(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

Electroacupuncture Stimulation Regulates Adipose Lipolysis via Catecholamine Signaling Mediated by NLRP3 Suppression in Obese Rats

Chronic low-grade inflammation of visceral adipose tissue can cause obesity-associated insulin resistance, leading to metabolic syndrome. However, anti-inflammatory drugs and those for obesity management can lead to serious side effects such as abnormal heart rate and blood pressure. Consequently, this study aimed to explore the therapeutic potential of electroacupuncture stimulation (ES) for obesity and associated chronic inflammation. Sprague-Dawley male rats were fed a high-fat diet (HFD) for ten weeks to build an obesity model, and half of the diet-induced obesity (DIO) rats were received ES. The levels of inflammatory factors were detected by ELISA and qPCR analysis. The nerve-associated macrophages were marked with immunofluorescence staining. The molecular mechanism of NLRP3 inflammasome in ES was determined by the NLRP3 inflammasome activation model. Compared to HDF rats, ES showed decreased body weight and chronic inflammatory damage. Specifically, this occurred via a decrease in monoamine oxidase-A (MAOA) expression, which suppressed noradrenaline degradation. MAOA is expressed in nerve-associated macrophages (NAMs), and ES attenuated NAMs by suppressing the NLRP3 inflammasome. The NLRP3 agonist blocked the noradrenaline degradation-reducing effect of ES, and an increase in lipolysis via the inhibition of the NLRP3 inflammasome attenuated NAMs. Thus, our findings suggest that ES induced lipolysis via activation of the NLRP3 inflammasome in nerve-associated macrophages (NAMs), independently of sympathetic nervous system activity.

Dietary Intake of Flavonoids and Carotenoids Is Associated with Anti-Depressive Symptoms: Epidemiological Study and In Silico—Mechanism Analysis

Flavonoids and carotenoids are bioactive compounds that have protective effects against depressive symptoms. Flavonoids and carotenoids are the two main types of antioxidant phytochemicals. This study investigated the association between flavonoid and carotenoid intake and depressive symptoms in middle-aged Korean females. We analyzed the mechanism of these associations using an in silico method. Depressive symptoms were screened using the Beck Depression Inventory-II (BDI-II), and flavonoid and carotenoid intake were assessed using a semi-quantitative food frequency questionnaire. Using a multivariate logistic regression model, we found that flavones, anthocyanins, individual phenolic compounds, lycopene, and zeaxanthin were negatively associated with depressive symptoms. In silico analysis showed that most flavonoids have high docking scores for monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB), which are two important drug targets in depression. The results of the docking of brain-derived neurotrophic factor (BDNF) and carotenoids suggested the possibility of allosteric activation of BDNF by carotenoids. These results suggest that dietary flavonoids and carotenoids can be utilized in the treatment of depressive symptoms.

Relationship between the monoamine oxidase gene overactivity and the other pathophysiological and behavioral parameters implicated in memory deficiency in albino Winstar rats as Alzheimer’s disease model

The current study aimed to assess the pathophysiology mechanisms that mediate the effect on albin winstar rats' memory induced by the co -administration of fluoride and aluminum sulfate, as a model of Alzheimer's disease. This was done by assessing monoamine oxidase-A (MAO-A) activity, antioxidant activity, H2O2 and amyloid-β concentration in the hippocampus, embedded deep into the brain's temporal lobe, and level of cytokines in serum. The polymerase chain reaction approach was used to genotyping MAO-A, followed by single -stranded conformational polymorphism (SSCP) coupled with sequencing technique. The experimental animals were divided into two groups: control and treated groups. The uptake of heavy metals led to significantly increased MAO-A activity, amyloid -β deposition, H2O2 and cytokines levels in the treated group. However, the finding showed a significant decrease in antioxidant activity in the treated group. The results indicated that metals caused memory and learning impairments. PCR -SSCP genotyping showed many SNPs and haplotypes of the MAO-A exon 2 region, which showed the MAO-A gene polymorphism changes associated with Alzheimer's disease. The overall results indicated a role of metals to induce oxidative stress stimulating pathophysiological hallmarks in the hippocampus due to an increase in the influx of monoamine oxidase expression, which has been implicated in impaired memory, this study focused on the genetic variation of the exon 2 in monoamine oxidase-A gene and its relationship to Alzheimer's disease with the presence of several single nucleotide polymorphisms that may be related to Alzheimer's disease model in rats.

In Silico Effects of Steviol on Depression, Inflammation and Cancer Biomarkers

Steviol (ST1), a known natural product, and methylated models (ST2-ST4) were investigated in this in silico work to see their effects were examined on each of depression, inflammation, and cancer biomarkers by participating in interactions with each of monoamine oxidase-A (MAO-A), cyclooxygenase-2 (COX-2), methyltransferase (MTN) enzymes, respectably. The stabilized structures of ST1-ST4 were achieved by performing optimization calculations. Subsequently, formations of interacting ligand-target complexes were examined by molecular docking (MD) simulations. The evaluated molecular orbital features showed a different tendency of ST1-ST4 models for contributing to electron transfer processes. Accordingly, the interacting ligand-target complexes showed differential interactions of each ligand towards each target, making ST1-ST4 as appropriate compounds for the detection of targets. The methylated ST2-ST4 models worked even better than the original ST1 model to affirm the benefit of steviol modification to achieve desired results. Meaningful interactions of ST1-ST4 with the targets also showed the possible application of steviol for the medication of each of depression, inflammation, and cancer cases.

Genomic Analysis of Human Population Structure

<p>Recent developments in technology and computation have encouraged a shift towards a whole-genome approach to genetic analysis. Two key contributors to this shift, the Human Genome Project and the HapMap project, sparked an interest in studying the genetic patterns found in particular groups of individuals. The Maori population of New Zealand is an ideal, yet untapped, model for such studies due to recent partial mixture of two distinct population groups, and a culture of good documentation of genealogical information. A previous study carried out by the author found observable genetic differences between Maori and European populations in markers of forensic significance, yet no particular genetic patterns were found that were uniquely Maori. This study extends the previous work by developing methods to determine to what scale these differences exist, as well as demonstrating that a knowledge of these differences and methods could be used to improve current practices for clinical diagnosis. The current project began by taking a ‘candidate gene’ approach, studying two regions where there were known large genetic differences between Maori and European individuals: the region of Alcohol Dehydrogenase genes on Chromosome 4 (Chapter 2), and the Monoamine Oxidase A gene region on Chromosome X (Chapter 3). In both of these regions, large frequency differences were observed between Maori and non-Maori populations at both a single mutation level, and at a haplotype level. Despite the differences that were observed, no particular combinations of mutations could be considered uniquely Maori or uniquely non-Maori, so studies were expanded to the entire genome. This epansion was made possible due to the recent and continuing developments in genome-wide technology and advancements in computational speed and efficiency. Once it was possible to carry out a genome-wide study of genetic differences, the goal of research changed from determining whether or not Maori and European individuals were uniquely different at a genotype level, to how small a marker set could be produced while maintaining population-uniqueness at a genotype level. A method that uses bootstrap sub-sampling and other internal validation techniques has been developed for the generation of such a signature set for a Maori tribe (Ngati Rakaipaaka), and the generated set has been validated in other similar populations (Chapter 4). As a consequence of producing this set, the degree of European admixture was estimated in the tribe (28.7%), with over 15% of individuals within Rakaipaaka found to have no discernible European genomic ancestry. In a validation of the signature set generation method itself, the marker selection procedure was repeated for Type 1 Diabetes, a disease with high heritability. An analysis of case and control individuals using this signature set found that the generated set is able to perform better than a genome-wide reference set of mutations known to be associated with Type 1 Diabetes. This validation study, other potential uses, and a more detailed discussion of the signature set generation method are presented in Chapter 5.</p>

Genomic Analysis of Human Population Structure

<p>Recent developments in technology and computation have encouraged a shift towards a whole-genome approach to genetic analysis. Two key contributors to this shift, the Human Genome Project and the HapMap project, sparked an interest in studying the genetic patterns found in particular groups of individuals. The Maori population of New Zealand is an ideal, yet untapped, model for such studies due to recent partial mixture of two distinct population groups, and a culture of good documentation of genealogical information. A previous study carried out by the author found observable genetic differences between Maori and European populations in markers of forensic significance, yet no particular genetic patterns were found that were uniquely Maori. This study extends the previous work by developing methods to determine to what scale these differences exist, as well as demonstrating that a knowledge of these differences and methods could be used to improve current practices for clinical diagnosis. The current project began by taking a ‘candidate gene’ approach, studying two regions where there were known large genetic differences between Maori and European individuals: the region of Alcohol Dehydrogenase genes on Chromosome 4 (Chapter 2), and the Monoamine Oxidase A gene region on Chromosome X (Chapter 3). In both of these regions, large frequency differences were observed between Maori and non-Maori populations at both a single mutation level, and at a haplotype level. Despite the differences that were observed, no particular combinations of mutations could be considered uniquely Maori or uniquely non-Maori, so studies were expanded to the entire genome. This epansion was made possible due to the recent and continuing developments in genome-wide technology and advancements in computational speed and efficiency. Once it was possible to carry out a genome-wide study of genetic differences, the goal of research changed from determining whether or not Maori and European individuals were uniquely different at a genotype level, to how small a marker set could be produced while maintaining population-uniqueness at a genotype level. A method that uses bootstrap sub-sampling and other internal validation techniques has been developed for the generation of such a signature set for a Maori tribe (Ngati Rakaipaaka), and the generated set has been validated in other similar populations (Chapter 4). As a consequence of producing this set, the degree of European admixture was estimated in the tribe (28.7%), with over 15% of individuals within Rakaipaaka found to have no discernible European genomic ancestry. In a validation of the signature set generation method itself, the marker selection procedure was repeated for Type 1 Diabetes, a disease with high heritability. An analysis of case and control individuals using this signature set found that the generated set is able to perform better than a genome-wide reference set of mutations known to be associated with Type 1 Diabetes. This validation study, other potential uses, and a more detailed discussion of the signature set generation method are presented in Chapter 5.</p>