Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Gastric ulcer (GU), a common digestive system disorder in clinical practice, often arises from excessive alcohol consumption and other factors that irritate the gastric mucosa. Effective treatment of GU remains challenging due to the poor targeting, limited efficacy, and significant side effects associated with current therapeutic approaches. To address these limitations, we developed a microenvironment-responsive hydrogel composed of sodium alginate (SA) and chitosan (CS), incorporating MnO₂ nanoparticles and pachymic acid (PA). This hydrogel was designed to evaluate its therapeutic potential for GU treatment in both in vitro and in vivo models. The SA/CS hydrogel system rapidly formed in response to acidic gastric conditions, leveraging the microenvironment to enhance therapeutic efficacy. Encapsulated MnO₂ nanoparticles could scavenge reactive oxygen species (ROS), mitigating oxidative stress, while PA further alleviated oxidative damage. In vitro studies demonstrated that this hydrogel system significantly promoted the migration of gastric mucosal epithelial cells (GES-1) and reduced oxidative stress-induced damage under H₂O₂ stimulation. Furthermore, in vivo evaluations using animal models of ethanol-induced acute GU and acetic acid-induced chronic GU confirmed the hydrogel's pronounced anti-ulcer effects. These results underscore the potential of MnO₂-and PA-loaded SA/CS hydrogels as a safe, targeted, and effective therapeutic strategy for ethanol-induced gastric injury. This novel approach offers a promising foundation for the development of future gastric ulcer treatments.

Genetically engineered immune cells hold great promise for treating immune-related diseases, but their development is hindered by technical challenges, primarily related to nucleic acid delivery. Polyethylenimine (PEI) is a cost-effective transfection agent, yet it requires significant optimization for effective T cell transfection. In this study, we comprehensively fine-tuned the characteristics of PEI/DNA nanoparticles, culture conditions, cellular physiology, and transfection protocols to enhance gene delivery into T cells. Gel retardation and dynamic light scattering (DLS) analyses confirmed that PEI effectively bound to DNA, forming size- and charge-adjustable particles based on the N/P ratio, which remained stable in RPMI 1640 medium for 3 days at 25°C. At an N/P ratio of 8.0, these nanoparticles achieved an optimal transfection rate, which improved further with adjustments in DNA dosage and complex volume. Additionally, increasing the cell seeding density and adding complete media shortly after transfection significantly boosted PEI-mediated gene delivery. Notably, reversing the transfection in vials resulted in a 20-fold increase in cellular uptake and transfection efficiency compared to the conventional direct transfection method in culture plates. Finally, modifying cellular physiology with hypotonic extracellular media at pH 9.0 dramatically enhanced transfection rates while maintaining minimal cytotoxicity. These findings could reduce the cost and complexity of preparing engineered T cells, potentially accelerating the development of immune cell therapies for human diseases.

Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSD1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSD1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSD1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSD1 and beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment.

Periodontitis, a chronic inflammatory condition of the oral cavity, is characterized by the progressive destruction of the supporting structures of the teeth. The pathogenic effects of periodontopathogens extend beyond the local periodontal environment, contributing to systemic health complications, thereby underscoring the need for effective therapeutic strategies. Current standard treatments, which involve mechanical debridement coupled with systemic anti-inflammatory and antibiotic therapies, are often associated with limited efficacy, adverse effects, and the emergence of antibiotic resistance. Recent advancements in localized drug delivery systems present an innovative alternative, offering site-specific targeting with sustained therapeutic action. Smart drug delivery platforms, designed to respond to the unique microenvironment of periodontal pockets, undergo physicochemical transformations such as gelation or controlled drug release, enhancing treatment efficacy. This review comprehensively explores the etiological and prognostic factors of periodontitis, critical diagnostic biomarkers, and an in-depth analysis of stimuli-responsive biomacromolecule-based gels. These systems are evaluated for their structural properties, biological compatibility, and therapeutic potential while addressing their limitations and barriers to clinical translation. By integrating insights into the interplay between material properties and biological performance, this review highlights the future role of these advanced delivery systems in overcoming challenges in periodontal healthcare. Such approaches aim to bridge the gap between bench-side innovation and bedside application, offering the transformative potential to enhance therapeutic outcomes and improve patient quality of life in managing periodontal diseases.

Researching disinfection strategies is pivotal because effectively eliminating bacteria and their byproducts during root canal treatment (RCT) remains a challenge. This study investigated the antimicrobial efficacy of natural antimicrobial compounds, propolis (PRO) and copaiba oil-resin (COR), compared to conventional agents in Endodontics. Antimicrobials were tested against endodontic pathogens via macrodilution with standardized inoculums to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). Biofilm killing efficacy were performed using two dual-species biofilms: Enterococcus faecalis (ATCC 29212) and Streptococcus mutans (ATCC 20523) and Streptococcus oralis (J22) and Actinomyces naeslundii (T14V-J1) grown on dentine discs. At the intratubular level (dentine cylinders), dentine tubule contamination was performed with E. faecalis and S. mutans. The specimens were exposed to antimicrobials to simulate their use at different sets of RCT and bacterial viability was quantified using Live/Dead staining via confocal laser scanning microscopy (CLSM). Biofilm characteristics and immediate removal of S. oralis and A. naeslundii biofilm model were evaluated employing optical coherence tomography (OCT) and CFU/mL counting. Statistical tests were applied according to data distribution for each analysis (α=0.05). Macrodilutions showed different effects against endodontic pathogens. Direct contact and intratubular analysis showed that PRO and COR promoted disinfection like conventional agents (p > 0.05). According to OCT analysis, PRO and COR showed similar biofilm reduction after immediate contact (p < 0.05). CFU/mL counting showed decontamination (p < 0.05) after using natural and conventional agents. PRO and COR showed antimicrobial effects, indicating their suitability as complementary approaches in RCT to eliminate as much microbial load as possible.

Platinum(IV) compounds possess distinct properties that set them apart from platinum(II) compounds. Often designed as prodrugs, they are reduced within cancer cells to their active platinum(II) form, enabling their cytotoxic effects. Their versatility also lies in their ability to be functionalized and conjugated with bioactive molecules to enhance cancer cell targeting. This report introduces new prodrugs that combine antitumor cisplatin with axially coordinated eugenol, leveraging their synergistic action to target cancer stem cells. A third bioactive ligand, 4-phenylbutyrate or octanoate, was added to further enhance biological activity, creating 'triple action' prodrugs. These new platinum(IV) prodrugs offer a novel approach to cancer therapy by improving targeting, increasing efficacy, overcoming drug resistance, and reducing tumor invasiveness while sparing healthy tissue.

Myocardial dysfunction, characterized by impaired cardiac muscle function, arises from diverse etiologies, including coronary artery disease, myocardial infarction, cardiomyopathies, hypertension, and valvular heart disease. Recent advancements have highlighted the roles of exosomes and non-coding RNAs in the pathophysiology of myocardial dysfunction. Exosomes are small extracellular vesicles released by cardiac and other cells that facilitate intercellular communication through their molecular cargo, including ncRNAs. ncRNAs are known to play critical roles in gene regulation through diverse mechanisms, impacting oxidative stress, fibrosis, and other factors associated with myocardial dysfunction. Dysregulation of these molecules correlates with disease progression, presenting opportunities for therapeutic interventions. This review explores the mechanistic interplay between exosomes and ncRNAs, underscoring their potential as biomarkers and therapeutic agents in myocardial dysfunction. Emerging evidence supports the use of engineered exosomes and modified ncRNAs to enhance cardiac repair by targeting signaling pathways associated with fibrosis, apoptosis, and angiogenesis. Despite promising preclinical results, delivery, stability, and immunogenicity challenges remain. Further research is needed to optimize clinical translation. Understanding these intricate mechanisms may drive the development of innovative strategies for diagnosing and treating myocardial dysfunction, ultimately improving patient outcomes.

Over 30 % of patients with schizophrenia experience treatment resistance and severe side effects. The limited efficacy of antipsychotic therapies poses a challenge, partly due to the blood-brain barrier (BBB) and the non-selective targeting of these drugs. Herein, we report on arecoline (ARE), a water soluble natural small molecule, which was successfully constructed a phospholipid complex by noncovalent interactions. Most striking, this arecoline-phospholipid complex nanoplatforms (ARE-PC NPs) could prevent the hydrolyzation of its ester group by carboxylesterases, which showed sustained release, superior physiological stability and long circulatory capability. Both in vitro cells and in vivo mice speculated that this ARE-PC NPs might has a high cellular uptake and stronger penetration ability of the BBB. Additionally, our results demonstrated that this phospholipid complex might facilitate ARE delivery to the brain tissue and obviously improve the schizophrenia-like behavior in cuprizone induced animal models. This study highlights ARE-PC NPs as a promising antipsychotic nanodrug for the therapy of schizophrenia.

Repeated traumatic brain injury has grown in importance as sports-related injuries have increased. Repetitive mild TBI (rmTBI) increases the risk of developing neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, as well as chronic comorbidities like PTSD, depression, substance abuse and neuroendocrine functions. However, no effective therapeutic strategies have been reported for the effective management of TBI. Herein, we examined the effectiveness of co-delivery of the phytonutrients curcumin, trans-resveratrol, and carnosic acid as a bioavailable complex (CGM+) in managing rmTBI in the rodent model. The rats were randomly assigned to sham, rmTBI, and CGM+ (300 mg/kg b.wt.) groups for a total of 21 days. On Days 6 and 7, all animals, except those in the sham group, were subjected to repeated mild traumatic brain injury (rmTBI). The CGM+ group received supplementation throughout the 21 days, while the other groups received a vehicle. Neurological severity score (NSS) was assessed 24 h after the last injury, and behavioral tests were completed within 14 days post-injury. Samples for the biochemical analysis were collected after euthanasia. CGM+ supplementation significantly decreased the sensory-motor deficits associated with rmTBI. Following TBI, the CGM+ group demonstrated enhanced memory and low-stress levels. Furthermore, CGM+ has been shown to modulate neurotransmitter levels and promote neurogenesis. The biochemical and molecular analysis revealed that CGM+ promotes recovery following rmTBI by modulating mitochondrial bioenergetics and BDNF pathways. The findings indicate that CGM+ can be used to manage cognitive and sensory-motor defects caused by rmTBI, such as in the case of sports injuries.

Viral infections have led to the deaths of millions worldwide and come with significant economic and social burdens. Emerging viral infections, as witnessed with coronavirus disease 2019 (COVID-19), can profoundly affect all aspects of human life, highlighting the imperative need to develop diagnostic, therapeutic, and effective control strategies in response. Numerous studies highlight the diverse applications of nanoparticles in diagnosing, controlling, preventing, and treating viral infections. Due to favorable and flexible physicochemical properties, small size, immunogenicity, biocompatibility, high surface-to-volume ratio, and the ability to combine with antiviral agents, gold nanoparticles (AuNPs) have shown great potential in the fight against viruses. The physical and chemical properties, the adjustability of characteristics based on the type of application, the ability to cross the blood-brain barrier, the ability to infiltrate cells such as phagocytic and dendritic cells, and compatibility for complexing with various compounds, among other features, transform AuNPs into a suitable tool for combating and addressing pathogenic viral agents through multiple applications. In recent years, AuNPs have been employed in various applications to fight viral infections. However, a comprehensive review article on the applications of AuNPs against viral infections has yet to be available. Given their versatility, AuNPs present an appealing option to address various gaps in combating viral infections. Hence, this review explores the attributes, antiviral properties, contributions to drug delivery, vaccine development, and diagnostic uses of AuNPs.