Production of high molecular-ordered stilbene oligomers for the study of their biological activity: total synthesis, bio-catalyzed synthesis and production by plant systems.

Though the iconic stilbene resveratrol and its related dimers constitute a top storyline in the field of natural product research, resveratrol oligomers (condensation >2) have been left aside despite their higher biological activity compared to that of the monomers. This situation largely results from the difficulty of getting them in sufficient quantities to enable evaluation of their biological properties in vivo. We present here a synthetic and critical analysis of the methods used for the production of high molecular-ordered stilbene oligomers of potential biomedical interest, gathering the most salient data regarding the approaches employed to prepare them by total synthesis, use of biomimetic approaches or through plant systems.

Mechanistic insight into immunomodulatory effects of food-functioned plant secondary metabolites.

Medicinally important plant-foods offer a balanced immune function, which is essential for protecting the body against antigenic invasion, mainly by microorganisms. Immunomodulators play pivotal roles in supporting immune function either suppressing or stimulating the immune system's response to invading pathogens. Among different immunomodulators, plant-based secondary metabolites have emerged as high potential not only for immune defense but also for cellular immunoresponsiveness. These natural immunomodulators can be developed into safer alternatives to the clinically used immunosuppressants and immunostimulant cytotoxic drugs which possess serious side effects. Many plants of different species have been reported to possess strong immunomodulating properties. The immunomodulatory effects of plant extracts and their bioactive metabolites have been suggested due to their diverse mechanisms of modulation of the complex immune system and their multifarious molecular targets. Phytochemicals such as alkaloids, flavonoids, terpenoids, carbohydrates and polyphenols have been reported as responsible for the immunomodulatory effects of several medicinal plants. This review illustrates the potent immunomodulatory effects of 65 plant secondary metabolites, including dietary compounds and their underlying mechanisms of action on cellular and humoral immune functions in in vitro and in vivo studies. The clinical potential of some of the compounds to be used for various immune-related disorders is highlighted.

Regulation of DAPK1 by Natural Products: An Important Target in Treatment of Stroke.

Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia-reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1ß (IL-1ß) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.

The Phytochemical Profile and Biological Activity of Malva neglecta Wallr. in Surgically Induced Endometriosis Model in Rats.

Leaves and aerial parts of Malva neglecta Wallr. have been traditionally used in Anatolia for the treatment of pain, inflammation, hemorrhoids, renal stones, constipation, and infertility. This study investigated the effects of M. neglecta leaves in a rat endometriosis model. The dried plant material was extracted with n-hexane, ethyl acetate, and methanol, successively. Experimental endometriosis was surgically induced in six-week-old female, non-pregnant, Wistar albino rats by autotransplant of endometrial tissue to the abdominal wall. After twenty-eight days, rats were evaluated for a second laparotomy. Endometrial foci areas were assessed, and intraabdominal adhesions were scored. Rats were divided into five groups as control, n-hexane, ethyl acetate, methanol, and aqueous extracts, as well as reference. At the end of the treatment, all rats were sacrificed and endometriotic foci areas and intraabdominal adhesions were re-evaluated and compared with the previous findings. Moreover, peritoneal fluid was collected to detect tumor necrosis factor- α (TNF-α), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels, and cDNA synthesis, and a quantitative real-time polymerase chain reaction (PCR) test was done. The phytochemical content of the most active extract was determined using High-Performance Liquid Chromatography (HPLC). Both endometrial volume and adhesion score decreased significantly in the group treated with methanol extract. In addition, significant decreases were observed in TNF-α, VEGF, and IL-6 levels in animals administered methanol extract. HPLC results showed that the activity caused by the methanol extract of M. neglecta was due to the polyphenols. Taken together, these novel findings indicate that M. neglecta may be a promising alternative for the treatment of endometriosis.

Phytostilbenes as agrochemicals: biosynthesis, bioactivity, metabolic engineering and biotechnology.

Covering: 1976 to 2020. Although constituting a limited chemical family, phytostilbenes represent an emblematic group of molecules among natural compounds. Ever since their discovery as antifungal compounds in plants and their ascribed role in human health and disease, phytostilbenes have never ceased to arouse interest for researchers, leading to a huge development of the literature in this field. Owing to this, the number of references to this class of compounds has reached the tens of thousands. The objective of this article is thus to offer an overview of the different aspects of these compounds through a large bibliography analysis of more than 500 articles. All the aspects regarding phytostilbenes will be covered including their chemistry and biochemistry, regulation of their biosynthesis, biological activities in plants, molecular engineering of stilbene pathways in plants and microbes as well as their biotechnological production by plant cell systems.

Targeting Mitochondria by Plant Secondary Metabolites: A Promising Strategy in Combating Parkinson's Disease.

Parkinson's disease (PD) is one of the most prevalent and debilitating neurodegenerative conditions, and is currently on the rise. Several dysregulated pathways are behind the pathogenesis of PD; however, the critical targets remain unclear. Accordingly, there is an urgent need to reveal the key dysregulated pathways in PD. Prevailing reports have highlighted the importance of mitochondrial and cross-talked mediators in neurological disorders, genetic changes, and related complications of PD. Multiple pathophysiological mechanisms of PD, as well as the low efficacy and side effects of conventional neuroprotective therapies, drive the need for finding novel alternative agents. Recently, much attention has been paid to using plant secondary metabolites (e.g., flavonoids/phenolic compounds, alkaloids, and terpenoids) in the modulation of PD-associated manifestations by targeting mitochondria. In this line, plant secondary metabolites have shown promising potential for the simultaneous modulation of mitochondrial apoptosis and reactive oxygen species. This review aimed to address mitochondria and multiple dysregulated pathways in PD by plant-derived secondary metabolites.

The Neuroprotective Role of Polydatin: Neuropharmacological Mechanisms, Molecular Targets, Therapeutic Potentials, and Clinical Perspective.

Neurodegenerative diseases (NDDs) are one of the leading causes of death and disability in humans. From a mechanistic perspective, the complexity of pathophysiological mechanisms contributes to NDDs. Therefore, there is an urgency to provide novel multi-target agents towards the simultaneous modulation of dysregulated pathways against NDDs. Besides, their lack of effectiveness and associated side effects have contributed to the lack of conventional therapies as suitable therapeutic agents. Prevailing reports have introduced plant secondary metabolites as promising multi-target agents in combating NDDs. Polydatin is a natural phenolic compound, employing potential mechanisms in fighting NDDs. It is considered an auspicious phytochemical in modulating neuroinflammatory/apoptotic/autophagy/oxidative stress signaling mediators such as nuclear factor-κB (NF-κB), NF-E2-related factor 2 (Nrf2)/antioxidant response elements (ARE), matrix metalloproteinase (MMPs), interleukins (ILs), phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), and the extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Accordingly, polydatin potentially counteracts Alzheimer's disease, cognition/memory dysfunction, Parkinson's disease, brain/spinal cord injuries, ischemic stroke, and miscellaneous neuronal dysfunctionalities. The present study provides all of the neuroprotective mechanisms of polydatin in various NDDs. Additionally, the novel delivery systems of polydatin are provided regarding increasing its safety, solubility, bioavailability, and efficacy, as well as developing a long-lasting therapeutic concentration of polydatin in the central nervous system, possessing fewer side effects.

Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates.

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.

Ageratum conyzoides L. and Its Secondary Metabolites in the Management of Different Fungal Pathogens.

Ageratum conyzoides L. (Family-Asteraceae) is an annual aromatic invasive herb, mainly distributed over the tropical and subtropical regions of the world. It owns a reputed history of indigenous remedial uses, including as a wound dressing, an antimicrobial, and mouthwash as well as in treatment of dysentery, diarrhea, skin diseases, etc. In this review, the core idea is to present the antifungal potential of the selected medicinal plant and its secondary metabolites against different fungal pathogens. Additionally, toxicological studies (safety profile) conducted on the amazing plant A. conyzoides L. are discussed for the possible clinical development of this medicinal herb. Articles available from 2000 to 2020 were reviewed in detail to exhibit recent appraisals of the antifungal properties of A. conyzoides. Efforts were aimed at delivering evidences for the medicinal application of A. conyzoides by using globally recognized scientific search engines and databases so that an efficient approach for filling the lacunae in the research and development of antifungal drugs can be adopted. After analyzing the literature, it can be reported that the selected medicinal plant effectively suppressed the growth of numerous fungal species, such as Aspergillus, Alternaria, Candida, Fusarium, Phytophthora, and Pythium, owing to the presence of various secondary metabolites, particularly chromenes, terpenoids, flavonoids and coumarins. The possible mechanism of action of different secondary metabolites of the plant against fungal pathogens is also discussed briefly. However, it was found that only a few studies have been performed to demonstrate the plant's dosage and safety profile in humans. Considered all together, A. conyzoides extract and its constituents may act as a promising biosource for the development of effective antifungal formulations for clinical use. However, in order to establish safety and efficacy, additional scientific research is required to explore chronic toxicological effects of ageratum, to determine the probability of interactions when used with different herbs, and to identify safe dosage. The particulars presented here not only bridge this gap but also furnish future research strategies for the investigators in microbiology, ethno-pharmacology, and drug discovery.

Oxidative Stress and Marine Carotenoids: Application by Using Nanoformulations.

Carotenoids are natural fat-soluble pigments synthesized by plants, algae, fungi and microorganisms. They are responsible for the coloration of different photosynthetic organisms. Although they play a role in photosynthesis, they are also present in non-photosynthetic plant tissues, fungi, and bacteria. These metabolites have mainly been used in food, cosmetics, and the pharmaceutical industry. In addition to their utilization as pigmentation, they have significant therapeutically applications, such as improving immune system and preventing neurodegenerative diseases. Primarily, they have attracted attention due to their antioxidant activity. Several statistical investigations indicated an association between the use of carotenoids in diets and a decreased incidence of cancer types, suggesting the antioxidant properties of these compounds as an important factor in the scope of the studies against oxidative stress. Unusual marine environments are associated with a great chemical diversity, resulting in novel bioactive molecules. Thus, marine organisms may represent an important source of novel biologically active substances for the development of therapeutics. Marine carotenoids (astaxanthin, fucoxanthin, ß-carotene, lutein but also the rare siphonaxanthin, sioxanthin, and myxol) have recently shown antioxidant properties in reducing oxidative stress markers. Numerous of bioactive compounds such as marine carotenoids have low stability, are poorly absorbed, and own very limited bioavailability. The new technique is nanoencapsulation, which can be used to preserve marine carotenoids and their original properties during processing, storage, improve their physiochemical properties and increase their health-promoting effects. This review aims to describe the role of marine carotenoids, their potential applications and different types of advanced nanoformulations preventing and treating oxidative stress related disorders.

Sedative and Anxiolytic Activities of Opuntia ficus indica (L.) Mill.: An Experimental Assessment in Mice.

Ethnobotanical field surveys revealed the use of fruits of Opuntia ficus indica (L.) Mill. for treating diabetes, burns, bronchial asthma, constipation, kidney stones, and rheumatic pains and as a sedative in Turkish folk medicine. This study aimed to verify the efficacy of the fruits of O. ficus indica experimentally and to define components responsible for the activity using bioassay-guided procedures. The crude methanolic extract of the fruits was sequentially fractionated into five subextracts: n-hexane, dichloromethane, ethyl acetate, n-butanol, and water. Further experiments were carried out on the most active subextract, that is, the ethyl acetate (EtOAc) subextract, which was further subjected to fractionation through successive column chromatographic applications on Sephadex LH-20. For activity assessment, each extract or fraction was submitted to bioassay systems; traction test, fireplace test, hole-board test, elevated plus-maze test, and open-field test were used for sedative and anxiolytic effects, and a thiopental-induced sleeping test was used for the hypnotic effect. Among the subextracts obtained from the methanolic extract, the EtOAc subextract showed significant sedative and anxiolytic effects in the bioassay systems. From the EtOAc subextract, major components were isolated, and their structures were determined as isorhamnetin, isorhamnetin 3-O-glucoside, isorhamnetin 3-O-rutinoside, and kaempferol 3-O-rutinoside using spectral techniques. In conclusion, this study confirmed the claimed use of the plant against anxiety in Turkish folk medicine.

Antidepressant Potential of Lotus corniculatus L. subsp. corniculatus: An Ethnobotany Based Approach.

As a Turkish traditional medicinal plant, aerial parts of Lotus corniculatus L. subsp. corniculatus (Fabaceae) are used as a painkiller, antihemoroidal, diuretic and sedative. In this study, the antidepressant potential of the plant has been attempted to clarify. Extracts with water, n-Hexane, ethyl acetate, and methanol were prepared respectively from the aerial parts. Antidepressant activity of the extracts were researched by using three different in vivo test models namely a tail suspension test, antagonism of tetrabenazine-induced hypothermia, ptosis, and suppression of locomotor activity and forced swimming test on male BALB/c mice and in vitro monoamine oxidase (MAO)-A and B inhibition assays. The results were evaluated through comparing with control and reference groups, and then active compounds of the active extract have been determined. Bioassay-guided fractionation of active fraction led to the isolation of three compounds and structures of the compounds were elucidated by spectroscopic methods. The data of this study demonstrate that the MeOH extract of the aerial parts of the plant showed remarkable in vivo antidepressant effect and the isolated compounds medicarpin-3-O-glucoside, gossypetin-3-O-glucoside and naringenin-7-O-glucoside (prunin) from the active sub-fractions could be responsible for the activity. Further mechanistic and toxicity studies are planned to develop new antidepressant-acting drugs.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications.

Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review.

Alzheimer's disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

Sedative Effects of Latexes Obtained from Some Lactuca L. Species Growing in Turkey.

Lactuca L. species belong to the Asteraceae family and these plants are traditionally used for therapeutic purposes around the world. The dried milky latex of L. serriola is known as "lettuce oil" and is used as a sedative in Turkey. This study aimed to evaluate the sedative effects and analyze the chemical compositions of latexes obtained from some Lactuca species growing in Turkey. The sedative effects were evaluated through various behavioral tests on mice. For this purpose, latexes were obtained from L. glareosa Boiss., L. viminea (L.) J. Presl and C. P, L. mulgedioides (Vis and Pancic) Boiss. and Kotschy ex. Boiss., L. saligna L., and L. serriola L. The latex from L. saligna showed the highest sedative effects, whilst L. serriola and L. viminea latexes also displayed significant sedative effects compared to the control group at a dose of 100 mg/kg. However, the latexes from L. glareosa and L. mulqedioides did not exhibit any sedative effects on mice. Characteristic sesquiterpene lactones (lactucin, lactucopicrin, 11,13ß-dihydrolactucin, and 11,13ß-dihydrolactucopicrin) were determined qualitatively and quantitatively by high-performance liquid chromatography (HPLC). Lactucin was identified as the main component.

Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aß) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aß peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aß peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer's pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

Evaluation of the status quo of polyphenols analysis: Part I-phytochemistry, bioactivity, interactions, and industrial uses.

Phytochemicals, especially polyphenols, are gaining more attention from both the scientific community and food, pharmaceutical, and cosmetics industries due to their implications in human health. In this line, lately new applications have emerged, and of great importance is the selection of accurate and reliable analytical methods for better evaluation of the quality of the end-products, which depends on diverse process variables as well as on the matrices and on the physicochemical properties of different polyphenols. The first of a two-part review on polyphenols will address the phytochemistry and biological activities of different classes of polyphenols including flavonoids, lignans and flavanolignans, stilbenoids, tannins, curcuminoids, and coumarins. Moreover, the possible interactions of polyphenols and current and potential industrial applications of polyphenols are discussed.

Novel therapeutic strategies for stroke: The role of autophagy.

Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.

Targeting STATs in neuroinflammation: The road less traveled!

JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.

The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective.

As the leading causes of human disability and mortality, neurological diseases affect millions of people worldwide and are on the rise. Although the general roles of several signaling pathways in the pathogenesis of neurodegenerative disorders have so far been identified, the exact pathophysiology of neuronal disorders and their effective treatments have not yet been precisely elucidated. This requires multi-target treatments, which should simultaneously attenuate neuronal inflammation, oxidative stress, and apoptosis. In this regard, astaxanthin (AST) has gained growing interest as a multi-target pharmacological agent against neurological disorders including Parkinson's disease (PD), Alzheimer's disease (AD), brain and spinal cord injuries, neuropathic pain (NP), aging, depression, and autism. The present review highlights the neuroprotective effects of AST mainly based on its anti-inflammatory, antioxidative, and anti-apoptotic properties that underlies its pharmacological mechanisms of action to tackle neurodegeneration. The need to develop novel AST delivery systems, including nanoformulations, targeted therapy, and beyond, is also considered.