Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 479
Страница 283 из 548-
On-Chip modeling of drug-gut interactions in Oral drug delivery.
The gastrointestinal tract is a dynamic ecosystem where biophysical forces, enzymatic gradients, and microbial metabolism converge to govern the fate of orally administered therapeutics. These multifactorial interactions-spanning shear stress, mucus transport, and microbial metabolism-collectively shape absorption, transformation, and therapeutic response. Such complexity drives the wide interindividual variability in oral pharmacokinetics and pharmacodynamics, challenging predictive modeling and formulation design. Capturing these intertwined processes requires experimental systems that bridge the physiological fidelity of human tissue with the analytical control of engineered models. Microphysiological Gut-on-a-Chip (GoC) platforms have emerged as promising tools that reconstruct human intestinal architecture and function with high precision. These devices integrate living epithelia, peristaltic motion, oxygen and nutrient gradients, immune and microbial co-cultures, and on-chip sensing within precisely engineered microenvironments. They enable direct observation and quantification of luminal-mesenchymal communication, barrier regulation, and metabolite exchange under physiologically relevant flow. This review delineates how GoC technology is advancing oral drug delivery by bridging biology, microengineering, and pharmacology. We summarize advances across three therapeutic domains-small-molecule drugs, macromolecular and biopharmaceutical agents, and microbiome-interacting therapeutics-highlighting how GoCs now recapitulate absorption, enzymatic metabolism, immune modulation, and microbial transformation in human-relevant contexts. By merging organ-level physiology with analytical precision, GoCs establish a unified platform for predicting oral bioavailability and systemic exposure. As these systems evolve toward sensor-integrated, multi-omics, and AI-enabled designs, they are poised to become the mechanistic backbone of next-generation preclinical drug discovery and personalized oral therapeutics.
-
A Microfluidic Cell Culture Platform for Modeling Aligned Peripheral Nerve Bundle, Connection, and Myelination.
The development of microfluidic platforms has advanced peripheral nervous system research; however, traditional polydimethylsiloxane (PDMS)-based systems lack scalability and physiological relevance. To overcome these limitations, we introduce a 3D-printed organ-on-a-chip that enables precise sensory neurite alignment and myelination studies in a standardized 384-well format. Our platform integrates open and closed microfluidic principles to ensure stable fluid dynamics. This design creates a controlled co-culture environment of primary sensory neurons (SN) - Schwann cells (SCs) that mimics in vivo nerve bundle organization. Finite element modeling and fluid dynamics simulations optimize nutrient distribution and biomechanical forces within the chip. Experimental results demonstrate that neurite alignment significantly enhances neuronal growth, with aligned neurites showing up to 2-fold greater area and length compared to random controls. This structured environment facilitates SCs-mediated myelination, producing compact myelin sheaths with physiologically relevant g-ratios (∼0.6) and nodes of Ranvier. Our platform also recapitulates both myelinated and non-myelinated Remak bundles observed in native sensory nerves. This platform is cost-effective, resource-efficient, and has high-throughput, making it a versatile tool for pain research, disease modeling, and regenerative medicine applications.
-
An immune-liver microphysiological system method for evaluation and quality control of hepatotoxicity induced by Polygonum multiflorum thunb. Extract.
ETHNOPHARMACOLOGICAL RELEVANCE: Clinical applications of Polygonum multiflorum Thunb. (PMT) have occasionally reported adverse effects on liver function, linking these instances of hepatotoxicity to PMT samples. Evaluating the hepatotoxicity of PMT, given its intricate composition and mechanisms, presents a notable challenge. Notably, three toxic components display additive/synergistic effects, further complicating the establishment of a toxicological quality control method. AIM OF THE STUDY: This study aims to develop a biology-based quality control method that can reflect the multi-mechanistic hepatotoxicity of PMT. MATERIALS AND METHODS: We designed a microphysiological system tailored for the immune-liver interplay, termed the i-LOC, featuring three-cell channels. This i-LOC integrates hepatic cells with two distinct immune cell types to mimic inflammatory cell infiltration. As a control, a liver-on-chip devoid of immune cells was utilized to characterize hepatotoxicity induced by inflammatory stress. RESULTS: The i-LOC system exhibited remarkable sensitivity in detecting both direct and inflammation-mediated hepatotoxic effects of the three PMT toxic components. This system significantly reduced the sample size requirements by thousandfold compared to animal models, presenting a cost-effective and attractive alternative for PMT toxicological assessments. Intriguingly, the system identified the present of previously unknown PMT compounds with potential hepatotoxic properties, emphasizing the need for a comprehensive biological evaluation method. CONCLUSION: This study successfully developed an i-LOC method for effectively evaluating PMT's hepatotoxicity, overcoming the complexities posed by its intricate composition and mechanisms.
-
Dysfunction of the neurovascular unit as a temporal driver in Alzheimer's pathogenesis.
Extensive studies have shown that cerebrovascular dysfunction is a critical factor in the onset and progression of Alzheimer's disease (AD). Neurovascular unit (NVU) is impaired in AD brains, including damage of tight junction between endothelial cells, degeneration of pericytes, activation of astrocytes and microglia, and apoptosis of neurons. As decreased cerebral blood flow is observed before amyloid-beta (Aβ) generation, it is supposed that NVU dysfunction may precede and exacerbate the pathological state of AD neural system, and that the events of NVU dysfunction and Aβ deposition synergistically promote AD progression. Technological breakthroughs of three-dimensional NVU organoids, spatial transcriptomics with single-cell resolution, and development of artificial intelligence technology, such as machine learning and deep learning, offer the possibility of constructing accurate functional structural models. Here we systematically review the NVU dysfunction during AD progression as well as the applications of spatial transcriptomics and organoid technology in NVU studies.
-
Lactate-Mediated Brain Acidosis Drives Epigenetic Dysregulation of TGFB2 and Associated Gene Networks in Schizophrenia and Bipolar Disorder.
Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in these disorders. As increased TGFB expression has been implicated in major psychiatric diseases and lactic acid induces TGFB2 upregulation in metabolic diseases, we hypothesized that lactate-induced brain acidosis may drive widespread gene dysregulation through TGFB2 activation. In our previous microarray studies, increased TGFB2 expression was observed in postmortem brains of SCZ and BD patients, while pathway analyses suggested a key role for TGFB2 in the dysregulation of other genes, particularly astrocytic genes. TGFB2 itself also exhibited promoter DNA hypomethylation in postmortem brains of these patients. Here, while brain pH was lower in SCZ and BD patients, we investigated the effects of pH alteration on the expression and promoter DNA methylation of TGFB2 and TGFB2-correlated genes in iPSC-derived neurons, astrocytes, and brain organoids (brainoids). Cultures were treated with lactic acid, HCl, bicarbonate, or NaOH to alter culture medium pH by ±0.4 units, and gene expression and promoter DNA methylation were evaluated by qPCR analyses. In our reanalysis of postmortem brain microarray data, nearly 80% of dysregulated genes, together with TGFB2, exhibited inverse correlations with brain pH. Lactic acid treatment induced increased expression and promoter DNA hypomethylation of TGFB2 and several correlated genes in astrocytes and brainoids, whereas bicarbonate and NaOH treatments showed opposite effects. These findings suggest that lactate-mediated brain acidosis may contribute to TGFB2 upregulation and widespread gene dysregulation implicated in SCZ and BD pathogenesis. Therapeutic interventions targeting lactic acid accumulation or TGFB2 hyperexpression may mitigate disease-associated brain gene dysregulation.
-
Multiscale brain research on a microfluidic chip.
One major challenge in current brain research is generating an integrative understanding of the brain's functions and disorders from its multiscale neuronal architectures and connectivity. Thus, innovative neurotechnology tools are urgently required for deciphering the multiscale functional and structural organizations of the brain at hierarchical scales from the molecular to the organismal level by multiple brain research initiatives launched by the European Union, United States, Australia, Canada, China, Korea, and Japan. To meet this demand, microfluidic chips (μFCs) have rapidly evolved as a trans-scale neurotechnological toolset to enable multiscale studies of the brain due to their unique advantages in flexible microstructure design, multifunctional integration, accurate microenvironment control, and capacity for automatic sample processing. Here, we review the recent progress in applying innovative μFC-based neuro-technologies to promote multiscale brain research and uniquely focus on representative applications of μFCs to address challenges in brain research at each hierarchical level. We discuss the current trend of combinational applications of μFCs with other neuro- and biotechnologies, including optogenetics, brain organoids, and 3D bioprinting, for better multiscale brain research. In addition, we offer our insights into the existing outstanding questions at each hierarchical level of brain research that could potentially be addressed by advancing microfluidic techniques. This review will serve as a timely guide for bioengineers and neuroscientists to develop and apply μFC-based neuro-technologies for promoting basic and translational brain research.
-
Decoding microglial functions in Alzheimer's disease: insights from human models.
Microglia, key orchestrators of the brain's immune responses, play a pivotal role in the progression of Alzheimer's disease (AD). Emerging human models, including stem cell-derived microglia and cerebral organoids, are transforming our understanding of microglial contributions to AD pathology. In this review, we highlight how these models have uncovered human-specific microglial responses to amyloid plaques and their regulation of neuroinflammation, which are not recapitulated in animal models. We also illustrate how advanced human models that better mimic brain physiology and AD pathology are providing unprecedented insights into the multifaceted roles of microglia. These innovative approaches, combined with sophisticated technologies for cell editing and analysis, are shaping AD research and opening new avenues for therapeutic interventions targeting microglia.
-
A common single nucleotide variant in the cytokine receptor-like factor-3 (CRLF3) gene causes neuronal deficits in human and mouse cells.
Single nucleotide variants in the general population are common genomic alterations, where the majority are presumed to be silent polymorphisms without known clinical significance. Using human induced pluripotent stem cell (hiPSC) cerebral organoid modeling of the 1.4 megabase Neurofibromatosis type 1 (NF1) deletion syndrome, we previously discovered that the cytokine receptor-like factor-3 (CRLF3) gene, which is co-deleted with the NF1 gene, functions as a major regulator of neuronal maturation. Moreover, children with NF1 and the CRLF3L389P variant have greater autism burden, suggesting that this gene might be important for neurologic function. To explore the functional consequences of this variant, we generated CRLF3L389P-mutant hiPSC lines and Crlf3L389P-mutant genetically engineered mice. While this variant does not impair protein expression, brain structure, or mouse behavior, CRLF3L389P-mutant human cerebral organoids and mouse brains exhibit impaired neuronal maturation and dendrite formation. In addition, Crlf3L389P-mutant mouse neurons have reduced dendrite lengths and branching, without any axonal deficits. Moreover, Crlf3L389P-mutant mouse hippocampal neurons have decreased firing rates and synaptic current amplitudes relative to wild type controls. Taken together, these findings establish the CRLF3L389P variant as functionally deleterious and suggest that it may be a neurodevelopmental disease modifier.
-
Human-induced pluripotent stem cell-derived cerebral organoid of leukoencephalopathy with vanishing white matter.
INTRODUCTION: Leukoencephalopathy with vanishing white matter (VWM) is a rare autosomal recessive leukoencephalopathy resulting from mutations in EIF2B1-5, which encode subunits of eukaryotic translation initiation factor 2B (eIF2B). Studies have found that eIF2B mutation has a certain influence on embryonic brain development. So far, the effect of the eIF2B mutations on the dynamic process of brain development is not fully understood yet. AIMS: Three-dimensional brain organoid technology has promoted the study of human nervous system developmental diseases in recent years, providing a potential platform for elucidating the pathological mechanism of neurodevelopmental diseases. In this study, we aimed to investigate the effects of eIF2B mutation on the differentiation and development of different nerve cells during dynamic brain development process using 3D brain organoids. RESULTS: We constructed eIF2B mutant and wild-type brain organoid model with induced pluripotent stem cell (iPSC). Compared with the wild type, the mutant brain organoids were significantly smaller, accompanied by increase in apoptosis, which might be resulted from overactivation of unfolded protein response (UPR). Neuronal development was delayed in early stage, but with normal superficial neuronal differentiation in later stage. eIF2B mutations resulted in immature astrocytes with increased expression of GFAPδ, nestin, and αB-crystallin, and there were increased oligodendrocyte progenitor cells, decreased mature oligodendrocytes, and sparse myelin in mutant cerebral organoids in the later stage. CONCLUSION: we constructed the first eIF2B mutant cerebral organoids to explore the dynamic brain development process, which provides a platform for further research on the specific pathogenesis of VWM.
-
Transformative advances in modeling brain aging and longevity: Success, challenges and future directions.
Research on brain aging is crucial for understanding age-related neurodegenerative disorders and developing several therapeutic interventions. Numerous models ranging from two-dimensional (2D) cell-based, invertebrate, vertebrate, and sophisticated three-dimensional (3D) models have been used to understand the process of brain aging. Invertebrate models are ideal for researching conserved aging processes because of their simplicity, short lifespans, and genetic tractability. Moreover, vertebrate models, including zebrafish and rodents, exhibit more complex nervous systems and behaviors, enabling the exploration of age-related neurodegeneration and cognitive decline. 2D cell culture models derived from primary cells or immortalized cell lines are widely used for mechanistic studies at the cellular level but lack the physiological complexity of brain tissue. Recent advancements have shifted focus to 3D models, which better recapitulate the brain's microenvironment. Organoids derived from induced pluripotent stem cells mimic human brain architecture and enable the study of cell-cell interactions and aging in a human-specific context. Brain-on-a-chip systems integrate microfluidics and 3D cultures to model blood-brain barrier dynamics and neuronal networks. Additionally, scaffold-based 3D cultures and spheroids provide intermediate complexity, allowing researchers to study extracellular matrix interactions and age-related changes in neuronal function. These 3D models bridge the gap between traditional 2D cultures and animal-based in vivo studies, offering unprecedented insights into brain aging mechanisms. By combining these diverse models, researchers can unravel the multifaceted processes of brain aging and accelerate the development of targeted therapies for age-related neurodegenerative disorders.