Beta-amyloid peptide (Aβ)-induced suppression of hippocampal GABAergic interneuron activity drives hyperexcitability, amyloid pathology, and cognitive impairment in Alzheimer's disease (AD), suggesting that enhancing hippocampal inhibition may be protective. However, hippocampal interneurons are highly diverse and differentially regulate inhibition and cognition, making it challenging to identify the affected subtypes and optimally restore hippocampal inhibition in AD. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation in excitatory neurons. Here, we further reveal that α7- and α4β2-nAChRs predominantly control nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. We also find that systemic co-stimulation of α7- and α4β2-nAChRs is required to reverse hippocampal hyperexcitability, dysfunction of fear learning-associated hippocampal oscillatory activity, and hippocampus-dependent memory loss, and to reduce Aβ pathology in AD model mice. This suggests that co-stimulation of PV+ and SST+ cells via activation of α7- and α4β2-nAChRs together is required to enhance hippocampal inhibition optimally, which reverses hippocampal dysfunction, reduces amyloid pathology, and ultimately prevents memory loss in AD.

The temporal lobes are key hubs for memory and cognition. Although 40 Hz transcranial alternating current stimulation (tACS) has shown potential cognitive benefits, evidence for accelerated bilateral temporal stimulation remains limited. This study aims to evaluate its cognitive and neural effects. In this randomized, double-blind, controlled trial, 100 Alzheimer's disease (AD) patients were randomized 1:1 to active or sham 40 Hz tACS over the bilateral temporal. Cognitive outcomes at three time points were analyzed using mixed repeated-measures analysis of variance (ANOVA). Resting-state functional near-infrared spectroscopy (fNIRS) data from baseline and Week 4 were analyzed using ANOVA, followed by network-based statistics with family-wise error (FWE) correction. Eighty-five participants completed the trial. Significant Group × Time interactions were observed for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) total (p = 0.010), memory (p = 0.007), and praxis (p = 0.002), but not for the Mini-Mental State Examination (MMSE) (p = 0.075). The fNIRS analysis revealed a functional network primarily involving the frontal and parietal regions, comprising 38 connections and 18 nodes (pFWE = 0.010). Active-group connectivity changes were associated with ADAS-Cog total, language, praxis, and MMSE variations, but not in the sham group. Accelerated bilateral temporal 40 Hz tACS improved cognition and modulated frontotemporoparietal connectivity. Larger multicenter studies with biomarkers are warranted.

Enterohemorrhagic Escherichia coli O157:H7 (EHEC O157:H7) is a globally significant foodborne pathogen. Infection disrupts the gut microbiota and exacerbates host immune dysfunction. Reuterin, a broad-spectrum antimicrobial metabolite produced by Limosilactobacillus reuteri during glycerol fermentation, exhibits potent antibacterial activity in vitro; however, its in vivo preventive efficacy and underlying mechanisms remain incompletely understood. This study aimed to comprehensively evaluate the protective effects of reuterin prophylaxis and to investigate its potential mechanisms in mitigating EHEC O157:H7 infection through gut microbiota modulation. In a murine infection model, prophylactic administration of reuterin (60 mM) conferred pronounced protection, as evidenced by alleviation of colonic pathology, oxidative stress, and systemic inflammation, together with restoration of intestinal barrier integrity. 16S rRNA sequencing and fecal microbiota transplantation (FMT) demonstrated that reuterin alleviated EHEC O157:H7 infection through gut microbiota remodeling, which was associated with elevated abundances of Ligilactobacillus and Alloprevotella and increased short-chain fatty acids (SCFAs) production. Exogenous SCFAs supplementation was associated with attenuated colonic damage and inflammation, consistent with a potential contribution of these metabolites to the observed protection. Furthermore, our data are compatible with a model wherein SCFAs-mediated activation of the intestinal receptor GPR43 may suppress NF-κB signaling. Collectively, this study provides a foundation for the further development of reuterin as a prophylactic agent against EHEC O157:H7 infection.

The optimal Impella purge solution in patients receiving concomitant ECMO and Impella (ECPELLA) support remains to be elucidated. We aimed to assess Impella device function in patients supported by ECPELLA receiving heparin-containing or anticoagulant-free (5% dextrose or sodium bicarbonate) purge solutions. Of 25 included patients, 14 received anticoagulant-free and 11 received heparin-containing purge solutions, with a median of five days of ECPELLA support. The only episode of Impella device malfunction occurred in the heparin-containing group. Given the low event rate and apparent maintenance of acceptable device longevity, use of anticoagulant-free purge solutions alongside systemic anticoagulation in ECPELLA patients may be reasonable but requires validation in an appropriately powered study.

Electroencephalography (EEG) has been investigated as a noninvasive approach for characterizing brain activity in neurodegenerative conditions. This study evaluated whether multidomain EEG biomarkers could distinguish Alzheimer's disease (AD), frontotemporal dementia (FTD), and healthy controls (HC). The publicly available dataset contained resting-state, eyes-closed EEG recordings from 88 participants, including 36 with AD, 23 with FTD, and 29 healthy controls. Multidomain EEG biomarkers and demographic features were extracted for machine learning classification. The EEG-derived features included root-mean-square (RMS), power spectral density (PSD), and entropy measures. A Random Forest classifier was trained using the combined feature set and interpreted using explainable artificial intelligence. Feature-stability and Cohen's d effect-size analyses were performed to evaluate feature contributions, followed by an ablation analysis. Entropy-based features showed the lowest contribution to classification. The complete multidomain model achieved 96% training accuracy and 92% test accuracy. After the removal of the entropy features, test accuracy increased to 94%. These results describe the classification performance of the selected multidomain EEG and demographic features within the Random Forest framework.

Breast cancer heterogeneity and its complex tumor microenvironment (TME) are key drivers of therapeutic failure and multidrug resistance (MDR). Drug delivery systems (DDS) provide an important approach, but their clinical translation remains limited by biological variability, formulation complexity, and manufacturing challenges. This review delineates the evolution of breast cancer DDS from passive carriers to increasingly functional and responsive platforms, focusing on three core dimensions. First, regarding decisive barriers, we dissect the constraints imposed by the three-dimensional collagen network, pH/glutathione (GSH) gradients, and tumor-associated macrophages (TAMs) on drug penetration. These factors not only act as physical and biochemical obstacles but can also be harnessed as endogenous triggers for responsive design. Second, in terms of diversified platforms, we critically evaluate liposomes, polymeric nanoparticles, hydrogels, extracellular vesicles, and antibody-drug conjugates (ADCs). We highlight the potential of solid lipid nanoparticles to address drug resistance, the development of carrier-free delivery enabled by prodrug self-assembly, and the clinical significance of ADCs (eg, T-DXd) in expanding treatment options for HER2-low breast cancer. Third, we examine inter- and intratumoral heterogeneity, metastatic site-specific delivery barriers in the brain, bone, and lung, the multilayered resistance network from efflux pumps to cancer stem cells, and the sequential barriers nanomedicines must traverse from systemic circulation to intracellular targets. We propose three strategic directions: personalized precision delivery integrating liquid biopsy, organoids, and functional imaging to support patient stratification and treatment adaptation; AI-assisted formulation optimization using machine learning to develop material-structure-function predictive models and support data-driven formulation design; and multi-responsive systems leveraging endogenous signals such as pH, GSH, and enzymes, together with exogenous stimuli including light, magnetism, and ultrasound, for spatiotemporally controlled combination therapy. This review summarizes key considerations from biological barriers to clinical translation, emphasizing that alignment of tumor subtype, metastatic site, microenvironmental characteristics, and patient-specific factors may improve the clinical applicability of drug delivery strategies.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that may require systemic therapy in patients with moderate-to-severe or refractory disease. Tofacitinib, a Janus kinase (JAK) inhibitor, has demonstrated efficacy in the treatment of severe inflammatory dermatoses, including refractory AD. However, its use may be associated with various adverse events, and acneiform eruptions have increasingly been reported with JAK inhibitor therapy. We report the case of an 18-year-old female patient with severe AD who was treated with tofacitinib, resulting in marked improvement of her eczematous lesions and pruritus. After several weeks of treatment, she developed inflammatory facial acne without a history of severe acne or any other identified precipitating factor. Clinical examination revealed multiple inflammatory papules and pustules predominantly involving the centrofacial region, associated with comedones and microcysts. Laboratory investigations were unremarkable. The acne was successfully managed with appropriate topical therapy while tofacitinib was continued. This case highlights acne as a potentially emerging cutaneous adverse event associated with JAK inhibitor therapy. Early recognition and appropriate management may help prevent impairment of quality of life and treatment adherence while allowing continuation of effective systemic therapy for severe AD.

Alzheimer's disease (AD) is the leading cause of dementia worldwide, disproportionately affecting individuals over 65 years of age and imposing a rapidly escalating burden on healthcare systems and caregivers globally. For decades, management relied on symptomatic agents-cholinesterase inhibitors and memantine-that provide modest cognitive benefits without altering disease progression. The recent approvals of the anti-amyloid monoclonal antibodies lecanemab (2023) and donanemab (2024) represent a paradigm shift, offering the first therapies that modestly but significantly slow clinical decline by targeting the underlying amyloid-β pathology. However, these advances are accompanied by important safety concerns, particularly amyloid-related imaging abnormalities, substantial costs, and unresolved questions regarding long-term clinical meaningfulness and equitable access. This comprehensive review synthesizes current knowledge across the full spectrum of AD, encompassing molecular pathophysiology (amyloid cascade, tau hyperphosphorylation, and neuroinflammation), genetic architecture (familial mutations and APOE-mediated risk), evolving biomarker-based diagnostic frameworks, established symptomatic treatments, and newly approved disease-modifying agents. We further examine emerging therapeutic strategies, including tau-targeted therapies, neuroinflammation-directed approaches, multi-target and combination strategies, drug delivery innovations, and prevention trials in preclinical populations. Throughout, we critically evaluate the evidence, acknowledging controversies and limitations while identifying promising future directions. Importantly, integrating these diagnostic and genetic advances into geriatric care settings presents unique implementation challenges, as aging populations often face comorbidities, polypharmacy, and limited access to specialized diagnostic infrastructure. As AD therapeutics enter a new era, integrating pharmacological interventions with biomarker-guided patient selection, rigorous safety monitoring, and modifiable risk factor management will be essential for optimizing outcomes in aging populations.

Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.

Postoperative gastrointestinal dysfunction (POGD) remains an important barrier to recovery after abdominal and non-abdominal surgery. This critical narrative review evaluates whether dexmedetomidine improves postoperative gastrointestinal recovery through an independent direct prokinetic action or predominantly through opioid-sparing and other indirect recovery pathways. Positive trials and meta-analyses report earlier flatus, defecation, or oral intake in selected settings, but most also permit simultaneous reductions in opioid exposure, pain, postoperative nausea and vomiting (PONV), inflammatory biomarkers, or sympathetic stress. These co-occurring effects limit causal attribution. We therefore propose a context-dependent dual-pathway model in which an opioid-sparing indirect pathway and a biologically plausible non-opioid pathway contribute with weights that vary according to baseline opioid burden, enhanced recovery after surgery (ERAS) maturity, dose, timing, and inflammatory phenotype. The available evidence is most consistent with, but does not prove, an opioid-sparing-dominant explanation; independent enteric effects remain clinically unisolated. Counter-evidence from healthy volunteers, isolated intestine, and sepsis models also argues against a universal prokinetic property. Clinically, dexmedetomidine should be positioned as a context-dependent multimodal adjunct rather than a stand-alone prokinetic therapy. Opioid-standardized trials with validated gastrointestinal endpoints and prespecified mediation analyses are needed to distinguish the two pathways.