BACKGROUND: Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality. Scope and Approach: This comprehensive review aims to elucidate the central role of the microbiotagut- brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy. CONCLUSION: Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.

• Keywords
• Neurodegenerative diseases, blood-brain barrier, dietary adaptations., gut microbiota, microbiota-gut-brain axis, therapy,
• MeSH
• Dysbiosis metabolism   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Humans MeSH
• Brain * metabolism   MeSH
• Neurodegenerative Diseases * microbiology   metabolism   MeSH
• Brain-Gut Axis * physiology   MeSH
• Probiotics MeSH
• Aging * MeSH
• Gastrointestinal Microbiome * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Mycotoxins have been shown to activate multiple mechanisms that may potentially lead to the progression of Alzheimer's disease (AD). Overexpression/aberrant cleavage of amyloid precursor protein (APP) and hyperphosphorylation of tau (P-tau) is hallmark pathologies of AD. Recent advances suggest that the neurotoxic effects of mycotoxins involve c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor-1α (HIF-1α) signaling, which are closely linked to the pathogenesis of AD. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters APP and P-tau formation in BV2 cells and determined the underlying roles of HIF-1α and JNK signaling. The findings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a "brake" on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK signaling, which broke this "brake" to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK might interfere with HIF-1α's protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins.

• Keywords
• Amyloid precursor protein, Hypoxia-inducible factor-1α, T-2 toxin, Tau, c-Jun N-terminal kinase,
• MeSH
• Amyloid beta-Protein Precursor * metabolism   MeSH
• Cell Line MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit * metabolism   genetics   MeSH
• Phosphorylation drug effects   MeSH
• JNK Mitogen-Activated Protein Kinases metabolism   MeSH
• Mice MeSH
• tau Proteins * metabolism   MeSH
• Signal Transduction drug effects   MeSH
• T-2 Toxin * toxicity   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Protein Precursor * MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit * MeSH
• Hif1a protein, mouse MeSH Browser
• JNK Mitogen-Activated Protein Kinases MeSH
• tau Proteins * MeSH
• T-2 Toxin * MeSH

Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases.

• Keywords
• Anti-aging, Cell senescence, Hypoxia, JNK, PARP1,
• MeSH
• Hypoxia MeSH
• JNK Mitogen-Activated Protein Kinases * metabolism   MeSH
• Humans MeSH
• MAP Kinase Signaling System MeSH
• Signal Transduction * MeSH
• Cellular Senescence MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• JNK Mitogen-Activated Protein Kinases * MeSH

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

• Keywords
• Alzheimer’s disease, amyloid beta, drug, mitochondria, tau protein,
• MeSH
• Alzheimer Disease * metabolism   MeSH
• Amyloid metabolism   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Amyloidogenic Proteins metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Amyloid MeSH
• Amyloid beta-Peptides MeSH
• Amyloidogenic Proteins MeSH