Role of Acetic Acid and Nitric Oxide against Salinity and Lithium Stress in Canola (Brassica napus L.).

In this study, canola (Brassica napus L.) seedlings were treated with individual and combined salinity and lithium (Li) stress, with and without acetic acid (AA) or nitric acid (NO), to investigate their possible roles against these stresses. Salinity intensified Li-induced damage, and the principal component analysis revealed that this was primarily driven by increased oxidative stress, deregulation of sodium and potassium accumulation, and an imbalance in tissue water content. However, pretreatment with AA and NO prompted growth, re-established sodium and potassium homeostasis, and enhanced the defense system against oxidative and nitrosative damage by triggering the antioxidant capacity. Combined stress negatively impacted phenylalanine ammonia lyase activity, affecting flavonoids, carotenoids, and anthocyanin levels, which were then restored in canola plants primed with AA and NO. Additionally, AA and NO helped to maintain osmotic balance by increasing trehalose and proline levels and upregulating signaling molecules such as hydrogen sulfide, γ-aminobutyric acid, and salicylic acid. Both AA and NO improved Li detoxification by increasing phytochelatins and metallothioneins, and reducing glutathione contents. Comparatively, AA exerted more effective protection against the detrimental effects of combined stress than NO. Our findings offer novel perspectives on the impacts of combining salt and Li stress.

Exogenous nitric oxide promotes salinity tolerance in plants: A meta-analysis.

Nitric oxide (NO) has received much attention since it can boost plant defense mechanisms, and plenty of studies have shown that exogenous NO improves salinity tolerance in plants. However, because of the wide range of experimental settings, it is difficult to assess the administration of optimal dosages, frequency, timing, and method of application and the overall favorable effects of NO on growth and yield improvements. Therefore, we conducted a meta-analysis to reveal the exact physiological and biochemical mechanisms and to understand the influence of plant-related or method-related factors on NO-mediated salt tolerance. Exogenous application of NO significantly influenced biomass accumulation, growth, and yield irrespective of salinity stress. According to this analysis, seed priming and foliar pre-treatment were the most effective methods of NO application to plants. Moreover, one-time and regular intervals of NO treatment were more beneficial for plant growth. The optimum concentration of NO ranges from 0.1 to 0.2 mM, and it alleviates salinity stress up to 150 mM NaCl. Furthermore, the beneficial effect of NO treatment was more pronounced as salinity stress was prolonged (>21 days). This meta-analysis showed that NO supplementation was significantly applicable at germination and seedling stages. Interestingly, exogenous NO treatment boosted plant growth most efficiently in dicots. This meta-analysis showed that exogenous NO alleviates salt-induced oxidative damage and improves plant growth and yield potential by regulating osmotic balance, mineral homeostasis, photosynthetic machinery, the metabolism of reactive oxygen species, and the antioxidant defense mechanism. Our analysis pointed out several research gaps, such as lipid metabolism regulation, reproductive stage performance, C4 plant responses, field-level yield impact, and economic profitability of farmers in response to exogenous NO, which need to be evaluated in the subsequent investigation.

Fluoride mitigates aluminum-toxicity in barley: morpho-physiological responses and biochemical mechanisms.

BACKGROUND: To our knowledge, the role of exogenous fluoride (F-) on aluminum (Al)-stress mitigation in plants has not been investigated yet. In this experiment, barley (Hordeum vulgaris) seedlings were exposed to excessive Al3+ concentrations (aluminum chloride, 0.5, 1.0, 2.0, 3.0, and 4.0 mM) with and without fluoride (0.025% sodium fluoride) to explore the possible roles of fluoride on the alleviation of Al-toxicity. RESULTS: Overall, Al-stress caused inhibition of growth and the production of photosynthetic pigments. Principal component analysis showed that the growth inhibitory effects were driven by increased oxidative stress and the interruption of water balance in barley under Al-stress. Fluoride priming, on the other hand, enhanced growth traits, chlorophyll a and b content, as well as invigorated the protection against oxidative damage by enhancing overall antioxidant capacity. Fluoride also improved osmotic balance by protecting the plasma membrane. Fluoride reduced endogenous Al3+ content, restored Al-induced inhibition of glutathione-S-transferase, and increased  the contents of phytochelatins and metallothioneins, suggesting that fluoride reduced Al3+ uptake and improved chelation of Al3+. CONCLUSIONS: Aluminum chloride-induced harmful effects are abridged by sodium fluoride on barely via enhancing antioxidative responses, the chelation mechanism causing reduction of Al uptake and accumulation of barely tissues. Advanced investigations are necessary to uncover the putative mechanisms underpinning fluoride-induced Al-stress tolerance in barley and other economically significant crops, where our results might serve as a solid reference.

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.

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.

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.

Phytochemicals as a Complement to Cancer Chemotherapy: Pharmacological Modulation of the Autophagy-Apoptosis Pathway.

Bioactive plant derived compounds are important for a wide range of therapeutic applications, and some display promising anticancer properties. Further evidence suggests that phytochemicals modulate autophagy and apoptosis, the two crucial cellular pathways involved in the underlying pathobiology of cancer development and regulation. Pharmacological targeting of autophagy and apoptosis signaling using phytochemicals therefore offers a promising strategy that is complementary to conventional cancer chemotherapy. In this review, we sought to highlight the molecular basis of the autophagic-apoptotic pathway to understand its implication in the pathobiology of cancer, and explore this fundamental cellular process as a druggable anticancer target. We also aimed to present recent advances and address the limitations faced in the therapeutic development of phytochemical-based anticancer drugs.

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.

Hydrogen sulfide priming can enhance the tolerance of artichoke seedlings to individual and combined saline-alkaline and aniline stresses.

Regulatory roles of hydrogen sulfide (H2S) under saline-alkaline and/or aniline stress have not been studied yet. In this study, we investigated the insights into saline-alkaline and/or aniline stresses-induced toxicity in artichoke plants and its alleviation by H2S priming. Individual saline-alkaline or aniline stress and their combination reduced plant growth and photosynthetic pigments. Principal component analysis (PCA) revealed that these detrimental impacts were caused by the higher oxidative damage and disruption of osmolyte homeostasis. Interestingly, only aniline stress (25 mg L-1) caused neither oxidative nor osmotic stress thus almost slight growth retarding effects had ensued. On the other hand, the presence of aniline in saline-alkaline conditions exacerbated stress-induced deleterious effects on plants, as evidenced by PCA and heatmap. However, H2S priming markedly eased the stress-induced deleteriousness as evident by enhanced chlorophyll, soluble proteins, soluble carbohydrates and up-regulated water relation in H2S-primmed plants compared with only stressed plants resulting in improved plant phenotypic features. Furthermore, H2S priming enhanced endogenous H2S content, phenylalanine ammonia-lyase, non-enzymatic antioxidants (ascorbic acid, flavonoids, glutathione, α-tocopherol, and anthocyanins) and enzymatic antioxidants (superoxide dismutase, catalase, and ascorbate peroxidase), whereas reduced oxidative stress markers (superoxide, hydrogen peroxide, hydroxyl radical, malondialdehyde, and methylglyoxal) compared with only stressed plants, indicating a protective function of H2S against oxidative damage. The PCA also clarified that H2S-mediated saline-alkaline and/or aniline stress tolerance strongly connected with the improved antioxidant system. Overall, our finding proposed that H2S priming could be an effective technique to mitigate saline-alkaline and/or aniline stress in artichoke, and perhaps in other crop plants.

Mechanistic Insight of Allantoin in Protecting Tomato Plants Against Ultraviolet C Stress.

Allantoin ((AT) a purine metabolite)-mediated ultraviolet C (UVC) stress mitigation has not been studied to date. Here, we reported the physicochemical mechanisms of UVC-induced stress in tomato (Solanum lycopersicum L.) plants, including an AT-directed mitigation strategy. UVC stress reduced plant growth and photosynthetic pigments. Heatmap and principal component analysis (PCA) revealed that these toxic impacts were triggered by the greater oxidative damage and disruption of osmolyte homeostasis. However, pre-treatment of AT noticeably ameliorated the stress-induced toxicity as evident by enhanced chlorophyll, soluble protein, and soluble carbohydrate contents in AT-pretreated UVC-stressed plants relative to only stressed plants leading to the improvement of the plant growth and biomass. Moreover, AT pre-treatment enhanced endogenous AT and allantoate content, phenylalanine ammonia-lyase, non-enzymatic antioxidants, and the enzymatic antioxidants leading to reduced oxidative stress markers compared with only stressed plants, indicating the protective effect of AT against oxidative damage. Moreover, PCA displayed that the protective roles of AT strongly associate with the improved antioxidants. On the other hand, post-treatment of AT showed less efficacy in UVC stress mitigation relative to pre-treatment of AT. Overall, this finding illustrated that AT pre-treatment could be an effective way to counteract the UVC stress in tomato, and perhaps in other crop plants.

Repositioning Vitamin C as a Promising Option to Alleviate Complications associated with COVID-19.

Vitamin C, also known as L-ascorbic acid, is an essential vitamin with pleiotropic functions, ranging from antioxidant to anti-microbial functions. Evidence suggests that vitamin C acts against inflammation, oxidative stress, autophagy chaos, and immune dysfunction. The ability to activate and enhance the immune system makes this versatile vitamin a prospective therapeutic agent amid the current situation of coronavirus disease 2019 (COVID-19). Being highly effective against the influenza virus, causing the common cold, vitamin C may also function against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its associated complications. Severe infections need higher doses of the vitamin to compensate for the augmented inflammatory response and metabolic demand that commonly occur during COVID-19. Compelling evidence also suggests that a high dose of vitamin C (1.5 g/kg body weight) in inflammatory conditions can result in effective clinical outcomes and thus can be employed to combat COVID-19. However, further studies are crucial to delineate the mechanism underlying the action of vitamin C against COVID-19. The current review aims to reposition vitamin C as an alternative approach for alleviating COVID-19-associated complications.

Revisiting potential druggable targets against SARS-CoV-2 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review.

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the most contagious diseases in human history that has already affected millions of lives worldwide. To date, no vaccines or effective therapeutics have been discovered yet that may successfully treat COVID-19 patients or contain the transmission of the virus. Scientific communities across the globe responded rapidly and have been working relentlessly to develop drugs and vaccines, which may require considerable time. In this uncertainty, repurposing the existing antiviral drugs could be the best strategy to speed up the discovery of effective therapeutics against SARS-CoV-2. Moreover, drug repurposing may leave some vital information on druggable targets that could be capitalized in target-based drug discovery. Information on possible drug targets and the progress on therapeutic and vaccine development also needs to be updated. In this review, we revisited the druggable targets that may hold promise in the development of the anti-SARS-CoV-2 agent. Progresses on the development of potential therapeutics and vaccines that are under the preclinical studies and clinical trials have been highlighted. We anticipate that this review will provide valuable information that would help to accelerate the development of therapeutics and vaccines against SARS-CoV-2 infection.

Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances.

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid ß, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer's disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: Crosstalk among calorie restriction, autophagy and immune response.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of deadly Coronavirus disease-19 (COVID-19) pandemic, which emerged as a major threat to public health across the world. Although there is no clear gender or socioeconomic discrimination in the incidence of COVID-19, individuals who are older adults and/or with comorbidities and compromised immunity have a relatively higher risk of contracting this disease. Since no specific drug has yet been discovered, strengthening immunity along with maintaining a healthy living is the best way to survive this disease. As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection. Currently, no review so far available proposing IF as an encouraging strategy in the prevention of COVID-19. A comprehensive review has therefore been planned to highlight the beneficial role of fasting in immunity and autophagy, that underlie the possible defense against SARS-CoV-2 infection. The COVID-19 pathogenesis and its impact on host immune response have also been briefly outlined. This review aimed at revisiting the immunomodulatory potential of IF that may constitute a promising preventive approach against COVID-19.

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System.

Oxidative stress (OS) plays a critical role in the pathophysiology of several brain-related disorders, including neurodegenerative diseases and ischemic stroke, which are the major causes of dementia. The Nrf2-ARE (nuclear factor erythroid 2-related factor 2/antioxidant responsive element antioxidant) system, the primary cellular defense against OS, plays an essential role in neuroprotection by regulating the expressions of antioxidant molecules and enzymes. However, simultaneous events resulting in the overproduction of reactive oxygen species (ROS) and deregulation of the Nrf2-ARE system damage essential cell components and cause loss of neuron structural and functional integrity. On the other hand, TrkB (tropomyosin-related kinase B) signaling, a classical neurotrophin signaling pathway, regulates neuronal survival and synaptic plasticity, which play pivotal roles in memory and cognition. Also, TrkB signaling, specifically the TrkB/PI3K/Akt (TrkB/phosphatidylinositol 3 kinase/protein kinase B) pathway promotes the activation and nuclear translocation of Nrf2, and thus, confers neuroprotection against OS. However, the TrkB signaling pathway is also known to be downregulated in brain disorders due to lack of neurotrophin support. Therefore, activations of TrkB and the Nrf2-ARE signaling system offer a potential approach to the design of novel therapeutic agents for brain disorders. Here, we briefly overview the development of OS and the association between OS and the pathogenesis of neurodegenerative diseases and brain injury. We propose the cellular antioxidant defense and TrkB signaling-mediated cell survival systems be considered pharmacological targets for the treatment of neurodegenerative diseases, and review the literature on the neuroprotective effects of phytochemicals that can co-activate these neuronal defense systems.

Insights into nitric oxide-mediated water balance, antioxidant defence and mineral homeostasis in rice (Oryza sativa L.) under chilling stress.

Being a chilling-sensitive staple crop, rice (Oryza sativa L.) is vulnerable to climate change. The competence of rice to withstand chilling stress should, therefore, be enhanced through technological tools. The present study employed chemical intervention like application of sodium nitroprusside (SNP) as nitric oxide (NO) donor and elucidated the underlying morpho-physiological and biochemical mechanisms of NO-mediated chilling tolerance in rice plants. At germination stage, germination indicators were interrupted by chilling stress (5.0 ± 1.0 °C for 8 h day-1), while pretreatment with 100 µM SNP markedly improved all the indicators. At seedling stage (14-day-old), chilling stress caused stunted growth with visible toxicity along with alteration of biochemical markers, for example, increase in oxidative stress markers (superoxide, hydrogen peroxide, and malondialdehyde) and osmolytes (total soluble sugar; proline and soluble protein content, SPC), and decrease in chlorophyll (Chl), relative water content (RWC), and antioxidants. However, NO application attenuated toxicity symptoms with improving growth attributes which might be related to enhance activities of antioxidants, mineral contents, Chl, RWC and SPC. Furthermore, principal component analysis indicated that water imbalance and increased oxidative damage were the main contributors to chilling injury, whereas NO-mediated mineral homeostasis and antioxidant defense were the critical determinants for chilling tolerance in rice. Collectively, our findings revealed that NO protects against chilling stress through valorizing cellular defense mechanisms, suggesting that exogenous application of NO could be a potential tool to evolve cold tolerance as well as climate resilience in rice.

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.

Deciphering Molecular Mechanism of the Neuropharmacological Action of Fucosterol through Integrated System Pharmacology and In Silico Analysis.

Fucosterol is an algae-derived unique phytosterol having several medicinal properties, including antioxidant, anti-inflammatory, anticholinesterase, neuroprotective, and so on. Accumulated evidence suggests a therapeutic promise of fucosterol in neurodegeneration; however, the in-depth pharmacological mechanism of its neuroprotection is poorly understood. Here, we employed system pharmacology and in silico analysis to elucidate the underlying mechanism of neuropharmacological action of fucosterol against neurodegenerative disorders (NDD). Network pharmacology revealed that fucosterol targets signaling molecules, receptors, enzymes, transporters, transcription factors, cytoskeletal, and various other proteins of cellular pathways, including tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), neurotrophin, and toll-like receptor (TLR) signaling, which are intimately associated with neuronal survival, immune response, and inflammation. Moreover, the molecular simulation study further verified that fucosterol exhibited a significant binding affinity to some of the vital targets, including liver X-receptor-beta (LXR-), glucocorticoid receptor (GR), tropomyosin receptor kinase B (TrkB), toll-like receptor 2/4 (TLR2/4), and ß -secretase (BACE1), which are the crucial regulators of molecular and cellular processes associated with NDD. Together, the present system pharmacology and in silico findings demonstrate that fucosterol might play a significant role in modulating NDD-pathobiology, supporting its therapeutic application for the prevention and treatment of NDD.