Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy—processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.

Endocan is a circulating proteoglycan secreted by several cell lines and identified as a potential biomarker of inflammation and angiogenesis. Endocan-increased expression has been found in a broad spectrum of human tumors, including lung cancer, and is associated with a poor prognosis. To elucidate the possible mechanism, this study aimed to investigate the role of endocan in non-small-cell lung carcinoma (NSCLC) using an in vitro model of cultured cells. Endocan expression was knocked down by using a specific small interfering RNA. The effects of endocan knockdown have been evaluated on VEGF-A, VEGFR-2, HIF-1α, the long non-coding RNAs H19 and HULC expression, and AKT and ERK 1/2 degree of activation. Cell migration and proliferation have been studied as well. VEGF-A, VEGFR-2, HIF-1α, and the long non-coding RNAs H19 and HULC expression were significantly affected by endocan knockdown. These effects correlated with a reduction of cell migration and proliferation and of AKT and ERK 1/2 activation. Our findings suggest that endocan promotes a more aggressive cancer cell phenotype in NSCLC.

Endocan is a small soluble proteoglycan (PG) known to be involved in inflammation and angiogenesis. Increased endocan expression was found in the synovia of arthritic patients and chondrocytes stimulated with IL-1ß. Considering these findings, we aimed to investigate the effects of endocan knockdown on the modulation of pro-angiogenic molecules expression in a model of IL-1ß-induced inflammation in human articular chondrocytes. Endocan, VEGF-A, MMP-9, MMP-13, and VEGFR-2 expression was measured in both normal and endocan knockdown chondrocytes stimulated with IL-1ß. VEGFR-2 and NF-kB activation were also measured. Results have shown that endocan, VEGF-A, VEGFR-2, MMP-9, and MMP-13 were significantly up-regulated during IL-1ß-induced inflammation; interestingly, the expression of such pro-angiogenic molecules and NF-kB activation were significantly reduced by endocan knockdown. These data support the hypothesis that endocan released by activated chondrocytes may be involved in the mechanisms that stimulate cell migration and invasion, as well as angiogenesis, in the pannus of arthritic joints.

Background/Objectives: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, for which a definitive cure is still missing. Recently, natural compounds have been investigated for their possible neuroprotective role, including the bioactivated product of glucoraphanin (GRA), the sulforaphane (SFN), which is highly rich in cruciferous vegetables. It is known that SFN alleviates neuronal dysfunction, apoptosis, and oxidative stress in the brain. In the light of this evidence, the aim of this study was to investigate the molecular effects of SFN pre-treatment in differentiated SH-SY5Y neurons exposed to β-amyloid (Aβ). Methods: To this end, we first evaluated first cell viability via the Thiazolyl Blue Tetrazolium Bromide (MTT) assay, and then we analyzed the transcriptomic profiles by next-generation sequencing (NGS). Finally, we used a network analysis in order to understand which biological processes are affected, validating them by Western blot assay. Results: SFN pre-treatment counteracted Aβ-induced loss of cell viability. The network-transcriptomic analysis revealed that SFN upregulates genes associated with DNA repair, such as ABRAXAS1, BRCA1, BRCA2, CDKN1A, FANCA, FANCD2, FANCE, NBN, and XPC. Finally, SFN also increased the phosphorylation of AKT, which is associated with DNA repair and cell survival. Conclusions: These data suggest that SFN is a natural compound that could be suitable in the prevention of AD, thanks to its neuroprotective role in increasing cell survival, potentially restoring DNA damage induced by Aβ exposure.

Neurodegenerative disorders are affecting millions of people worldwide, impacting the healthcare system of our society. Among them, Alzheimer’s disease (AD) is the most common form of dementia, characterized by severe cognitive impairments. Neuropathological hallmarks of AD are β-amyloid (Aβ) plaques and neurofibrillary tangles, as well as endoplasmic reticulum and mitochondria dysfunctions, which finally lead to apoptosis and neuronal loss. Since, to date, there is no definitive cure, new therapeutic and prevention strategies are of crucial importance. In this scenario, cannabinoids are deeply investigated as promising neuroprotective compounds for AD. In this study, we evaluated the potential neuroprotective role of cannabinerol (CBNR) in an in vitro cellular model of AD via next-generation sequencing. We observed that CBNR pretreatment counteracts the Aβ-induced loss of cell viability of differentiated SH-SY5Y cells. Moreover, a network-based transcriptomic analysis revealed that CBNR restores normal mitochondrial and endoplasmic reticulum functions in the AD model. Specifically, the most important genes regulated by CBNR are related mainly to oxidative phosphorylation (COX6B1, OXA1L, MT-CO2, MT-CO3), protein folding (HSPA5) and degradation (CUL3, FBXW7, UBE2D1), and glucose (G6PC3) and lipid (HSD17B7, ERG28, SCD) metabolism. Therefore, these results suggest that CBNR could be a new neuroprotective agent helpful in the prevention of AD dysfunctions.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain widely detectable in the environment and human tissues decades after their ban, raising concerns for brain health. Both dioxin-like (DL) and non-dioxin-like (NDL) congeners interfere with neuronal function through partially distinct pathways, including aryl hydrocarbon receptor activation, disruption of calcium and dopaminergic signaling, oxidative stress, and epigenetic remodeling. Experimental and epidemiological studies indicate that developmental PCB exposure is associated with impaired cognition, attention, motor function, and increased risk of neurodevelopmental disorders. Furthermore, chronic exposure in adulthood has been linked to neurodegenerative diseases. At the cellular level, NDL-PCBs sensitize ryanodine receptors, alter dendritic and axonal growth, promote mitochondrial dysfunction, generate reactive oxygen and nitrogen species, and compromise blood–brain barrier integrity, thereby fostering neuroinflammation, synaptic dysfunction, and neuronal loss. This review synthesizes current evidence on the molecular and cellular mechanismtable s underlying PCB-induced neurotoxicity across the lifespan, highlighting oxidative stress as a central factor, integrating calcium dysregulation, neurotransmitter imbalance, and apoptotic and epigenetic pathways. Finally, potential neuroprotective roles of antioxidant strategies are discussed, emphasizing their relevance for mitigating PCB-related neurodevelopmental and neurodegenerative risk.