Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases.

Over the past few decades, it has been well established that gut microbiota-derived metabolites can disrupt gut function, thus resulting in an array of diseases. Notably, phenylacetylglutamine (PAGln), a bacterial derived metabolite, has recently gained attention due to its role in the initiation and progression of cardiovascular and cerebrovascular diseases. This meta-organismal metabolite PAGln is a byproduct of amino acid acetylation of its precursor phenylacetic acid (PAA) from a range of dietary sources like egg, meat, dairy products, etc. The microbiota-dependent metabolism of phenylalanine produces PAA, which is a crucial intermediate that is catalyzed by diverse microbial catalytic pathways. PAA conjugates with glutamine and glycine in the liver and kidney to predominantly form phenylacetylglutamine in humans and phenylacetylglycine in rodents. PAGln is associated with thrombosis as it enhances platelet activation mediated through the GPCRs receptors α2A, α2B, and ß2 ADRs, thereby aggravating the pathological conditions. Clinical evidence suggests that elevated levels of PAGln are associated with pathology of cardiovascular, cerebrovascular, and neurological diseases. This Review further consolidates the microbial/biochemical synthesis of PAGln and discusses its role in the above pathophysiologies.

Trimethylamine-N-oxide and cerebral stroke risk: A review.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono­oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.

Evaluation of Antidepressant Activity of Capsaicin Nanoemulsion in Nicotine Withdrawal-Induced Depression in Mice.

Depression is a low-energy condition that has an impact on a person's thoughts, actions, propensities, emotional state, and sense of wellbeing. According to the World Health Organization (WHO), 5% of adults are depressed. Individuals who are depressed are commonly prescribed antidepressants, and sometimes, individuals may have other psychiatric conditions that share overlapping symptoms with depression. These cooccurring conditions can complicate the diagnostic process, leading to a misdiagnosis and the prescription of antidepressants. Capsaicin (CAP) is a known antidepressant. Hence, this study aimed to assess the antidepressant activity of CAP nanoemulsion in nicotine (NC) withdrawal-induced depression in mice. Mice treated with CAP (3 mg/kg) showed reduced immobility in the forced swimming test (FST), tail-suspension test (TST), and open field test (OFT). During the OFT, the animals treated with nanoemulsion (CAP 3 mg/kg) spent less time in the corners than the control animals. Biochemical parameters, such as superoxide dismutase (SOD) and glutathione (GSH), were observed in reduced quantities in the NC withdrawal model (NWM), where they were slightly increased in the high-dose nanoemulsion (CAP 3 mg/kg) compared to the low-dose nanoemulsion (CAP 1 mg/kg). These results suggest that CAP caused antidepressant activity in the NWM via the nanoemulsion.