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.

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.

Use of relevancy and complementary information for discriminatory gene selection from high-dimensional gene expression data.

With the advent of high-throughput technologies, life sciences are generating a huge amount of varied biomolecular data. Global gene expression profiles provide a snapshot of all the genes that are transcribed in a cell or in a tissue under a particular condition. The high-dimensionality of such gene expression data (i.e., very large number of features/genes analyzed with relatively much less number of samples) makes it difficult to identify the key genes (biomarkers) that are truly attributing to a particular phenotype or condition, (such as cancer), de novo. For identifying the key genes from gene expression data, among the existing literature, mutual information (MI) is one of the most successful criteria. However, the correction of MI for finite sample is not taken into account in this regard. It is also important to incorporate dynamic discretization of genes for more relevant gene selection, although this is not considered in the available methods. Besides, it is usually suggested in current studies to remove redundant genes which is particularly inappropriate for biological data, as a group of genes may connect to each other for downstreaming proteins. Thus, despite being redundant, it is needed to add the genes which provide additional useful information for the disease. Addressing these issues, we proposed Mutual information based Gene Selection method (MGS) for selecting informative genes. Moreover, to rank these selected genes, we extended MGS and propose two ranking methods on the selected genes, such as MGSf-based on frequency and MGSrf-based on Random Forest. The proposed method not only obtained better classification rates on gene expression datasets derived from different gene expression studies compared to recently reported methods but also detected the key genes relevant to pathways with a causal relationship to the disease, which indicate that it will also able to find the responsible genes for an unknown disease data.

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.

N-acetyl-D-glucosamine kinase binds dynein light chain roadblock 1 and promotes protein aggregate clearance.

Emerging evidence indicates that neurodegenerative diseases (NDs) result from a failure to clear toxic protein aggregates rather than from their generation. We previously showed N-acetylglucosamine kinase (NAGK) promotes dynein functionality and suggested this might promote aggregate removal and effectively address proteinopathies. Here, we report NAGK interacts with dynein light chain roadblock type 1 (DYNLRB1) and efficiently suppresses mutant huntingtin (mHtt) (Q74) and α-synuclein (α-syn) A53T aggregation in mouse brain cells. A kinase-inactive NAGKD107A also efficiently cleared Q74 aggregates. Yeast two-hybrid selection and in silico protein-protein docking analysis showed the small domain of NAGK (NAGK-DS) binds to the C-terminal of DYNLRB1. Furthermore, a small peptide derived from NAGK-DS interfered with Q74 clearance. We propose binding of NAGK-DS to DYNLRB1 'pushes up' the tail of dynein light chain and confers momentum for inactive phi- to active open-dynein transition.

Phytosterols of marine algae: Insights into the potential health benefits and molecular pharmacology.

BACKGROUND: Marine algae are rich in some unique biologically active secondary metabolites having diverse pharmacological benefits. Of these, sterols comprise a group of functional lipid compounds that have attracted much attention to natural product scientists. PURPOSE: This review was aimed to update information on the health effects of algae-derived phytosterols and their molecular interactions in various aspects of human health and diseases and to address some future perspectives that may open up a new dimension of pharmacological potentials of algal sterols. METHODS: A literature-based search was carried out to retrieve published research information on the potential health effects of algal phytosterols with their pharmacological mechanisms from accessible online databases, such as Pubmed, Google Scholar, Web of Science, and Scopus, using the key search terms of 'marine algae sterol' and 'health potentials such as antioxidant or anti-inflammatory or anti-Alzheimer's or anti-obesity or cholesterol homeostasis or hepatoprotective, antiproliferative, etc.' RESULTS: Phytosterols of marine algae, particularly fucosterol, have been investigated for a plethora of health benefits, including anti-diabetes, anti-obesity, anti-Alzheimer's, antiaging, anticancer, and hepatoprotection, among many others, which are attributed to their antioxidant, anti-inflammatory, immunomodulatory and cholesterol-lowering properties, indicating their potentiality as therapeutic leads. These sterols interact with enzymes and various other proteins that are actively participating in different cellular pathways, including antioxidant defense system, apoptosis and cell survival, metabolism, and homeostasis. CONCLUSION: In this review, we briefly overview the chemistry, pharmacokinetics, and distribution of algal sterols, and provide critical insights into their potential health effects and the underlying pharmacological mechanisms, beyond the well-known cholesterol-lowering paradigm.

3ß, 6ß-dichloro-5-hydroxy-5α-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron.

Potentiating neuritogenesis through pharmacological intervention might hold therapeutic promise in neurodegenerative disorders and acute brain injury. Here, we investigated the novel neuritogenic potentials of a steroidal chlorohydrin, 3ß, 6ß-dichloro-5-hydroxy-5α-cholestane (hereafter, SCH) and the change in cellular proteome to gain insight into the underlying mechanism of its neurotrophic activity in hippocampal neurons. Morphometric analysis showed that SCH promoted early neuronal differentiation, dendritic arborization and axonal maturation. Proteomic and bioinformatic analysis revealed that SCH induced upregulation of several proteins, including those associated with neuronal differentiation and development. Immunocytochemical data further indicates that SCH-treated neurons showed upregulation of Hnrnpa2b1 and Map1b, validating their proteomic profiles. In addition, a protein-protein interaction network analysis identified TrkA as a potential target connecting most of the upregulated proteins. The neurite outgrowth effect of SCH was suppressed by TrkA inhibitor, GW441756, verifying TrkA-dependent activity of SCH, which further supports the connection of TrkA with the upregulated proteins. Also, the computational analysis revealed that SCH interacts with the NGF-binding domain of TrkA through Phe327 and Asn355. Collectively, our findings provide evidence that SCH promotes neuronal development via upregulating TrkA-signaling proteins and suggest that SCH could be a promising therapeutic agent in the prevention and treatment of neurodegenerative disorders.

Calotropis gigantea Promotes Neuritogenesis and Synaptogenesis through Activation of NGF-TrkA-Erk1/2 Signaling in Rat Hippocampal Neurons.

Calotropis gigantea (L.) R. Br (Apocynaceae) (commonly known as milkweed or crown flower) is a large shrub native to temperate regions of Asia, including China, Bangladesh and India and has a long history of use in traditional medicines. In this study, we investigated the neuromodulatory effects of the ethanol extracts of C. gigantea leaves (CGE) during synaptogenesis in the late stage of neuronal development and during early stage neuritogenesis in cultured rat hippocampal neurons. Maximum neuritogenic activity was achieved at a CGE concentration of 7.5 µ g/ml. At this concentration, CGE facilitated the early development of cytoarchitecture, as evidenced by increases in morphometric parameters, such as, the numbers, lengths, and number of branches of initial neurites, axon and dendrites. During the synaptogenic stage (DIV 14), immunocytochemistry (ICC) showed that CGE upregulated synaptic vesicle 2 (SV2, a marker of axon terminals) and postsynaptic density-95 (PSD-95, a postsynaptic marker) and their colocalization. CGE upregulated nerve growth factor (NGF) and activated extracellular signal-regulated kinase 1/2 (Erk1/2), which is blocked by a TrkA-specific inhibitor suggesting the neuritogenic and synaptogenic potential of CGE was due to the activation of NGF-TrkA-Erk1/2 signaling. Moreover, UPLC of CGE did not detect stigmasterol, an active component of C. gigantea. However, the chloroform-methanol and ethyl acetate subfractions of CGE exhibited initial neuritogenic activity, suggesting that multiple active components were responsible for the neurotrophic-mimetic properties of CGE. Our data prove the neuromodulatory ability of CGE and provide a means of identifying new active phytochemicals with potential nootropic, preventative or therapeutic effects on the human brain.