Showing papers by "Sandra M. Cardoso published in 2022"

Enzyme Promiscuity in Serotonin Biosynthesis, From Bacteria to Plants and Humans

Abstract: Serotonin is a phylogenetically ancient compound found in animals, plants, and some bacteria. In eukaryotes, serotonin is synthesized from the aromatic amino acid tryptophan via the key enzymes aromatic amino acid hydroxylase (AAAH) and aromatic amino acid decarboxylase (AAAD). Serotonin is also an intermediate in the melatonin biosynthetic pathway and is involved in several vital functions. In humans, serotonin is produced in the gut and in the brain, is critical in the regulation of multiple body functions, and its depletion has been implicated in multiple neurological disorders including depression and Alzheimer’s disease, as well as other peripheral conditions namely irritable bowel syndrome and fibromyalgia. The serotonin biosynthetic pathway is well described in eukaryotes, but very little is known about this pathway in bacteria. Evidence points to similar pathways since eukaryote-like AAAH and AAAD (and their genes) have been identified in multiple bacteria, even though serotonin production has not yet been detected in most species. Although data on bacterial tryptophan decarboxylase genes are very limited and no bacterial tryptophan hydroxylase genes have been identified to date, evidence suggests that serotonin production in bacteria might occur through different AAAH and AAAD. Substrate promiscuity in these enzymes has been previously reported and seems to be the key aspect in bacterial serotonin synthesis. Considering the human gut microbiota as a potential source of serotonin, further investigation on its biosynthetic pathways in microbes might lead to important discoveries, which may ultimately foster the development of new therapeutic strategies to treat serotonin depletion-related disorders in humans.

Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation

Abstract: Inflammation and oxidative stress characterize a number of chronic conditions including neurodegenerative diseases and aging. Inflammation is a key component of the innate immune response in Alzheimer’s disease and Parkinson’s disease of which oxidative stress is an important hallmark. Immune dysregulation and mitochondrial dysfunction with concomitant reactive oxygen species accumulation have also been implicated in both diseases, both systemically and within the Central Nervous System. Mitochondria are a centrally positioned signalling hub for inflammatory responses and inflammatory cells can release reactive species at the site of inflammation often leading to exaggerated oxidative stress. A growing body of evidence suggests that disruption of normal gut microbiota composition may induce increased permeability of the gut barrier leading to chronic systemic inflammation, which may, in turn, impair the blood–brain barrier function and promote neuroinflammation and neurodegeneration. The gastrointestinal tract is constantly exposed to myriad exogenous substances and microbial pathogens, which are abundant sources of reactive oxygen species, oxidative damage and pro-inflammatory events. Several studies have demonstrated that microbial infections may also affect the balance in gut microbiota composition (involving oxidant and inflammatory processes by the host and indigenous microbiota) and influence downstream Alzheimer’s disease and Parkinson’s disease pathogenesis, in which blood–brain barrier damage ultimately occurs. Therefore, the oxidant/inflammatory insults triggered by a disrupted gut microbiota and chronic dysbiosis often lead to compromised gut barrier function, allowing inflammation to “escape” as well as uncontrolled immune responses that may ultimately disrupt mitochondrial function upwards the brain. Future therapeutic strategies should be designed to “restrain” gut inflammation, a goal that could ideally be attained by microbiota modulation strategies, in alternative to classic anti-inflammatory agents with unpredictable effects on the microbiota architecture itself.

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.