Experimental Biology and Medicine最新文献

Natural killer (NK) cells represent a fundamental component of the innate immune system, endowed with the ability to identify and eradicate virus-infected and malignant cells. The advent of chimeric antigen receptor (CAR) technology has introduced innovative strategies for augmenting the antitumor potential of natural killer (NK) cells. Chimeric antigen receptor natural killer (CAR-NK) cells exert dual cytotoxic effects against tumor cells through CAR-mediated antigen-specific recognition in concert with the nonspecific cytolytic activity mediated by intrinsic NK receptors. This review critically evaluates the clinical progression of CAR-NK cells specifically against solid tumors, focusing on mechanisms to overcome the immunosuppressive tumor microenvironment (TME), the complexity of allogeneic manufacturing, and the latest engineering strategies for enhanced homing and persistence. Specifically, we emphasize the urgent need for robust Phase II/III clinical data and standardized Good Manufacturing Practice (GMP) protocols to realize the full potential of off-the-shelf allogeneic CAR-NK therapies. Additionally, we examine technological advancements and emerging directions addressing persistent challenges in this domain to offer theoretical underpinnings and research perspectives for the clinical deployment of CAR-NK cell therapy in solid tumor management.

Oxidative stress is a critical factor in the development of cardiometabolic diseases. The Oxidative Balance Score (OBS), integrating dietary and lifestyle factors, has been proposed as a measure of the balance between pro-oxidants and antioxidants. This study aims to explore the relationship between OBS and prevalent cardiometabolic multimorbidity (CMM), and to evaluate whether adding OBS into clinical practice is associated with better CMM identification in the general population. A total of 26,191 participants were selected from the National Health and Nutrition Examination Survey. CMM was defined as having a history of two or more conditions: diabetes mellitus, stroke, or coronary heart disease. The prevalence of CMM was 2.95%. After adjusting for demographic, anthropometric, laboratory, and medical history data, each standard deviation increase in OBS was associated with a 26.1% reduction in the risk of prevalent CMM. Participants in the highest quartile of OBS had a 0.530-fold risk of prevalent CMM compared to those in the lowest quartile. Smooth curve fitting indicated a proportional reduction in CMM risk with increasing OBS. Sensitivity analysis confirmed significant associations between both dietary and lifestyle OBS with prevalent CMM. ROC analysis revealed that incorporating OBS into conventional cardiometabolic risk factors was associated with a slight improvement in CMM identification (AUC: 0.912 vs. 0.916, P = 0.001). Reclassification analysis further indicated the incremental value of OBS. This study revealed a negative, linear, and robust association between OBS and prevalent CMM in the general population. However, reverse causation cannot be ruled out. Future studies should use longitudinal or Mendelian randomization approaches to establish causality.

Berberine, known as an antioxidant agent, can improve glycemic indices in animal models of diabetes; however, it is clinically limited by poor bioavailability. Nanoparticles show the desirable capacity as delivery platforms for improving the bioavailability of medicinal agents. Here, we aimed to enhance the bioavailability and therapeutic impacts of berberine in streptozotocin (STZ)-induced gestational diabetes mellitus (GDM) rats by its encapsulation into the chitosan-coated solid lipid nanoparticles (SLNs) formulation. Berberine-loaded chitosan/SLN nanoparticles were formulated by the solvent-injection approach followed by a homogenization operation. The particle size, surface charge, and polydispersity index, as well as encapsulation efficiency percent (EE%), in vitro stability and berberine release, and in vivo pharmacokinetics were studied. Glycemic indices, such as fasting glucose and insulin, oral glucose tolerance, insulin tolerance, and homeostasis model of insulin resistance (HOMA-IR) scores, as well as the activity level of liver antioxidant and pro-oxidant enzymes, were evaluated in STZ-induced GDM rats. The particle size of berberine-loaded chitosan/SLN formulation was detected in the nano-range with high stability and high EE% as well as a sustained-release profile. Berberine nanoparticle treatment could provide a significantly higher oral bioavailability of berberine in experimental rats. Berberine nanoparticles remarkably reversed the altered glycemic indices, body weight, and pro-oxidant/antioxidant balance in STZ-induced GDM rats, with significantly higher effects than free berberine. In conclusion, chitosan-coated SLN nanoparticles firmly enhanced the therapeutic impacts of berberine on STZ-induced GDM, suggesting chitosan-coated SLN nanoparticles as an efficient oral delivery system for enhancing the bioavailability of berberine and, thus, improving its pharmacological impacts.

Peripheral artery disease (PAD) is a disease of both atherosclerotic and thromboembolic pathology, affecting more than 230 million people globally. PAD patients are at an increased risk of thrombotic events and often require lifelong antithrombotic therapy. Thromboembolism can lead to complete occlusion of affected arteries and put patients at risk for critical limb threatening ischemia (CTLI). PAD blockages are cleared using drug-eluting stents (DES) and drug-coated balloons (DCB). However, PAD treatment below the knee (BTK) presents unique challenges. While DCB are frequently used to treat BTK disease, no DCB has gained FDA approval for this indication. However, innovation in the field has produced drug delivery systems and formulations that may yet enhance the effectiveness of these therapies. In this review, we will provide a brief overview of the pathological mechanisms associated with PAD and review the materials and drugs frequently used in DCBs with an emphasis on excipients and drug carriers. Finally, we will highlight emerging devices undergoing clinical trials to treat BTK disease and how they differ from their predecessors.

Sickle cell disease (SCD) is a severe inherited hemoglobinopathy with limited curative treatment options. In December 2023, the U.S. FDA approved two autologous gene therapies, lovo-cel (bluebird bio) and exa-cel (Vertex/CRISPR Therapeutics), offering potentially transformative outcomes. We performed a comparative analysis of these therapies based on published clinical trial design, patient eligibility, manufacturing requirements, and reported efficacy and safety outcomes. Overall, participants treated with lovo-cel had more severe baseline disease, reflected by a higher median rate of vaso-occlusive events (VOEs), despite the use of a more stringent VOE definition. Mobilization of hematopoietic stem cells (HSCs) with single-agent plerixafor proved challenging in both trials, with most participants requiring multiple mobilization and apheresis cycles. A greater proportion of exa-cel participants required three or more apheresis procedures, driven by higher CD34⁺ cell dose targets needed to compensate for CRISPR-associated HSC loss. Both therapies demonstrated greater than 90% resolution of severe VOEs, with near-complete resolution in pediatric participants. A small subset of participants experienced VOEs post-treatment, including events occurring beyond the primary efficacy assessment period. Notably, no recurrent strokes were reported among lovo-cel treated participants with a history of overt stroke. Both therapies provide durable, clinically meaningful benefit and represent a major advancement in SCD management. However, differences in trial populations, cell collection logistics, and manufacturing have important implications for real-world applications. Continued long-term follow-up and the establishment of standardized post-treatment registries will be critical to fully assess durability, monitor late effects, and inform patient selection.

Apolipoprotein E (ApoE = protein; APOE = gene), a lipid carrier that modulates inflammatory responses, may influence Clostridioides difficile (C. difficile) infection (CDI) outcomes. We explored the role of the APOE gene using apoE-deficient mice challenged by C. difficile toxin A (TcdA)-induced enteritis, and the potential use of the ApoE mimetic peptide in repairing the intestinal damage induced by TcdA. 4-cm ileal loops from C57BL/6 wild-type and APOE knockout (-/-) were ligated and injected with either PBS or TcdA (50 µg). After 4 h of incubation, the intestinal loops were harvested for measurement of length, weight, volume of secretion, and histopathology scores. In mouse ileal loops, TcdA induced a significant increase in weight/ileal loop length in the wild-type mice. When APOE^-/- mice were infected with 1 × 10⁴-10⁵ CFUs of C. difficile, they had higher deaths and diarrhea scores compared to wild-type. APOE^-/- mice under the toxin A (TcdA) had worse inflammatory changes in the ileal loop. APOE^-/- mice treated with COG133 (3 mg/kg) showed fewer deaths, and lower diarrhea scores, but no change in C. difficile shedding. This suggests a potential anti-inflammatory role of COG133 in CDI. More studies are neede to these intial findings in depth.

Microglia, the brain's primary immune cells, play crucial roles in Alzheimer's disease (AD) pathogenesis. However, existing research remains abundant yet fragmented. Therefore, this study aimed to systematically identify hotspots and trends in microglia-related AD research, while providing an in-depth analysis of the underlying mechanisms to advance mechanistic understanding and therapeutic development. To achieve this, articles on microglia in AD were retrieved from the Web of Science Core Collection (WoSCC) database, and bibliometric analysis was performed using the WoSCC platform and CiteSpace 6.3.R1, with a focus on global collaboration, institutional and journal contributions, keyword bursts, and high-impact articles to comprehensively elucidate the underlying mechanisms. In total, 1,043 articles from 67 countries and regions were included.Among them, the United States led with 484 articles and an H-index of 100, followed by China with 276 articles. The University of California system (77 articles) and Harvard University (74 articles) had the highest H-index, both at 41. Journal of Neuroinflammation published the most articles (57 articles). Burst keywords persisting until 2024 included "memory," "NLRP3 inflammasome," and "system." High-impact studies emphasized microglial roles in AD pathology, including Aβ clearance, synaptic pruning, inflammation, metabolism, phenotype shifts, immune memory, and genetic variation. Overall, microglial mechanisms are at the forefront of AD research. The United States leads in both article number and influence, followed by China. The University of California system and Harvard University demonstrate the greatest output and impact. Journal of Neuroinflammation is the leading journal. Microglial NLRP3 activation, system-level interactions, and memory impairment have emerged as key research hotspots in AD. Future research will focus on microglial mechanisms and therapeutic targets in AD.

Parkinson's disease (PD) is a complex neurodegenerative disease that involves many interlinking pathways and genetic elements that remain to be fully understood and characterised. Non-coding genetic elements have long been overlooked, however recent advancements in the field have highlighted their importance with an area of interest being transposable elements. SINE-VNTR-Alu (SVA) elements are the youngest and smallest subset of retrotransposons that are only found within hominid species. SVAs have been shown to have strong regulatory impacts within our genome and can affect progression of neurodegenerative disease such as PD. Previous studies identified an SVA, polymorphic for its presence/absence, that was associated with changes in gene expression at the MAPT locus. This particular SVA is located within a long non-coding RNA (lncRNA) and is known as SVA_67. Here, we evaluated the SVA67-lncRNA effects on gene expression within the MAPT locus, a region associated with several neurodegenerative diseases in the SH-SY5Y cell line. The expression of SVA67-lncRNA in the SH-SY5Y cell line was associated with differential expression of several genes at the MAPT locus including MAPT, KANSL1, ARL17A/B, LRRC37A/2, and NSF. This study provides the first analysis of this SVA67-lncRNA and potential evidence for its involvement in complex diseases, such as PD.

Obstructive sleep apnea (OSA) is manifested as periodic collapse of the upper airway during sleep. Otitis media is a spectrum of infectious and inflammatory diseases involving the middle ear. In this study, we sought to determine the causal effect of OSA on otitis media using a bidirectional, two-sample Mendelian randomization (MR) analysis. We analyzed the data from two different, extensive genome-wide association studies (GWAS) and selected OSA-related single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Bidirectional MR analysis was conducted using the inverse-variance weighted (IVW) method. To ensure the robustness of the results, alternative sensitivity analysis procedures were performed, including MR-Egger, the MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis. In the forward MR analysis, OSA was correlated with an increased risk of acute suppurative otitis media (odds ratio, 1.164; 95% confidence interval, 1.056-1.283; P = 0.002) and suppurative and unspecified otitis media (odds ratio, 1.150; 95% confidence interval, 1.059-1.249; P < 0.001). All reverse MR analyses showed that otitis media had no causal effect on OSA (P > 0.05). The MR analysis supports that OSA contributes to the development of otitis media. Thus, managing OSA may be beneficial in treating otitis media.

HIV-associated neurocognitive disorders (HAND) persist in up to 50% of people living with HIV (PLWH) despite effective antiretroviral therapy (ART), driven by chronic neuroinflammation, oxidative stress, and neuronal damage. This study investigates the therapeutic potential of combining elvitegravir (EVG), an integrase strand transfer inhibitor, with curcumin (CUR), a natural polyphenol with anti-inflammatory and antioxidant properties, in a murine EcoHIV model of HAND. EcoHIV-infected mice were treated with EVG, CUR, or their combination (EVG + CUR), and cognitive, motor, and molecular outcomes were evaluated. Behavioral assays revealed that EcoHIV infection significantly impaired non-spatial working memory, spatial learning, and motor performance, as assessed by the Novel Object Recognition (NOR)and Morris water Maize (MWM) tests and CatWalk gait analysis. While EVG or CUR alone showed modest improvements, the EVG + CUR combination significantly restored cognitive function, reduced escape latencies in the MWM, and improved motor performance, including gait stability and interlimb coordination. At the molecular level, EVG + CUR treatment attenuated neuroinflammation by reducing pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and chemokine (MCP-1) in the brain and plasma, particularly following intranasal administration. Additionally, EVG + CUR significantly reduced oxidative DNA damage and preserved neuronal integrity without disrupting CNS homeostasis. These findings demonstrate that the EVG + CUR combination effectively targets both viral persistence and the underlying neuroinflammatory and oxidative mechanisms driving HAND. By improving cognitive and motor function while mitigating neuroinflammation and oxidative stress, EVG + CUR represents a promising adjunctive therapy for HAND, offering a multifaceted approach to addressing the complex pathophysiology of HIV-associated neurocognitive disorders.