Impact of Parental Time-Restricted Feeding on Offspring Metabolic Phenotypic Traits.

Intermittent fasting (IF) is widely recognized for its numerous health benefits, yet its impact on metabolic health across generations remains relatively unexplored. This study investigates the intergenerational effects of parental IF, specifically through 8-hour daily time-restricted feeding, on the metabolic health of offspring. By examining four different combinations of parental mating groups, we demonstrate that parental IF can influence offspring metabolic health in distinct ways.

A Neuroimmune-Oncology Microphysiological Analysis Platform (NEO-MAP) for Evaluating Astrocytic Scar Formation and Microgliosis in Glioblastoma Microenvironment.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, characterized by its heterogeneity in cellular components, including reactive astrocytes and microglia. Since neuroimmune responses like astrogliosis and microgliosis gain recognition as vital factors in brain tumor progression, there is a growing need for clinically relevant models that assess the interactions between astrocytes, microglia, and GBM. Here, a NEuroimmune-Oncology Microphysiological Analysis Platform (NEO-MAP) is presented as a "new map" to observe astrocytic scar formation and microgliosis in response to GBM.

RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer's disease mouse models.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies.

N-((perfluorophenyl)amino)glutamine regulates BACE1, tau phosphorylation, synaptic function, and neuroinflammation in Alzheimer's disease models.

Alzheimer's disease (AD) is the most common type of dementia. Its incidence is rising rapidly as the global population ages, leading to a significant social and economic burden. AD involves complex pathologies, including amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation.

EBP1 potentiates amyloid β pathology by regulating γ-secretase.

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction.

A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease.

β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology.

HDAC6 mediates NLRP3 inflammasome activation in the pathogenesis of diabetic retinopathy.

Background: Diabetic retinopathy (DR), a major blindness cause in developed countries, is intricately linked to diabetes management and its duration. Here, we demonstrate that HDAC6 mediates NLRP3 inflammasome activation under diabetic conditions, leading to retinal inflammation and degeneration.

Methods: This study demonstrated the therapeutic effects of HDAC6 genetic ablation, pharmacological inhibition, and HDAC6-deficient bone marrow transplantation in a diabetes model induced by streptozotocin and a high-fat diet.

Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson's disease.

The application of extracellular vesicles (EVs) as vehicles for anti-Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood-brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose-derived stem cell EVs (Dopa-EVs) utilizing a facile, two-step cross-linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies.

Therapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent.

The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice.

Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1, and in Wt mice administered CDCA, stroke infarct area was reduced.

PEDF-Enriched Extracellular Vesicle for Vessel Normalization to Potentiate Immune Checkpoint Blockade Therapy.

The abnormal tumor vasculature acts as the physical and functional barrier to the infiltration and activity of effector T cells, leading to the low response rate of immune checkpoint inhibitors (ICIs). Herein, antiangiogenic extracellular vesicles that enable normalization of the tumor-associated vasculature were prepared to potentiate the efficacy of ICIs. Small extracellular vesicles were exploited as the delivery platform to protect the antiangiogenic protein, pigment epithelium-derived factor (PEDF), from proteolytic degradation.

Engineered exosomes with a photoinducible protein delivery system enable CRISPR-Cas-based epigenome editing in Alzheimer's disease.

Effective intracellular delivery of therapeutic proteins can potentially treat a wide array of diseases. However, efficient delivery of functional proteins across the cell membrane remains challenging. Exosomes are nanosized vesicles naturally secreted by various types of cells and may serve as promising nanocarriers for therapeutic biomolecules.

The Role of IRF9 Upregulation in Modulating Sensitivity to Olaparib and Platinum-Based Chemotherapies in Breast Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors are targeted therapies that accumulate DNA damage by interfering with DNA repair mechanisms and are approved for treating several cancers with BRCA1/2 mutations. In this study, we utilized CRISPR-dCas9 interference screening to identify genes regulating sensitivity to PARP inhibitors in breast cancer cell lines. Our findings indicated that the interferon (IFN) signaling gene IRF9 was critically involved in modulating sensitivity to these inhibitors.

Stem Cell-Derived Extracellular Vesicle-Bearing Injectable Hydrogel for Collagen Generation in Dermis.

Despite the remarkable advances of dermal fillers that reduce wrinkles caused by dermis thickness reduction, they still lack effective hydrogel systems that stimulate collagen generation along with injection convenience. Here, we develop a stem cell-derived extracellular vesicle (EV)-bearing thermosensitive hydrogel (EVTS-Gel) for effective in vivo collagen generation. The TS-Gel undergoes sol-gel transition at 32.

Extracellular Vesicles Derived from Adipose Stem Cells Alleviate Systemic Sclerosis by Inhibiting TGF-β Pathway.

Systemic sclerosis is an autoimmune disease characterized by inflammatory reactions and fibrosis. Myofibroblasts are considered therapeutic targets for preventing and reversing the pathogenesis of fibrosis in systemic sclerosis. Although the mechanisms that differentiate into myofibroblasts are diverse, transforming growth factor β (TGF-β) is known to be a key mediator of fibrosis in systemic sclerosis.

Dysregulation of histone deacetylases in ocular diseases.

Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy are the most prevalent ocular diseases. Their prevalence and the global market size are also increasing.

Mucoadhesive chitosan microcapsules for controlled gastrointestinal delivery and oral bioavailability enhancement of low molecular weight peptides.

A bioactive compound, collagen peptide (CP), is widely used for biological activities such as anti-photoaging and antioxidant effects, with increased oral bioavailability because of its low molecular weight and high hydrophilicity. However, controlling release time and increasing retention time in the digestive tract for a more convenient oral administration is still a challenge. We developed CP-loaded chitosan (CS) microcapsules via strong and rapid ionic gelation using a highly negative phytic acid (PA) crosslinker.

Multiomics analyses reveal dynamic bioenergetic pathways and functional remodeling of the heart during intermittent fasting.

Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis.

Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment.

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI.

Chronic cerebral hypoperfusion alters the CypA-EMMPRIN-gelatinase pathway: Implications for vascular dementia.

Chronic cerebral hypoperfusion (CCH) is postulated to underlie multiple pathophysiological processes in vascular dementia (VaD), including extracellular matrix dysfunction. While several extracellular matrix proteins, namely cyclophilin A (CypA), extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases (matrix metalloproteinases, MMP-2 and -9) have been investigated in acute stroke, their involvement in CCH and VaD remains unclear. In this study, CypA-EMMPRIN-gelatinase proteins were analysed in a clinical cohort of 36 aged, cognitively unimpaired subjects and 48 VaD patients, as well as in a bilateral carotid artery stenosis mouse model of CCH.