Christina Alves Peixoto

This study investigated the effects of 1, 10, or 100 μg/mL thymol on bovine secondary follicles cultured in vitro for 18 days at 38.5 °C with 5% CO₂. After culture, the following parameters were evaluated: (1) the follicular growth, antrum formation, viability, and ultrastructure, (2) the levels of malondialdehyde, reduced glutathione, and nitrite in the culture medium, and (3) mRNA levels of catalase (CAT), glutathione peroxidase 1 (GPX1), superoxide dismutase (SOD), peroxiredoxin 6 (PRDX6), proliferating cell nuclear antigen (PCNA), and growth differentiation factor 9 (GDF-9). The results showed that 10 μg/mL thymol increased cell viability, antrum formation and follicular development. At day 18, nitrite levels were higher in medium of follicles cultured with 10 μg/mL thymol than those found in control medium alone or with 1 μg/mL thymol. Gene expression analysis revealed that 10 μg/mL thymol increased catalase and glutathione peroxidase 1 mRNA levels, while the expression of other transcripts was unaffected. Transmission electron microscopy showed that granulosa cells exhibited rounded nuclei, elongated mitochondria, and sparse cytoplasmic vacuoles in all treatments, except for those cultured in control medium that had signs of degeneration. In conclusion, 10 μg/mL thymol increased mRNA expression of catalase and glutathione peroxidase 1, stimulated antrum and preserved granulosa cells of bovine secondary follicles in vitro.

Schistosomiasis remains as a parasitic disease with major morbidity, ongoing transmission, and economic burden, particularly in tropical regions. Praziquantel is the first-line treatment but has limited efficacy against juvenile stages of the parasite. In this context, this study assessed the repurposing potential of anthelmintics against Schistosoma mansoni, focusing on the schistosomicidal activity of nitazoxanide (NTZ), levamisole (LVZ), and thiabendazole (TBZ). In vitro, NTZ exhibited a significant schistosomicidal activity, emerging as a repurposing candidate. In contrast, LVZ and TBZ showed no significant schistosomicidal activity. NTZ was active from 40 µg/mL, affecting schistosomula and adult worms in a dose-dependent manner. Ultrastructural analysis revealed wrinkling of the oral and ventral suckers and tegumental alterations in male worms, including shortening of ridges near the tubercles and the presence of multiple small protrusions. In vivo, NTZ showed partial efficacy, with 57.14% reduction in adult worm recovery, whereas PZQ achieved complete elimination. Infected animals presented a mean of 541.86 ± 273.13 viable eggs/cm², while treatment with nitazoxanide (205 mg/kg) or praziquantel (400 mg/kg) reduced these values to 247.98 ± 109.68 and 144.92 ± 133.46 eggs/cm², respectively. Combined administration of NTZ and PZQ resulted in the greatest reduction in viable egg counts, with a mean of 96.75 ± 49.55 eggs/cm². Although praziquantel resistance has been reported, in this study it fully eliminated adult worms, while nitazoxanide showed lower but relevant activity against both schistosomula and adult stages. These findings confirm the efficacy of praziquantel against adult worms and highlight therapeutic potential of nitazoxanide, underscoring the need for further bioavailability studies. Graphical Abstract The alternative text for this image may have been generated using AI.

Parkinson’s disease (PD) remains a challenging disease for treatment, which is usually polypharmacological. In addition to motor symptoms, non-motor symptoms such as depression are present in approximately 40% of patients, contributing to the loss of quality of life. In the last two decades, a growing body of evidence has emerged regarding the involvement of the microbiota-gut-brain axis in both PD and depression. Fructooligosaccharides (FOS) and galactooligosaccharides (GOS) are prebiotic fibers that can be fermented by the gut microbiota, which produce metabolites called short-chain fatty acids (SCFAs), whose effects can contribute to improvement in neurodegenerative and psychiatric conditions. This study analyzed the effects of FOS and GOS administration in a rotenone-induced PD model and demonstrated a relief of motor symptoms and depressive-like behavior, followed by an increase of brain serotonin and its respective receptor (SERT). FOS and GOS treatment also led to an increase in SCFAs-producing gut bacteria with significantly higher levels of serum and brain butyrate. Furthermore, in the intestine, prebiotics reduced the accumulation of α-synuclein, decreased inflammation, and improved the expression of zonula occludens and occludin. FOS and GOS also attenuated the loss of dopaminergic neurons and reduced neuroinflammation by decreasing α-synuclein, IBA-1, GFAP, iNOS, p-NFkB, and IL1-β levels in the substantia nigra and prefrontal cortex. In addition, these prebiotics improved neuroplasticity by promoting the expression of butyrate receptors (GPR43 and GPR109), BDNF, p-CREB, and synaptic protein PSD-95. In conclusion, FOS and GOS administration attenuatted depressive-like behavior, neuroinflammation, and synaptic plasticity in Parkinson’s disease by modulating butyrate-producing gut bacteria.

Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut–brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases. image

Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®—0.05 mg/Kg—translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer’s disease, Parkinson’s disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.