The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Due to the high prevalence of obesity and type 2 diabetes, adipogenesis dysfunction and metabolic disorders are common features in the elderly population. Thus, the identification of novel compounds with anti-adipogenic and lipolytic effects is highly desirable to reduce diabetes complications. Plants represent an important source of bioactive compounds. To date, the antidiabetic potential of several traditional plants has been reported, among which Ficus carica L. is one of the most promising. Considering that plant metabolome changes in response to a number of factors including seasonality, the aim of this study was to evaluate whether Ficus carica leaves extracts collected in autumn (FCa) and spring (FCs) differently modulate lipid metabolism and adipogenesis in 3T3-L1 adipocytes. The ¹H-NMR profile of the extracts showed that FCs have a higher content of caffeic acid derivatives, glucose, and sucrose than FCa. In contrast, FCa showed a higher concentration of malic acid and furanocoumarins, identified as psoralen and bergapten. In vitro testing showed that only FCa treatments were able to significantly decrease the lipid content (Ctrl vs. FCa 25 μg/mL, 50 μg/mL and 80 μg/mL; p < 0.05, p < 0.01 and p < 0.001, respectively). Furthermore, FCa treatments were able to downregulate the transcriptional pathway of adipogenesis and insulin sensitivity in 3T3-L1 adipocytes. In more detail, FCa 80 μg/mL significantly decreased the gene expression of PPARγ (p < 0.05), C/EBPα (p < 0.05), Leptin (p < 0.0001), adiponectin (p < 0.05) and GLUT4 (p < 0.01). In conclusion, this study further supports an in-depth investigation of F. carica leaves extracts as a promising source of active compounds useful for targeting obesity and diabetes.

Gamma-oryzanol (ORY), found in rice (Oryza sativa L.), is a mixture of ferulic acid esters with triterpene alcohols, well-known for its antioxidant and anti-inflammatory properties. Our past research demonstrated its positive impact on cognitive function in adult mice, influencing synaptic plasticity and neuroprotection. In this study, we explored whether ORY can exert neuro-differentiating effects by using different experimental models. For this purpose, chemical characterization identified four components that are most abundant in ORY. In human neuroblastoma cells, we showed ORY’s ability to stimulate neurite outgrowth, upregulating the expression of GAP43, BDNF, and TrkB genes. In addition, ORY was found to guide adult mouse hippocampal neural progenitor cells (NPCs) toward a neuronal commitment. Microinjection of ORY in zebrafish Tg (-3.1 neurog1:GFP) amplified neurog1-GFP signal, islet1, and bdnf mRNA levels. Zebrafish nrf2a and nrf2b morphants (MOs) were utilized to assess ORY effects in the presence or absence of Nrf2. Notably, ORY’s ability to activate bdnf was nullified in nrf2a-MO and nrf2b-MO. Furthermore, computational analysis suggested ORY’s single components have different affinities for the Keap1-Kelch domain. In conclusion, although more in-depth studies are needed, our findings position ORY as a potential source of bioactive molecules with neuro-differentiating potential involving the Nrf2 pathway.

A growing body of evidence links the gastrointestinal tract to Parkinson's disease (PD) development. The research by Braak and colleagues, based on analyzing post-mortem samples from PD patients, suggests that the pathology begins in the gut and progresses to the brain. Our recent work shows that PD brains and PD PBMCs display reduced DNA-binding activity of the NF-κB/c-Rel subunit, a neuroprotective transcription factor that promotes brain expression of mitochondrial regulators such as B-cell lymphoma-extra-large (Bcl-xL), uncoupling protein 4 (UCP4), and manganese superoxide dismutase (MnSOD). Previous studies have also shown that male mice lacking the NF-κB/c-Rel subunit (c-rel^-/- mice) develop age-related parkinsonian neuropathology linked to both non-motor and motor symptoms. They exhibit a Braak pattern of α-synuclein (α-syn) deposition, beginning with early gut involvement marked by constipation and α-syn accumulation in the distal colon from 2 months old. Here, we further examine the progression of intestinal pathology in the proximal colon of c-rel^-/- male mice which is connected to the brain via the vagus nerve, using microscopy, biochemistry, and multispectral optoacoustic tomography. At 2 months, α-syn and phosphorylated α-syn accumulation was detected in the myenteric plexus of c-rel^-/- mice, with significantly greater accumulation at 10 months. Intestinal synucleinopathy was accompanied by notable oxidative stress, evidenced by increased NADPH oxidase activity and higher levels of 3-nitrotyrosine-modified proteins in the proximal colon. By 10 months, c-rel^-/- mice showed gut inflammation with elevated interleukin-6 expression, infiltration of CD11b+Ly6G+ neutrophils, and increased oxygenated hemoglobin in the proximal colon, along with colon shortening and loss of TH-positive neurons. These findings, in addition to supporting the role of NF-κB/c-Rel dysregulation in PD pathophysiology, show that c-rel^-/- mice develop progressive PD-like pathology in the proximal colon and provide an invaluable model for studying the potential gut-to-brain spread of endogenous α-syn via the vagus.