Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway

Aging and Disease, Год журнала: 2023, Номер 14(6), С. 2193 - 2193

Опубликована: Янв. 1, 2023

Increasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation Parkinson's disease (PD). However, the specific mechanisms link microbiota to PD remain unexplored. Given critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial development PD, we aimed evaluate interactions among microbiota, BBB, resistance oxidation inflammation PD. We investigated effects fecal transplantation (FMT) on physiopathology 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was explore from patients healthy human controls neuroinflammation, BBB components, antioxidative capacity via AMPK/SOD2 pathway. Compared control mice, MPTP-treated mice exhibited elevated levels Desulfovibrio, whereas given FMT enriched Akkermansia humans showed no significant alterations microbiota. Strikingly, significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation colonic inflammation, inhibited signaling greatly improved aforementioned MPTP-caused effects. Surprisingly, displayed loss pericytes, which restored by controls. Our findings demonstrate can correct ameliorate neurodegeneration MPTP-induced mouse model suppressing microgliosis astrogliosis, ameliorating impairments pathway, restoring pericytes integrity. These raise possibility alteration be risk factor for provide potential application preclinical treatment.

Язык: Английский

---

Assessment of Inner Blood–Retinal Barrier: Animal Models and Methods

Cells, Год журнала: 2023, Номер 12(20), С. 2443 - 2443

Опубликована: Окт. 12, 2023

Proper functioning of the neural retina relies on unique retinal environment regulated by blood–retinal barrier (BRB), which restricts passage solutes, fluids, and toxic substances. BRB impairment occurs in many vascular diseases breakdown significantly contributes to disease pathology. Understanding different molecular constituents signaling pathways involved development maintenance is therefore crucial developing treatment modalities. This review summarizes major inner (iBRB) formation maintenance, representative animal models eye with leakage. Studies Wnt/β-catenin are highlighted, critical for brain angiogenesis barriergenesis. Moreover, multiple vivo vitro methods detection analysis leakage described, along their advantages limitations. These pre-clinical assessing iBRB provide valuable experimental tools delineating mechanisms evaluating therapeutic drugs.

Язык: Английский

---

Predicting blood–brain barrier permeability of molecules with a large language model and machine learning

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 9, 2024

Abstract Predicting the blood–brain barrier (BBB) permeability of small-molecule compounds using a novel artificial intelligence platform is necessary for drug discovery. Machine learning and large language model on (AI) tools improve accuracy shorten time new development. The primary goal this research to develop computing models deep architectures capable predicting whether molecules can permeate human (BBB). in silico (computational) vitro (experimental) results were validated by Natural Products Research Laboratories (NPRL) at China Medical University Hospital (CMUH). transformer-based MegaMolBART was used as simplified molecular input line entry system (SMILES) encoder with an XGBoost classifier method check if molecule could cross through BBB. We Morgan or Circular fingerprints apply algorithm set atomic invariants baseline also compare results. BBB assessed three-dimensional (3D) spheroids (human brain microvascular endothelial cells, vascular pericytes, astrocytes). Using multiple databases, final transformer achieved area under receiver operating characteristic curve 0.88 held-out test dataset. Temozolomide (TMZ) 21 randomly selected permeable (Pred scores = 1, indicating BBB-permeable) from NPRL penetrated spheroid cells. No evidence suggests that ferulic acid five BBB-impermeable < 1.29423E−05, which designate pass BBB) cells Our validation experiments indicated prediction permeation accurate. Transformer-based like MegaMolBART, leveraging SMILES representations molecules, show great promise applications These have potential accelerate development targeted treatments disorders central nervous system.

Язык: Английский

---

A new frontier in neuropharmacology: Recent progress in natural products research for blood–brain barrier crossing

Current Research in Biotechnology, Год журнала: 2024, Номер 8, С. 100235 - 100235

Опубликована: Янв. 1, 2024

Neuropharmacology faces challenges due to the intricate nervous system, diverse neurological disorders, and existence of blood–brain barrier (BBB), which hinder development effective treatments. Although primary function BBB is expel toxins pathogens, this structure also prevents optimal drug delivery. Natural products, with their chemical diversity sustainability, have long been recognized as potential neuroprotective compounds, making permeability studies mandatory. Over last ten years, biotechnological advances in two-dimensional vitro models (monoculture co-culture), vivo imaging techniques, pharmacokinetic modeling contributed expanding our current knowledge. In study, we reviewed crossing natural products such different terpenoids, polyphenolic alkaloids. The findings, obtained through vitro, vivo, silico methods, revealed moderate high for many these products. However, other compounds showed not be able reach brain. To better understand behavior humans improve ability pass across blood-brainier, new three-dimensional dynamic BBB, nanosystems complexes encapsulation or in-depth transport mechanism are future lines research.

Язык: Английский

---

Microphysiological Blood‐Brain Barrier Systems for Disease Modeling and Drug Development

Advanced Healthcare Materials, Год журнала: 2024, Номер 13(21)

Опубликована: Март 2, 2024

Abstract The blood‐brain barrier (BBB) is a highly controlled microenvironment that regulates the interactions between cerebral blood and brain tissue. Due to its selectivity, many therapeutics targeting various neurological disorders are not able penetrate into Pre‐clinical studies using animals other in vitro platforms have shown ability fully replicate human BBB leading failure of majority clinical trials. However, recent innovations ex vivo modeling called organs‐on‐chips potential create more accurate disease models for improved drug development. These microfluidic induce physiological stressors on cultured cells generate physiologically BBBs compared previous models. In this review, different approaches BBBs‐on‐chips explored alongside their application therapeutic efficacy. Additionally, use delivery discussed, advances linking onto multiorgan mimic organ crosstalk reviewed.

Язык: Английский

---

Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Апрель 17, 2023

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow molecules from blood to brain parenchyma, protecting brain’s microenvironment. If one BBB components starts fail, its dysfunction can lead a cascade neuroinflammatory events leading neuronal degeneration. Preliminary imaging findings suggest could serve as an early diagnostic prognostic biomarker for number neurological diseases. This review aims provide clinicians with overview emerging field in humans by answering three key questions: (1. Disease) In which diseases be useful? (2. Device) What are currently available methods evaluating integrity? And (3. Distribution) what is potential different environments, particularly resource limited settings? We conclude further advances needed, such validation, standardization implementation readily available, low-cost non-contrast techniques, useful clinical both resource-limited well-resourced settings.

Язык: Английский

---

Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip

Pharmaceutics, Год журнала: 2024, Номер 16(5), С. 574 - 574

Опубликована: Апрель 23, 2024

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage some compounds. A predictive model BBB important in early stages drug development. predicted permeabilities drugs have been confirmed using a variety vitro methods to reduce quantities candidates needed preclinical and clinical trials. Most prior studies relied on animal or cell-culture models, which do not fully recapitulate human BBB. development microfluidic models human-derived cells could address this issue. We analyzed for predicting Emulate BBB-on-a-chip machine. Ten compounds were evaluated, their estimated. Our study demonstrated that trends ten our microfluidic-based system resembled those observed previous cell-based experiments. Furthermore, we established general correlation between partition coefficient (Kp) apparent (Papp). In conclusion, introduced new paradigm systems.

Язык: Английский

---

The road ahead to successful BBB opening and drug-delivery with focused ultrasound

Journal of Controlled Release, Год журнала: 2024, Номер 372, С. 901 - 913

Опубликована: Июль 15, 2024

Язык: Английский

---

Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Июнь 6, 2024

Abstract Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in processes. In this review, we will look at data linking variety of viral, bacterial, fungal, and protozoan to Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, multiple sclerosis unspecified dementia. This narrative review aims bring together broad range currently supporting the involvement central development diseases. The idea that no single pathogen or group responsible diseases be discussed. Instead, suggest wide susceptibility factors may make individuals differentially vulnerable different infectious pathogens subsequent pathologies.

Язык: Английский

---

MRI detects blood-brain barrier alterations in a rat model of Alzheimer’s disease and lung infection

npj Imaging, Год журнала: 2025, Номер 3(1)

Опубликована: Март 4, 2025

Pneumonia is a common infection in people suffering with Alzheimer's disease, leading to delirium, critical illness or severe neurological decline, which may be due an amplified response of the blood-brain barrier (BBB) peripheral insult. We assess BBB repeated Streptococcus pneumoniae lung rat model disease (TgF344-AD), at 13- and 18-months old, using dynamic contrast-enhanced (DCE) MRI filter exchange imaging. Higher water rate initially detected infected TgF344-AD rats. rates correlated hippocampus aquaporin-4 channel expression animals. no differences permeability gadolinium contrast agent measured by DCE-MRI, confirmed staining for tight junction proteins, occludin claudin-5. These findings provide insight into mechanisms how inflammation impacts BBB.

Язык: Английский

---