The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to global health, not only due to respiratory symptoms but also due to its impact on psychiatric disorders. Understanding the biological mechanisms underlying psychiatric manifestations in individuals with COVID-19 is crucial. This study aimed to investigate potential alterations in caspase 3 and 8 levels, as well as brain-derived neurotrophic factor (BDNF) levels, in individuals with COVID-19. The association of these markers with mental health was also assessed. A cross-sectional study was conducted, including individuals with COVID-19 and those without the disease. The stress levels were higher in individuals with COVID-19. Caspase 3 and 8 and BDNF levels were increased in individuals with COVID-19 compared to individuals without COVID-19. No significant differences were found in caspase 3 and 8 and BDNF levels between moderate/severe and asymptomatic/mild symptoms of COVID-19. The results indicate that no significant differences were observed between the diagnosis of anxiety disorders and the levels of markers. However, higher caspase 3 levels in individuals without anxiety and COVID-19 were found. No significant associations between the diagnosis of major depressive disorder or psychiatric symptoms and caspase 3, caspase 8, and BDNF levels were found. The results indicate that, although caspase 3, caspase 8, and BDNF levels are increased in individuals with COVID-19, these elevations are not associated with the severity of COVID-19 symptoms or psychiatric conditions and symptoms in post-COVID-19. These findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may influence cellular activity and neurotrophic markers, but that other factors likely contribute to psychiatric disorders.

Ketamine is an anesthetic drug that has been illegally used due to its hallucinogenic effects. Its use is often concomitant with drugs such as ethanol, which can cause irreversible damage to the central nervous system. This study investigates the neurotoxicity of ketamine-ethanol combination in human neuroblastoma SH-SY5Y cell line, exploring the mechanisms preceding cell death. Cell viability, oxidative stress parameters, and apoptosis pathways were assessed after 3 and 6h of drug exposure. A concentration-response curve using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay determined the lowest observed adverse effect levels for ketamine (1 mM; K1) and ethanol (100 mM; E100). After 12, 24 and 48h, MTT assay revealed a decrease in cell viability, with a possible synergistic effect in K1E100 at 48h, confirmed by annexin-V/7-aminoactinomycin D flow cytometry analysis, which showed a higher proportion of late apoptotic cells. Mechanisms preceding cell death were assessed by measuring reduced glutathione (GSH) levels, glutathione-related enzymes activities, and apoptosis markers (caspase-8, Bax, Bcl-2, and caspase-3). GSH levels decreased after 6h in E100 and K1E100. Glutathione peroxidase activity increased for all groups after 3h and in K1 and K1E100 after 6h. Glutathione reductase and glutathione S-transferase activities increased only for K1E100 after 3h. K1E100 also showed increased caspase-8 and Bax expression after 3 and 6h, respectively, indicating activation of both extrinsic and intrinsic apoptotic pathways. These results suggest that ketamine-ethanol combination induces neurotoxicity by triggering oxidative stress and apoptosis in a time-dependent manner prior to cell death, increasing the risk for neuronal damage compared to individual drug exposure. While these findings are promising, they should be interpreted with caution due to certain limitations, such as variability in enzyme activity measurements, reduced sample size for some markers, and the use of an immortalized, proliferative cell line. Further studies using differentiated neuronal cells are needed to validate and expand these observations.

Increasing evidence of ocular impairments in Alzheimer's disease (AD) has drawn the attention of researchers worldwide towards retinal neurodegeneration in AD. The AD-associated changes observed in the retina include visual discrepancies, pupil size modulations, retinal nerve layer changes, retinal blood flow alterations and histopathological changes. The brain cells that act as pathological triggers for the progression of retinal neurodegeneration associated with AD are microglia, astrocytes and neurons. Various molecular pathways lead to structural and functional abnormalities in the retina, significantly affecting the brain including Aβ accumulation, apoptosis, inflammation and oxidative stress. Therapeutic agents under development that ameliorate disease conditions by targeting retinal anomalies include mesenchymal stem cell-conditioned media, BDNF, glatiramer acetate, salvianolic acid B, Lycium barbarum extract and exosomes. Investigating real-time alterations in the retina in AD may not only affect diagnostic approaches but also help to clarify neuropathological pathways and offer helpful measurements for assessing novel therapeutic approaches for AD.

Recent studies have identified the angiotensin-converting enzyme (ACE) gene as a potential candidate influencing Alzheimer's disease (AD) risk. It is crucial to investigate the impact of ACE on AD pathology and its underlying mechanisms. A total of 450 non-demented participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with data on cerebrospinal fluid (CSF) ACE, AD core biomarkers and inflammation-related biomarkers were included. Multiple linear regression was used to assess the associations among CSF ACE, AD core biomarkers and inflammation-related biomarkers. And we used the mediation models to investigate the potential mechanisms through which ACE influenced AD pathology. The results of multiple linear regression were shown that CSF ACE was significantly correlated with CSF Aβ42, P-tau, T-tau (all P < 0.001), and inflammation-related biomarkers (soluble triggering receptor expressed on myeloid cells 2 [sTREM2], progranulin [PGRN], glial fibrillary acidic protein [GFAP], transforming growth factor [TGF]-β1, TGF-β2, TGF-β3, tumor necrosis factor [TNF]-R1, TNF-R2, TNF-α, interleukin [IL]-21, IL-6, IL-7, IL-9, IL-10, IL-12p40, vascular cell adhesion molecule-1 [VCAM-1], and intercellular adhesion molecule-1 [ICAM-1]) (all P < 0.05). In addition, the mediation analysis results showed that the association of CSF ACE and inflammation-related biomarkers (sTREM2, PGRN, TGF-β1, TGF-β2, TNFR1, IL-6, IL-7, IL-9, and VCAM-1) mediated the correlation of CSF Aβ42 with P-tau. Our findings show that CSF ACE and neuroinflammation are correlated and that their correlation mediates the link between Aβ pathology and P-tau. This suggests ACE may play a significant role in the progression from Aβ pathology to tau pathology.

This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM) and striatum. Key markers were analyzed at 4, 8, 24, and 48 h post-injections: the hydroxylated form of the purine guanine (8-hydroxy-2'-deoxyguanosine; 8-OHdG), a marker of oxidative stress; the methylated form of cytosine (5-methylcytosine; 5-mC), associated with gene silencing; the hydroxy methylated form of cytosine (5-hydroxymethylcytosine; 5-hmC), involved in demethylation and gene regulation. The results showed a pronounced decrease in 8-OHdG levels in the VM, suggesting a rapid oxidative stress response, whereas the striatum exhibited a less pronounced response, reflecting regional differences in oxidative stress vulnerability DNA methylation patterns revealed complex and biphasic changes in 5-mC levels in the VM, contrasted with a less pronounced response in the striatum, suggesting disrupted methylation homeostasis and regional epigenetic variability. MPTP treatment also significantly reduced in 5-hmC levels in the VM, pointing to impaired active DNA demethylation and compromised epigenetic flexibility. In contrast, the striatum maintained consistently high 5-hmC levels, reflecting compensatory hydroxymethylation mechanisms specific to this region. These findings highlight pronounced regional differences in oxidative stress vulnerability and epigenetic regulation, with the VM showing heightened sensitivity to oxidative damage and impaired epigenetic flexibility. This underscores the importance of understanding the role of oxidative and epigenetic mechanisms in Parkinson’s disease pathophysiology, The changes pave the way for novel therapeutic strategies targeting oxidative DNA damage and epigenetic homeostasis.

Monosodium glutamate (MSG) is a silent excitotoxin used as a flavour enhancer but exerts serious health hazards to consumers. MSG plays a role in neuronal function as the dominant excitatory neurotransmitter. It is transferred into the blood and ultimately increases brain glutamate levels, causing functional disruptions notably via oxidative stress. The study evaluated the toxic effect of high consumption of MSG and the modulatory role of vitamin C on ATPase activities in the striatum and cerebellum of male Wistar rats for five weeks. Rats were grouped into four (A-D): group A was fed with rat's show only; Group B was fed with diet containing 15% MSG; Group C was treated with vitamin C (200mg/kg b.wgt orally in 0.9% saline solution) only for 3weeks; and group D rats were fed with MSG and vitamin C. The findings show that MSG does not affect body and cerebellum weights but increases striatal weight. MSG increases the malondialdehyde (MDA) level and significantly decreases catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) levels. MSG significantly impaired striatal and cerebellar ATPases activities (Na+/K+-, Ca2+-, Mg2+- and total ATPases). Vitamin C treatment abolishes MSG-induced oxidative stress and improves ATPase activities. The findings show that vitamin C has beneficial effects in improving the functions of membrane-bound ATPases against MSG toxicity in rat's striatum and cerebellum.

Alzheimer's disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped. Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5'-dimethylallyl and 4'-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3β-mediated tau phosphorylation previously reported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3β. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD.