Essential oil of Pterocarpus santalinus L. alleviates behavioral impairments in social defeat stress-exposed mice by regulating neurotransmission and neuroinflammation.

BACKGROUND: Pterocarpus santalinus L. essential oil (PSEO) is traditionally employed for treating fever and mental aberrations. We aim to explore the antidepressant potential of intranasal PSEO in social defeat stress (SDS)-expose mice and identify its mechanisms and components. METHODS: PSEO components were analyzed using gas chromatography-mass spectrometry (GC-MS). C57BL/6 mice underwent a 10-day SDS with intranasal PSEO (10, 20 mg/kg) for 21 days. Efficacy was evaluated through changes in behaviors and serum corticosterone (CORT), hippocampal neurotransmitter, and inflammatory cytokine levels. In vitro effects were examined using primary hippocampal neurons, PC12 and BV2 cells. RESULTS: GC-MS identified 22 volatile compounds in PSEO, and (+)-ledene (16.7%), cedrol (13.5%), and isoaromadendrene epoxide (7.0%) as major components. PSEO (20 mg/kg) significantly reversed SDS-induced social withdrawal, increased open-area explorations in the open field test (OFT) and elevated plus maze (EPM) test, and reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). PSEO downregulated serum CORT and hippocampal interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, while increasing hippocampal gamma-aminobutyric acid (GABA), norepinephrine (NE), and serotonin (5-HT) levels. PSEO (0.1, 1, 10 µg/mL) reduced neurotoxicity and neuroinflammation in PC12 and BV2 cells, respectively. PSEO (10 µg/mL) enhanced glutamic acid decarboxylase 6 (GAD6)- and GABA B receptor 1 (GABABR1)-positive puncta in the hippocampal neurons and FM1-43 fluorescence intensity. CONCLUSION: Intranasal PSEO exhibited antidepressant-like effects on SDS-exposed mice, potentially through modulating stress hormone, neurotransmission, and neuroinflammation. Further investigation into the pharmacokinetics, bioavailability, and mechanisms of (+)-ledene, cedrol, and isoaromadendrene epoxide is needed.

Differential Effects of the Processed and Unprocessed Garlic (Allium sativum L.) Ethanol Extracts on Neuritogenesis and Synaptogenesis in Rat Primary Hippocampal Neurons.

Garlic (Allium sativum L.) is an aromatic herb known for its culinary and medicinal uses for centuries. Both unprocessed (white) and processed (black) garlic are known to protect against the pathobiology of neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), which has been attributed to their anti-inflammatory and antioxidant properties. The information on the effects of processed and unprocessed garlic on neuronal process outgrowth, maturation, and synaptic development is limited. This study aimed at investigating and comparing the effects of the ethanol extracts of unprocessed (white garlic extract, WGE) and processed (black garlic extract, BGE) garlic on the maturation of primary hippocampal neurons. Neurite outgrowth was stimulated in a dose-dependent manner by both WGE and BGE and the most effective doses were 15 µg/mL and 60 µg/mL, respectively, without showing cytotoxicity. At this optimal concentration, both extracts promoted axonal and dendritic growth and maturation. Furthermore, both extracts substantially increased the formation of functional synapses. However, the effect of WGE was more robust at every developmental stage of neurons. In addition, the gas chromatography and mass spectrometry (GC-MS) analysis revealed a chemical profile of various bioactives in both BGE and WGE. Linalool, a compound that was found in both extracts, has shown neurite outgrowth-promoting activity in neuronal cultures, suggesting that the neurotrophic activity of garlic extracts is attributed, at least in part, to this compound. By using network pharmacology, linalool's role in neuronal development can also be observed through its modulatory effect on the signaling molecules of neurotrophic signaling pathways such as glycogen synthase kinase 3 (GSK3ß), extracellular signal-regulated protein kinase (Erk1/2), which was further verified by immunocytochemistry. Overall, these findings provide information on the molecular mechanism of processed and unprocessed garlic for neuronal growth, survival, and memory function which may have the potential for the prevention of several neurological disorders.

N-Acetylglucosamine Kinase-Small Nuclear Ribonucleoprotein Polypeptide N Interaction Promotes Axodendritic Branching in Neurons via Dynein-Mediated Microtubule Transport.

N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in the neuron. However, the precise role in neurodevelopment is elusive. In this study, we investigate the role of NAGK and SNRPN in the axodendritic development of neurons. NAGK and SNRPN interaction is significantly increased in neurons at the crucial stages of neurodevelopment. Furthermore, overexpression of the NAGK and SNRPN proteins increases axodendritic branching and neuronal complexity, whereas the knockdown inhibits neurodevelopment. We also observe the interaction of NAGK and SNRPN with the dynein light-chain roadblock type 1 (DYNLRB1) protein variably during neurodevelopment, revealing the microtubule-associated delivery of the complex. Interestingly, NAGK and SNRPN proteins rescued impaired axodendritic development in an SNRPN depletion model of Prader-Willi syndrome (PWS) patient-derived induced pluripotent stem cell neurons. Taken together, these findings are crucial in developing therapeutic approaches for neurodegenerative diseases.

Neuronal Differentiation and Outgrowth Effect of Thymol in Trachyspermum ammi Seed Extract via BDNF/TrkB Signaling Pathway in Prenatal Maternal Supplementation and Primary Hippocampal Culture.

Reviving the neuronal functions in neurodegenerative disorders requires the promotion of neurite outgrowth. Thymol, which is a principal component of Trachyspermum ammi seed extract (TASE), is reported to have neuroprotective effects. However, the effects of thymol and TASE on neuronal differentiation and outgrowth are yet to be studied. This study is the first report investigating the neuronal growth and maturation effects of TASE and thymol. Pregnant mice were orally supplemented with TASE (250 and 500 mg/kg), thymol (50 and 100 mg/kg), vehicle, and positive controls. The supplementation significantly upregulated the expression of brain-derived neurotrophic factor (BDNF) and early neuritogenesis markers in the pups' brains at post-natal day 1 (P1). Similarly, the BDNF level was significantly upregulated in the P12 pups' brains. Furthermore, TASE (75 and 100 µg/mL) and thymol (10 and 20 µM) enhanced the neuronal polarity, early neurite arborization, and maturation of hippocampal neurons in a dose-dependent manner in primary hippocampal cultures. The stimulatory activities of TASE and thymol on neurite extension involved TrkB signaling, as evidenced by attenuation via ANA-12 (5 µM), which is a specific TrkB inhibitor. Moreover, TASE and thymol rescued the nocodazole-induced blunted neurite extension in primary hippocampal cultures, suggesting their role as a potent microtubule stabilizing agent. These findings demonstrate the potent capacities of TASE and thymol in promoting neuronal development and reconstruction of neuronal circuitry, which are often compromised in neurodegenerative diseases and acute brain injuries.

Gut Microbiota in Autophagy Regulation: New Therapeutic Perspective in Neurodegeneration.

Gut microbiota and the brain are related via a complex bidirectional interconnective network. Thus, intestinal homeostasis is a crucial factor for the brain, as it can control the environment of the central nervous system and play a significant role in disease progression. The link between neuropsychological behavior or neurodegeneration and gut dysbiosis is well established, but many involved pathways remain unknown. Accumulating studies showed that metabolites derived from gut microbiota are involved in the autophagy activation of various organs, including the brain, one of the major pathways of the protein clearance system that is essential for protein aggregate clearance. On the other hand, some metabolites are evidenced to disrupt the autophagy process, which can be a modulator of neurodegeneration. However, the detailed mechanism of autophagy regulation by gut microbiota remains elusive, and little research only focused on that. Here we tried to evaluate the crosstalk between gut microbiota metabolites and impaired autophagy of the central nervous system in neurodegeneration and the key to future research regarding gut dysbiosis and compromised autophagy in neurodegenerative diseases.

Thymol in Trachyspermum ammi seed extract exhibits neuroprotection, learning, and memory enhancement in scopolamine-induced Alzheimer's disease mouse model.

Several reports have stated the neuroprotective and learning/memory effects of Tachyspermum ammi seed extract (TASE) and its principal component thymol; however, little is known about its underlying molecular mechanisms and neurogenesis potential. This study aimed to provide insights into TASE and a thymol-mediated multifactorial therapeutic approach in a scopolamine-induced Alzheimer's disease (AD) mouse model. TASE and thymol supplementation significantly reduced oxidative stress markers such as brain glutathione, hydrogen peroxide, and malondialdehyde in mouse whole brain homogenates. Tumor necrosis factor-alpha was significantly downregulated, whereas the elevation of brain-derived neurotrophic factor and phospho-glycogen synthase kinase-3 beta (serine 9) enhanced learning and memory in the TASE- and thymol-treated groups. A significant reduction in the accumulation of Aß 1-42 peptides was observed in the brains of TASE- and thymol-treated mice. Furthermore, TASE and thymol significantly promoted adult neurogenesis, with increased doublecortin positive neurons in the subgranular and polymorphic zones of the dentate gyrus in treated-mice. Collectively, TASE and thymol could  potentially act as natural therapeutic agents for the treatment of  neurodegenerative disorders, such as  AD.

Mechanistic study of Coriandrum sativum on neuritogenesis and synaptogenesis based on computationally guided in vitro analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Acceleration of neurite outgrowth and halting neurodegeneration are the most critical factors that are negatively regulated in various neurodegenerative diseases or injuries in the central nervous system (CNS). Functional foods or nutrients are considered alternative sources of bioactive components to alleviate various CNS injuries by promoting neuritogenesis and synaptogenesis, while their exact molecular mechanism remains unexplored. AIM OF THE STUDY: Coriandrum sativum L. (CS) is one of the popular herbs in the Apiaceae family, of which CNS modulating action is a well-documented traditionally but detailed study on memory boosting function yet remains unexplored. Consequently, this study aims to analyze the neurogenic and synaptogenic modulation of CS aqueous ethanol (CSAE) extract in the primary hippocampal neurons. MATERIALS AND METHODS: Primary hippocampal neurons were cultured and allowed to incubate with CSAE or vehicle. To observe the early neuronal differentiation, axonal and dendritic arborization, and synapse formation, neurons were immune-stained against indicated antibodies or stained directly with a lipophilic dye (1, 1'-dioctadecyl-3, 3, 3', 3'-tetramethyl indocarbocyanine perchlorate, DiL). Meanwhile, western blot was used to validate the synaptogenesis effect of CSAE compared to vehicle. Additionally, molecular docking and system pharmacology approaches were applied to confirm the possible secondary metabolites and pathways by which CSAE promotes neuritogenesis. RESULTS: Results show that CSAE can induce neuritogenesis and synaptogenesis at 30 µg/mL concentration. The treatment impacts early neuronal polarization, axonal and dendritic arborization, synaptogenesis, and synaptic plasticity via NMDARs expressions in primary neurons. In silico network pharmacology of CS metabolites show that the CSAE-mediated neurogenic effect is likely dependent on the NTRK2 (TrkB) mediated neurotrophin signaling pathway. Indeed, the observed neurogenic activity of CSAE is markedly reduced upon the co-treatment with a TrkB-specific inhibitor. Furthermore, molecular docking following binding energy calculation shows that one of the CS metabolites, scoparone, has a high affinity to bind in the BDNF mimetic binding site of TrkB, suggesting its role in TrkB activation. Scoparone was found to enhance neuritogenesis, but not to the same extent as CSAE. Moreover, the expression of TrkB signaling-related proteins (BCL2, CASP3, GSK3, and BDNF), which was found to be modulated by scoparone, was significantly affected by the co-treatment of TrkB inhibitor (ANA-12). These results further suggest that the modulation of neuritogenesis by scoparone is TrkB-dependent. CONCLUSIONS: This study provides deeper insights into the molecular mechanism of CS in boosting neuronal growth and memory function, which might implicate the prevention of many neurological disorders.

Targeting Estrogen Signaling in the Radiation-induced Neurodegeneration: A Possible Role of Phytoestrogens.

Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.

Brain modulation by the gut microbiota: From disease to therapy.

BACKGROUND: The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal function and influence many cascades in age-related neurodegenerative disorders (NDDs). Because of the dual role of GM in neuroprotection and neurodegeneration, understanding the balance between beneficial and harmful bacteria is crucial for applying this approach to clinical therapies. AIM OF THE REVIEW: This review briefly discusses the role of the gut-brain relationship in promoting brain and cognitive function. Although a healthy gut environment is helpful for brain function, gut dysbiosis can disrupt the brain's environment and create a vicious cycle of degenerative cascades. The ways in which the GM population can affect brain function and the development of neurodegeneration are also discussed. In the treatment and management of NDDs, the beneficial effects of methods targeting GM populations and their derivatives, including probiotics, prebiotics, and fecal microbial transplantation (FMT) are also highlighted. KEY SCIENTIFIC CONCEPT OF THE REVIEW: In this review, we aimed to provide a deeper understanding of the mechanisms of the gut microbe-brain relationship and their twin roles in neurodegeneration progression and therapeutic applications. Here, we attempted to highlight the different pathways connecting the brain and gut, together with the role of GM in neuroprotection and neuronal development. Furthermore, potential roles of GM metabolites in the pathogenesis of brain disorders and in strategies for its treatment are also investigated. By analyzing existing in vitro, in vivo and clinical studies, this review attempts to identify new and promising therapeutic strategies for central nervous system (CNS) disorders. As the connection between the gut microbe-brain relationship and responses to NDD treatments is less studied, this review will provide new insights into the global mechanisms of GM modulation in disease progression, and identify potential future perspectives for developing new therapies to treat NDDs.

Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration.

Glioblastoma multiforme (GBM) is one of the most common aggressive, resistant, and invasive primary brain tumors that share neurodegenerative actions, resembling many neurodegenerative diseases. Although multiple conventional approaches, including chemoradiation, are more frequent in GBM therapy, these approaches are ineffective in extending the mean survival rate and are associated with various side effects, including neurodegeneration. This review proposes an alternative strategy for managing GBM and neurodegeneration by targeting heat shock protein 90 (Hsp90). Hsp90 is a well-known molecular chaperone that plays essential roles in maintaining and stabilizing protein folding to degradation in protein homeostasis and modulates signaling in cancer and neurodegeneration by regulating many client protein substrates. The therapeutic benefits of Hsp90 inhibition are well-known for several malignancies, and recent evidence highlights that Hsp90 inhibitors potentially inhibit the aggressiveness of GBM, increasing the sensitivity of conventional treatment and providing neuroprotection in various neurodegenerative diseases. Herein, the overview of Hsp90 modulation in GBM and neurodegeneration progress has been discussed with a summary of recent outcomes on Hsp90 inhibition in various GBM models and neurodegeneration. Particular emphasis is also given to natural Hsp90 inhibitors that have been evidenced to show dual protection in both GBM and neurodegeneration.

Protective Mechanisms of Nootropic Herb Shankhpushpi (Convolvulus pluricaulis) against Dementia: Network Pharmacology and Computational Approach.

Convolvulus pluricaulis (CP), a Medhya Rasayana (nootropic) herb, is a major ingredient in Ayurvedic and Traditional Chinese formulae indicated for neurological conditions, namely, dementia, anxiety, depression, insanity, and epilepsy. Experimental evidence suggests various neuroactive potentials of CP such as memory-enhancing, neuroprotective, and antiepileptic. However, precise mechanisms underlying the neuropharmacological effects of CP remain unclear. The study, therefore, aimed at deciphering the molecular basis of neuroprotective effects of CP phytochemicals against the pathology of dementia disorders such as Alzheimer's (AD) and Parkinson's (PD) disease. The study exploited bioinformatics tools and resources, such as Cytoscape, DAVID (Database for annotation, visualization, and integrated discovery), NetworkAnalyst, and KEGG (Kyoto Encyclopedia of Genes and Genomes) database to investigate the interaction between CP compounds and molecular targets. An in silico analysis was also employed to screen druglike compounds and validate some selective interactions. ADME (absorption, distribution, metabolism, and excretion) analysis predicted a total of five druglike phytochemicals from CP constituents, namely, scopoletin, 4-hydroxycinnamic acid, kaempferol, quercetin, and ayapanin. In network analysis, these compounds were found to interact with some molecular targets such as prostaglandin G/H synthase 1 and 2 (PTGS1 and PTGS2), endothelial nitric oxide synthase (NOS3), insulin receptor (INSR), heme oxygenase 1 (HMOX1), acetylcholinesterase (ACHE), peroxisome proliferator-activated receptor-gamma (PPARG), and monoamine oxidase A and B (MAOA and MAOB) that are associated with neuronal growth, survival, and activity. Docking simulation further confirmed interaction patterns and binding affinity of selected CP compounds with those molecular targets. Notably, scopoletin showed the highest binding affinity with PTGS1, NOS3, PPARG, ACHE, MAOA, MAOB, and TRKB, quercetin with PTGS2, 4-hydroxycinnamic acid with INSR, and ayapanin with HMOX1. The findings indicate that scopoletin, kaempferol, quercetin, 4-hydroxycinnamic acid, and ayapanin are the main active constituents of CP which might account for its memory enhancement and neuroprotective effects and that target proteins such as PTGS1, PTGS2, NOS3, PPARG, ACHE, MAOA, MAOB, INSR, HMOX1, and TRKB could be druggable targets against dementia.

The Edible Seaweed Gelidium amansii Promotes Structural Plasticity of Hippocampal Neurons and Improves Scopolamine-Induced Learning and Memory Impairment in Mice.

BACKGROUND: Gelidium amansii has been gaining profound interest in East Asian countries due to its enormous commercial value for agar production and its extensive pharmacological properties. Previous studies have shown that the ethanol extract of Gelidium amansii (GAE) has promising neurotrophic effects in in vitro conditions. OBJECTIVES: The present study aimed at investigating the protective effects of GAE against scopolamine-induced cognitive deficits and its modulatory effects on hippocampal plasticity in mice. METHODS: For memory-related behavioral studies, the passive avoidance test and radial arm maze paradigm were conducted. The brain slices of the hippocampus CA1 neurons of experimental mice were then prepared to perform Golgi staining for analyzing spine density and its characteristic shape, and immunohistochemistry for assessing the expression of different pre- and postsynaptic proteins. RESULTS: Following oral administration of GAE (0.5 mg/g body weight), mice with memory deficits exhibited a significant increase in the latency time on the passive avoidance test and a decrease in the number of working and reference memory errors and latency time on the radial arm maze test. Microscopic observations of Golgi-impregnated tissue sections and immunohistochemistry of hippocampal slices showed that neurons from GAE-treated mice displayed higher spine density and spine dynamics, increased synaptic contact, and the recruitment of memory-associated proteins such as N-methyl-D-aspartate receptors (NR2A and NR2B) and postsynaptic density-95 (PSD-95) when compared with the control group. CONCLUSION: With these memory-protective functions and a modulatory role in underlying memory-related events, GAE could be a potential functional food and a promising source of pharmacological agents for the prevention and treatment of memory-related brain disorders.

Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function.

Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extracellular domain of TREM2. However, the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in TREM2 on disease progression remain unknown. In this study, we identified several high-risk nsSNPs in the TREM2 gene using various deleterious SNP predicting algorithms and analyzed their destabilizing effects on the ligand recognizing region of the TREM2 immunoglobulin (Ig) domain by molecular dynamics (MD) simulation. Cumulative prediction by all tools employed suggested the three most deleterious nsSNPs involved in loss of TREM2 function are rs549402254 (W50S), rs749358844 (R52C), and rs1409131974 (D104G). MD simulation showed that these three variants cause substantial structural alterations and conformational remodeling of the apical loops of the TREM2 Ig domain, which is responsible for ligand recognition. Detailed analysis revealed that these variants substantially increased distances between apical loops and induced conformation remodeling by changing inter-loop nonbonded contacts. Moreover, all nsSNPs changed the electrostatic potentials near the putative ligand-interacting region (PLIR), which suggested they might reduce specificity or loss of binding affinity for TREM2 ligands. Overall, this study identifies three potential high-risk nsSNPs in the TREM2 gene. We propose further studies on the molecular mechanisms responsible for loss of TREM2 function and the associations between TREM2 nsSNPs and neurodegenerative diseases.

A Systematic Review on Marine Algae-Derived Fucoxanthin: An Update of Pharmacological Insights.

Fucoxanthin, belonging to the xanthophyll class of carotenoids, is a natural antioxidant pigment of marine algae, including brown macroalgae and diatoms. It represents 10% of the total carotenoids in nature. The plethora of scientific evidence supports the potential benefits of nutraceutical and pharmaceutical uses of fucoxanthin for boosting human health and disease management. Due to its unique chemical structure and action as a single compound with multi-targets of health effects, it has attracted mounting attention from the scientific community, resulting in an escalated number of scientific publications from January 2017 to February 2022. Fucoxanthin has remained the most popular option for anti-cancer and anti-tumor activity, followed by protection against inflammatory, oxidative stress-related, nervous system, obesity, hepatic, diabetic, kidney, cardiac, skin, respiratory and microbial diseases, in a variety of model systems. Despite much pharmacological evidence from in vitro and in vivo findings, fucoxanthin in clinical research is still not satisfactory, because only one clinical study on obesity management was reported in the last five years. Additionally, pharmacokinetics, safety, toxicity, functional stability, and clinical perspective of fucoxanthin are substantially addressed. Nevertheless, fucoxanthin and its derivatives are shown to be safe, non-toxic, and readily available upon administration. This review will provide pharmacological insights into fucoxanthin, underlying the diverse molecular mechanisms of health benefits. However, it requires more activity-oriented translational research in humans before it can be used as a multi-target drug.

Unveiling the effect of Withania somnifera on neuronal cytoarchitecture and synaptogenesis: A combined in vitro and network pharmacology approach.

Withania somnifera (WS), is known for its remarkable contribution in herbal medicine and Ayurveda, which is therapeutically applied to improve memory and anxiety in patients. However, the pharmacological details of this plant on memory boosting yet remained undefined. This study provides mechanistic insights on the effect of ethanol solution extract of the whole plant of WS (WSEE) on neuritogenesis by combining in vitro and in silico network pharmacology approaches. WSEE promoted significant neuronal growth through early differentiation, axodendritic arborization, and synaptogenesis on primary hippocampal neurons. The network pharmacological study confirmed that the neuritogenic activity is potentially mediated by modulating the neurotrophin signaling pathway, where NRTK1 (TrkA) was revealed as the primary target of WS secondary metabolites. This neurotrophic activity of WSEE was significantly stifled by the presence of TrkA inhibitor, which further confirms the TrkA-dependent activity of WSEE. In addition, a molecular docking study suggested steroidal lactones present in the WS might act as nerve growth factor (NGF)-mimetics, activating TrkA by binding to the NGF-binding domain. As a whole, the findings of the study suggest a significant role of WSEE on neuritogenesis and its potential to function as a therapeutic agent and in drug designing for the prevention and treatment of memory-related neurological disorders.

Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1.

Disruptive neuronal migration during early brain development causes severe brain malformation. Characterized by mislocalization of cortical neurons, this condition is a result of the loss of function of migration regulating genes. One known neuronal migration disorder is lissencephaly (LIS), which is caused by deletions or mutations of the LIS1 (PAFAH1B1) gene that has been implicated in regulating the microtubule motor protein cytoplasmic dynein. Although this class of diseases has recently received considerable attention, the roles of non-synonymous polymorphisms (nsSNPs) in LIS1 on lissencephaly progression remain elusive. Therefore, the present study employed combined bioinformatics and molecular modeling approach to identify potential damaging nsSNPs in the LIS1 gene and provide atomic insight into their roles in LIS1 loss of function. Using this approach, we identified three high-risk nsSNPs, including rs121434486 (F31S), rs587784254 (W55R), and rs757993270 (W55L) in the LIS1 gene, which are located on the N-terminal domain of LIS1. Molecular dynamics simulation highlighted that all variants decreased helical conformation, increased the intermonomeric distance, and thus disrupted intermonomeric contacts in the LIS1 dimer. Furthermore, the presence of variants also caused a loss of positive electrostatic potential and reduced dimer binding potential. Since self-dimerization is an essential aspect of LIS1 to recruit interacting partners, thus these variants are associated with the loss of LIS1 functions. As a corollary, these findings may further provide critical insights on the roles of LIS1 variants in brain malformation.

Molecular pharmacology and therapeutic advances of the pentacyclic triterpene lupeol.

BACKGROUND: Plant triterpenoids are major sources of nutraceuticals that provide many health benefits to humans. Lupeol is one of the pentacyclic dietary triterpenoids commonly found in many fruits and vegetables, which is highly investigated for its pharmacological effect and benefit to human health. PURPOSE: This systematic review critically discussed the potential pharmacological benefits of lupeol and its derivatives as evidenced by various cellular and animal model studies. To gain insight into the pharmacological effects of lupeol, the network pharmacological approach is applied. Pharmacokinetics and recent developments in nanotechnology-based approaches to targeted delivery of lupeol along with its safety use are also discussed. METHODS: This study is dependent on the systematic and non-exhaustive literature survey for related research articles, papers, and books on the chemistry, pharmacological benefits, pharmacokinetics, and safety of lupeol published between 2011 and 2021. For online materials, the popular academic search engines viz. Google Scholar, PubMed, Science Direct, Scopus, ResearchGate, Springer, as well as official websites were explored with selected keywords. RESULTS: Lupeol has shown promising benefits in the management of cancer and many other human diseases such as diabetes, obesity, cardiovascular diseases, kidney and liver problems, skin diseases, and neurological disorders. The pharmacological effects of lupeol primarily rely on its capacity to revitalize the cellular antioxidant, anti-inflammatory and anti-apoptotic mechanisms. Network pharmacological approach revealed some prospective molecular targets and pathways and presented some significant information that could help explain the pharmacological effects of lupeol and its derivatives. Despite significant progress in molecular pharmacology, the clinical application of lupeol is limited due to poor bioavailability and insufficient knowledge on its mode of action. Structural modification and nanotechnology-guided targeted delivery of lupeol improve the bioavailability and bioactivity of lupeol. CONCLUSION: The pentacyclic triterpene lupeol possesses numerous human health-benefiting properties. This review updates current knowledge and critically discusses the pharmacological effects and potential applications of lupeol and its derivatives in human health and diseases. Future studies are needed to evaluate the efficacies of lupeol and its derivatives in the management and pathobiology of human diseases.

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function.

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein-protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein-protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders.

Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety.

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

Prospects of Marine Sterols against Pathobiology of Alzheimer's Disease: Pharmacological Insights and Technological Advances.

Alzheimer's disease (AD) is a degenerative brain disorder characterized by a progressive decline in memory and cognition, mostly affecting the elderly. Numerous functional bioactives have been reported in marine organisms, and anti-Alzheimer's agents derived from marine resources have gained attention as a promising approach to treat AD pathogenesis. Marine sterols have been investigated for several health benefits, including anti-cancer, anti-obesity, anti-diabetes, anti-aging, and anti-Alzheimer's activities, owing to their anti-inflammatory and antioxidant properties. Marine sterols interact with various proteins and enzymes participating via diverse cellular systems such as apoptosis, the antioxidant defense system, immune response, and cholesterol homeostasis. Here, we briefly overview the potential of marine sterols against the pathology of AD and provide an insight into their pharmacological mechanisms. We also highlight technological advances that may lead to the potential application of marine sterols in the prevention and therapy of AD.