS) can modulate cortical excitability in a polarity-specific manner, yet identical protocols often produce inconsistent outcomes across sessions or individuals. This narrative review proposes that much of this variability arises from the brain’s intrinsic temporal landscape. Integrating evidence from chronobiology, sleep research, and non-invasive brain stimulation, we argue that tDCS produces reliable, polarity-specific after-effects only within a circadian–homeostatic “window of efficacy”. On the circadian (Process C) axis, intrinsic alertness, membrane depolarisation, and glutamatergic gain rise in the late biological morning and early evening, whereas pre-dawn phases are marked by reduced excitability and heightened inhibition. On the homeostatic (Process S) axis, consolidated sleep renormalises synaptic weights, widening the capacity for further potentiation, whereas prolonged wakefulness saturates plasticity and can even reverse the usual anodal/cathodal polarity rules. Human stimulation studies mirror this two-process fingerprint: sleep deprivation abolishes anodal long-term-potentiation-like effects and converts cathodal inhibition into facilitation, while stimulating at each participant’s chronotype-aligned (phase-aligned) peak time amplifies and prolongs after-effects even under equal sleep pressure. From these observations we derive practical recommendations: (i) schedule excitatory tDCS after restorative sleep and near the individual wake-maintenance zone; (ii) avoid sessions at high sleep pressure or circadian troughs; (iii) log melatonin phase, chronotype, recent sleep and, where feasible, core temperature; and (iv) consider mild pre-heating or time-restricted feeding as physiological primers. By viewing Borbély’s two-process model and allied metabolic clocks as adjustable knobs for plasticity engineering, this review provides a conceptual scaffold for personalised, time-sensitive tDCS protocols that could improve reproducibility in research and therapeutic gain in the clinic. Full article

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

Sugar production generates wastewater rich in dissolved solids and organic matter, and improper disposal poses severe environmental risks, exacerbates water scarcity, and creates regulatory challenges. Conventional treatment methods, such as evaporation and chemical precipitation, are energy-intensive and often ineffective at removing fine particulates and dissolved impurities. This study evaluates membrane-based separation as a sustainable alternative for water reclamation and sugar recovery from sugar industry effluents, focusing on replacing evaporation with membrane processes, ensuring high permeate quality, and mitigating membrane fouling. Cross-flow filtration experiments were conducted on a lab-scale membrane system at 70 °C to suppress microbial growth, comparing direct reverse osmosis (RO) of the raw effluent to an integrated ultrafiltration (UF)–RO process. Direct RO resulted in rapid membrane fouling. A tight UF (5 kDa) pre-treatment before RO significantly mitigated fouling and improved performance, enabling 28% water recovery and 79% sugar recovery, maintaining permeate conductivity below 0.5 mS/cm, sustaining stable flux, and reducing membrane blocking. Additionally, the UF and RO membranes were tested via SEM, EDS, and FTIR to elucidate the fouling mechanisms. Full article

Limbal dermoids are congenital, benign, choristomatous growths affecting the corneal-limbal junction. Conventional excision techniques often result in persistent epithelial defects, corneal thinning, and vascularization due to sectoral limbal stem cell deficiency. This study investigated a novel surgical approach for limbal dermoid excision, utilizing Bowman’s membrane lenticule and autologous limbal stem cell transplantation, aimed at improving epithelial healing and visual outcomes. Thirty-four subjects (24 females, 10 males; mean age 8.33 ± 6.47 years) with limbal dermoids underwent the procedure. After dermoid excision, a Bowman’s membrane lenticule was placed over the defect and tucked 1 mm beneath the surrounding tissue. Sectoral limbal reconstruction was then performed using the AutoSLET technique. Pre- and postoperative assessments included visual acuity, corneal thickness, and epithelialization time. Statistical analysis employed paired t-tests. The mean epithelialization time was 3.36 ± 0.74 weeks, indicating rapid healing. Best-corrected visual acuity (BCVA) significantly improved from a preoperative mean of 0.136 ± 0.121 decimal units to a postoperative mean of 0.336 ± 0.214 decimal units (p < 0.001). Corneal thickness also demonstrated a significant increase, rising from a preoperative mean of 294 ± 49.68 microns to a postoperative mean of 484 ± 5.037 microns (p < 0.001). There is a transient edema below the Bowman lenticule observed in many cases, which resolves with deposition of granulation tissue. The findings suggest that the combined use of Bowman’s membrane lenticule and autologous limbal stem cell transplantation offers a promising surgical strategy for limbal dermoid excision. This technique promotes rapid epithelialization and leads to significant improvements in visual acuity and corneal thickness compared to conventional methods. The utilization of Bowman’s membrane as a natural basement membrane and the direct application of limbal stem cells facilitate enhanced epithelial healing and visual rehabilitation. While the study is limited by its small sample size, the results demonstrate the potential of this novel approach in managing limbal dermoids effectively. Full article

Burn wounds present a significant challenge to both the medical and scientific communities, contributing to the global economic burden on healthcare systems. Due to the complexity and highly variability of burn injuries, along with intricate pathophysiological mechanisms, the development of appropriate and effective treatment strategies remains particularly demanding. The development of robust pre-clinical models that recapitulate specific molecular and cellular events underlying burn injury are essential to advance the understanding of associated biological mechanisms and facilitate the screening of innovative therapeutic interventions. While conventional in vivo models can replicate the key aspects of human burn wound pathology, they are often associated with ethical, logistical, and cost-related limitations. In this context, this study aims to explore the potential of the chicken chorioallantoic membrane (CAM) as an alternative model for burn wound research. Thus, we describe a reproducible and ethically favorable protocol for establishing standardized burn injuries on the CAM and provide a comprehensive evaluation of tissue responses through macroscopic, morphometric, and histological analyses. Our findings support the CAM as a viable pre-clinical platform for the study of burn wound healing and for the early-stage screening of candidate therapeutic agents. Full article

Background Veno-venous extracorporeal membrane oxygenation (VV-ECMO) supports critically ill patients with respiratory failure. However, ECMO may induce systemic inflammation, hemolysis, and hemodilution, potentially resulting in endothelial activation and damage. Therefore, this study explored the longitudinal changes in circulating markers of inflammation, hemolysis, and endothelial activation and damage in patients with COVID-19 on VV-ECMO. Methods Plasma was obtained before, within 48 h as well as on day 4, week 1, and week 2 of ECMO support and after decannulation. Circulating markers were measured using Luminex, ELISA, and spectrophotometry. Human pulmonary endothelial cells were exposed to patient plasma, and in vitro endothelial permeability was assessed using electric cell-substrate impedance sensing. Results From April 2020 to January 2022, plasma was collected from 14 patients (71.4% male; age 54 (45–61) years). IL-6 levels decreased (1.238 vs. 0.614 ng/mL, p = 0.039) while ICAM-1 increased (667 vs. 884 ng/mL, p = 0.003) over time when compared to pre-ECMO. Angiopoietin-1 decreased after ECMO initiation (7.57 vs. 3.58 ng/mL, p = 0.030), whereas angiopoietin-2 increased (5.20 vs. 10.19 ng/mL, p = 0.017), particularly in non-survivors of ECMO. Cell-free hemoglobin decreased directly after VV-ECMO initiation but remained stable thereafter (55.29 vs. 9.19 mg/dL, p = 0.017). Moreover, the plasma obtained at several time points during the ECMO run induced in vitro pulmonary endothelial hyperpermeability. Conclusions This exploratory study shows that patients on VV-ECMO support due to COVID-ARDS exhibit progressive endothelial activation and damage but not inflammation and hemolysis. Larger prospective studies are necessary to elucidate pathophysiological pathways leading to endothelial activation and damage, thereby reducing organ failure in these critically ill patients. Full article

Skin is the first line of defence between the human body and the outside world, and it is constantly exposed to external injuries and wounds for a variety of reasons. Collagen is a structural protein of the extracellular matrix and an important component of the dermis. As a wound dressing, collagen not only provides nutrients to wounds but also enhances the immune response in the pre-healing phase, making it an excellent biomaterial for healing. In this study, we used electrospinning and freeze-drying technology to prepare a Bovine Achilles Tendon Collagen (BATC) electrospun composite membrane and a BATC freeze-dried composite membrane using BATC as a substrate supplemented with 16.7% Polyethylene oxide (PEO) and 0.2% Kukoamine B (KuB). The physicochemical properties and biocompatibility of the BATC composite membrane were verified via scanning electron microscopy, Fourier-transform infrared spectroscopy, and DSC analysis and by measuring the DPPH radical-scavenging capacity, water absorption, water retention, in vitro drug release, and extract cytotoxicity. The BATC composite membrane was found to have a significant effect on skin wound healing, especially in the middle stage of healing, in a mouse full-thickness skin injury model. The BATC/PEO/KuB electrospun composite membrane (EBPK) had the best capacity for promoting wound healing and can be used as a wound dressing for in-depth research and development, and KuB, a monomer component with a clear structure and mechanism of action, can be used as a candidate component of composite dressings. Full article

Respiratory syncytial virus (RSV) is a major etiological agent of lower respiratory tract infections, particularly among infants and the elderly. Activation of B cells in the mucosa and the production of specific neutralizing antibodies are essential for protective immunity against pulmonary infection. B-cell activating factor (BAFF) is a critical survival factor for B cells and has been associated with antiviral responses; however, its regulation during RSV infection remains poorly understood. This study examined BAFF regulation in BEAS-2B cells exposed to RSV or IFN-β. The treatments resulted in a progressive increase in gene expression over time, accompanied by higher protein levels. BAFF mRNA peaked at 12 h post-infection and declined by 48 h, coinciding with the release of soluble BAFF protein into the culture supernatant. Pre-treatment with anti-IFN-β antibodies prior to RSV infection reduced both BAFF mRNA and protein levels, indicating that IFN-β plays a regulatory role in BAFF production by airway epithelial cells. Western blot analysis revealed membrane-bound BAFF (~31 kDa) in non-infected cells, with elevated expression at 24 h post-infection. By 48 h, this form was cleaved into a soluble ~17 kDa form, which was detected in the supernatant. Immunostaining further demonstrated reduced surface expression of membrane-bound BAFF in RSV-infected cells compared to uninfected controls, suggesting that RSV infection promotes the cleavage and release of BAFF into the extracellular environment. Additionally, the release of BAFF was not affected by furin convertase inhibition or ER–Golgi transport blockade, indicating a potentially novel cleavage mechanism. Co-culturing BAFF produced by BEAS-2B cells with isolated B cells enhanced B cell viability. Overall, these results indicate that RSV infection stimulates BAFF production in airway epithelial cells through a pathway involving IFN-β, potentially contributing to B cell activation and promoting local antibody-mediated immunity. Understanding this mechanism may offer valuable insights for improving mucosal vaccine strategies and enhancing immunity against respiratory pathogens. Full article

Introduction: Monteggia fractures, first described by Giovanni Battista Monteggia, involve a fracture of the proximal ulna with anterior dislocation of the radial head. Bado’s 1967 classification divides these injuries into four types. Rare mixed patterns exist, overlapping with other forearm injuries such as Galeazzi and Essex–Lopresti lesions. These complex fractures/dislocations pose significant diagnostic and therapeutic challenges and are not adequately represented in current classification systems. Methods and Case Presentation: We report the case of a 56-year-old woman with a complex forearm injury sustained from a fall, presenting with radial head fracture/dislocation, mid-shaft radial fracture, distal ulna fracture, and ulnar collateral ligament rupture. Intraoperative imaging confirmed DRUJ stability and partial interosseous membrane disruption. Surgical management included radial head prosthesis implantation, radial shaft fixation with an anatomical locking plate, intramedullary nailing of the distal ulna, and ligament reconstruction. At two-year follow-up, the patient demonstrated full recovery of elbow flexion–extension and satisfactory forearm function. A narrative literature review was also conducted, focusing on hybrid injury variants. Results: Intraoperative examination under anesthesia revealed good elbow stability with 130° flexion, 15° extension lag, and forearm pronation/supination of 70°/60°. An initial Mayo Elbow Performance Score (MEPS) of 65 was recorded, limited by range of motion and stability. Pain during passive mobilization was mild, with a Visual Analogue Scale (VAS) score of 3/10. Postoperative recovery included 15 days of immobilization followed by structured rehabilitation. At two years, the patient regained full elbow flexion–extension but had residual deficits in pronation–supination, attributed to pre-existing conditions. Conclusions: This case illustrates a previously unreported hybrid Monteggia variant, combining features of Monteggia, Galeazzi, and Essex–Lopresti injuries. It highlights the limitations of current classification systems and supports the need for an expanded diagnostic framework. Successful management required a multidisciplinary surgical approach tailored to the injury’s complexity. Further studies are warranted to refine classification and treatment strategies for these rare combined injuries. Full article

Creatinine serves as a crucial diagnostic biomarker for assessing kidney disease. This work developed portable non-enzymatic and multienzyme-modified electrochemical biosensors for the detection of creatinine based on commercial screen-printed carbon electrodes (SPCEs). The non-enzymatic creatinine sensor was constructed by the electrochemical deposition of AuNPs onto the surface of a pre-activated SPCE by electrochemical activation, followed by the surface modification of a Nafion membrane. The developed AuNPs/SCPE exhibited excellent reproducibility, and the proposed Nafion/AuNPs/SPCE sensor showed excellent detection sensitivity and selectivity toward creatinine. In comparison, the enzymatic creatinine biosensor was gradually established by the electrodeposition of a Prussian blue (PB) membrane on the optimal AuNPs/SCPE surface, followed by multi-enzyme cascade modification (which consisted of creatinine amidohydrolase (CA), creatine oxidase (CI) and sarcosine oxidase (SOx)) and drop-casting the Nafion membrane to stabilize the interface. The introduction of a PB interlayer acted as the redox layer to monitor the generation of hydrogen peroxide (H₂O₂) produced by the enzymatic reaction, while the Nafion membrane enhanced the detection selectivity toward creatine, and the multi-enzyme cascade modification further increased the detection specificity. Both non-enzymatic and enzymatic creatinine sensors could detect the lowest concentrations of less than or equal to 10 μM. In addition, the efficiency and reproducibility of the proposed composite biosensor were also confirmed by repetitive electrochemical measurements in human serum, which showed a positive linear calibration relation of peak currents versus the logarithm of the concentration between 10 μM and 1000 μM, namely, i_p (μA) = −7.06 lgC (μM) −5.30, R² = 0.996. This work offers a simple and feasible approach to the development of enzymatic and non-enzymatic creatinine biosensors. Full article