The therapeutic effects and mechanisms of glucagon-like peptide-1 receptor agonists in neurocognitive disorders DOI Creative Commons
Junchen Si, Kai Yu,

Jiheng Hao

et al.

Therapeutic Advances in Neurological Disorders, Journal Year: 2025, Volume and Issue: 18

Published: Jan. 1, 2025

Chronic cerebral hypoperfusion (CCH) represents a key pathogenic contributor to neurocognitive disorders. It can lead multifaceted pathological alterations including neuroinflammation, neuronal apoptosis, blood–brain barrier disruption, synaptic plasticity deficits, and mitochondrial dysfunction. The glucagon-like peptide-1 receptor (GLP-1R), ubiquitously expressed across multiple organ systems, exerts neuroprotective effects by maintaining intracellular homeostasis mitigating damage triggered oxidative stress, inflammatory cascades, apoptotic signaling, ischemic insults. Furthermore, GLP-1R activity is modulated gut microbiota composition short-chain fatty acid abundance, implicating the gut–brain axis in its regulatory influence on neurological function. This review systematically examines pathophysiological mechanisms underlying CCH highlights therapeutic potential of activation. Specifically, GLP-1R-targeted interventions attenuate hypoperfusion-induced through pleiotropic pathways crosstalk, thereby offering novel perspectives for advancing both fundamental research clinical management

Language: Английский

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases DOI Creative Commons
Antero Salminen

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(6), P. 733 - 750

Published: April 11, 2024

Abstract The accumulation of senescent cells within tissues is a hallmark the aging process. Senescent are also commonly present in many age-related diseases and cancer microenvironment. escape abnormal from immune surveillance indicates that there some defect function cytotoxic cells, e.g., CD8 + T natural killer (NK) cells. Recent studies have revealed expression programmed death-ligand 1 (PD-L1) protein abundantly increased An increase amount PD-L1 protects clearance by PD-1 checkpoint receptor In fact, activation suppresses properties NK promoting state immunosenescence. inhibitory PD-1/PD-L1 pathway acts cooperation with immunosuppressive cells; for example, can enhance differentiation regulatory (Treg), myeloid-derived suppressor (MDSC), M2 macrophages, whereas cytokines secreted stimulate protein. Interestingly, signaling pathways known to promote cellular senescence process crucial stimulators protein, epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, AhR signaling. It seems axis has role thus it promotes tissues. Thus, blockade might be potential anti-aging senolytic therapy. Key messages accumulate during diseases. able Expression markedly increases Age-related stimulates Inhibitory

Language: Английский

Citations

23
The communication mechanism of the gut-brain axis and its effect on central nervous system diseases: A systematic review DOI Creative Commons
Shengwen Lu, Qiqi Zhao, Yu Guan

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117207 - 117207

Published: July 26, 2024

Language: Английский

Citations

21
Modulation of immunity by tryptophan microbial metabolites DOI Creative Commons
Siying Li

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: June 21, 2023

Tryptophan (Trp) is an essential amino acid that can be metabolized via endogenous and exogenous pathways, including the Kynurenine Pathway, 5-Hydroxyindole Pathway (also Serotonin pathway), Microbial pathway. Of these, Trp metabolic pathways in gut have recently been extensively studied for their production of bioactive molecules. The microbiota plays important role host metabolism immunity, microbial metabolites influence development progression various diseases, inflammatory, cardiovascular neurological cancer, by mediating body’s immunity. This review briefly outlines crosstalk between microorganisms body, starting from three Trp. mechanisms which act on organism immunity are summarized, potential implications disease prevention treatment highlighted.

Language: Английский

Citations

29
Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration DOI Creative Commons
Jun Sun,

Qiuhua Zeng,

Zhimin Wu

et al.

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(4), P. e00347 - e00347

Published: April 3, 2024

Berberine (BBR) has demonstrated potent anti-inflammatory effects by modulating macrophage polarization. Nevertheless, the precise mechanisms through which berberine regulates post-injury inflammation within peripheral nerve system remain elusive. This study seeks to elucidate role of BBR and its underlying in following injury (PNI). Adult male C57BL/6J mice subjected PNI were administered daily doses (0, 60, 120, 180, 240 ​mg/kg) via gavage from day 1 28. Evaluation sciatic function index (SFI) paw withdrawal threshold revealed that dose-dependently enhanced both motor sensory functions. Immunofluorescent staining for anti-myelin basic protein (anti-MBP) anti-neurofilament-200 (anti-NF-200), along with histological comprising hematoxylin-eosin (HE), luxol fast blue (LFB), Masson staining, promoted structural regeneration. Molecular analyses including qRT-PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence confirmed inactivation NLRP3 inflammasome MCC950 shifted macrophages pro-inflammatory M1 phenotype M2 phenotype, while also impeding infiltration. Furthermore, significantly downregulated expression associated molecules macrophages, thereby mitigating activation-induced polarization inflammation. In summary, BBR's neuroprotective concomitant suppression after PNI, achieved inhibition

Language: Английский

Citations

14
Gut microbiota-host lipid crosstalk in Alzheimer’s disease: implications for disease progression and therapeutics DOI Creative Commons
Yaxi Luo,

Ling-Ling Yang,

Xiu‐Qing Yao

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: April 16, 2024

Abstract Trillions of intestinal bacteria in the human body undergo dynamic transformations response to physiological and pathological changes. Alterations their composition metabolites collectively contribute progression Alzheimer’s disease. The role gut microbiota disease is diverse complex, evidence suggests lipid metabolism may be one potential pathways. However, mechanisms that mediate pathology remain unclear, necessitating further investigation for clarification. This review highlights current understanding how disrupts discusses implications these discoveries guiding strategies prevention or treatment based on existing data.

Language: Английский

Citations

14
Lifelong partners: Gut microbiota-immune cell interactions from infancy to old age DOI Creative Commons
Julia A. Brown, Hilal Bashir, Melody Yue Zeng

et al.

Mucosal Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Recent Insights on the Role of Nuclear Receptors in Alzheimer’s Disease: Mechanisms and Therapeutic Application DOI Open Access

Xiaoxiao Shan,

Dawei Li,

Huihui Yin

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1207 - 1207

Published: Jan. 30, 2025

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family NRs, peroxisome proliferator-activated (PPARs), estrogen receptor (ER), liver X (LXR), farnesoid (FXR), retinoid (RXR), aryl hydrocarbon (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer’s disease (AD). NRs influence pathophysiology AD through mechanisms such as modulation amyloid-beta (Aβ) deposition, regulation inflammatory pathways, improvement neuronal function. However, dual role progression, where some may exacerbate while others offer therapeutic potential, presents critical challenge application treatment. This review explores functional diversity highlighting involvement AD-related processes discussing prospects NR-targeting strategies. Furthermore, key challenges, necessity precise identification beneficial detailed structural analysis molecular dynamics simulations, further investigation NR AD, tau pathology autophagy, also discussed. Collectively, continued research is essential to clarify ultimately facilitating potential use diagnosis, prevention, treatment AD.

Language: Английский

Citations

1
Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota DOI Creative Commons
Junjie Hou,

A-Huo Ma,

Yuehua Qin

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: Oct. 24, 2023

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal that affects more than 3.5 million people, with rising prevalence. It deeply patients’ daily life, increasing the burden on patients, families, and society. Presently, etiology of IBD remains incompletely clarified, while emerging evidence has demonstrated altered gut microbiota decreased aryl hydrocarbon receptor (AHR) activity are closely associated IBD. Furthermore, microbial metabolites capable AHR activation as ligands, AHR, in turn, through various pathways. In light complex connection among microbiota, IBD, it urgent to review latest research progress this field. review, we describe role discussed crosstalk between context Taken whole, propose new therapeutic strategies targeting AHR–microbiota axis for even other related diseases caused by AHR-microbiota dysbiosis.

Language: Английский

Citations

18
Indole-3-Carbinol and Its Derivatives as Neuroprotective Modulators DOI Creative Commons
Alka Ashok Singh, Dhananjay Yadav, Fazlurrahman Khan

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(7), P. 674 - 674

Published: July 2, 2024

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience action of antidepressant drugs, making them prominent targets psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, mental illnesses, exacerbates aging process. The nuclear erythroid 2-related 2 (Nrf2)-antioxidant responsive element (ARE) serves as primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection OS-related damage; notably, TrkB/phosphoinositide 3-kinase (PI3K)/protein (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates promotes translocation. However, insufficient neurotrophin support often leads downregulation diseases. targeting Nrf2-ARE system is a promising therapeutic strategy for treating Phytochemicals, indole-3-carbinol (I3C) metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF’s mimetic activity; Akt phosphorylation induced, antioxidant activated blocking Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes potential I3C derivatives concurrently activating neuronal mechanisms treatment

Language: Английский

Citations

8
Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice DOI Creative Commons

Xiuli Lin,

Yufeng Peng,

Zhimei Guo

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: July 8, 2024

The function of astrocytes in response to gut microbiota-derived signals has an important role the pathophysiological processes central nervous system (CNS) diseases. However, specific effects metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced female C57BL/6 mice as a classical MS model. alterations microbiota and levels short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that exhibit low Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, microbial-derived SCFAs metabolites. supplementation suppressed by increasing level tryptophan (Trp)-derived AhR ligands activating AhR. beneficial clinical scores, histopathological alterations, blood brain barrier (BBB)-glymphatic abolished intracisterna magna injection AAV-GFAP-shAhR. Moreover, loss AQP4 polarity within AhR-dependent manner. Together, potentially suppresses amplifying Trp-AhR-AQP4 signaling mice. Our study demonstrates may serve viable therapy for inflammatory disorders CNS.

Language: Английский

Citations

4