Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review.

Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.

Targeting the key players of phenotypic plasticity in cancer cells by phytochemicals.

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.

Current advances in nanoformulations of therapeutic agents targeting tumor microenvironment to overcome drug resistance.

The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/ß-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed.

Defining the mechanisms behind the hepatoprotective properties of curcumin.

As a critical cause of human dysfunctionality, hepatic failure leads to approximately two million deaths per year and is on the rise. Considering multiple inflammatory, oxidative, and apoptotic mechanisms behind hepatotoxicity, it urges the need for finding novel multi-targeting agents. Curcumin is a phenolic compound with anti-inflammatory, antioxidant, and anti-apoptotic roles. Curcumin possesses auspicious health benefits and protects against several diseases with exceptional safety and tolerability. This review focused on the hepatoprotective mechanisms of curcumin. The need to develop novel delivery systems of curcumin (e.g., nanoparticles, self-micro emulsifying, lipid-based colloids, solid lipid nanoparticles, cyclodextrin inclusion, phospholipid complexes, and nanoemulsions) is also considered.

Exploiting new strategies in combating head and neck carcinoma: A comprehensive review on phytochemical approaches passing through PI3K/Akt/mTOR signaling pathway.

Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.

Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review.

Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe natural compounds has been a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment.

Therapeutic potential of marine peptides in cervical and ovarian cancers.

Cervical and ovarian cancers contribute significantly to female morbidity and mortality worldwide. The current standard of treatment, including surgical removal, radiation therapy, and chemotherapy, offers poor outcomes. There are many side effects to traditional chemotherapeutic agents and treatment-resistant types, and often the immune response is depressed. As a result, traditional approaches have evolved to include new alternative remedies, such as natural compounds. Aquatic species provide a rich supply of possible drugs. The potential anti-cancer peptides are less toxic to normal cells and can attenuate multiple drug resistance by providing an efficacious treatment approach. The physiological effects of marine peptides are described in this review focusing on various pathways, such as apoptosis, microtubule balance disturbances, suppression of angiogenesis, cell migration/invasion, and cell viability. The review also highlights the potential role of marine peptides as safe and efficacious therapeutic agent for the treatment of cervical and ovarian cancers.

Targeting Akt/CREB/BDNF signaling pathway by ginsenosides in neurodegenerative diseases: A mechanistic approach.

Neurodegenerative diseases (NDDs) are leading causes of death and morbidity in the elderly worldwide. From the mechanistic/pathological view, oxidative stress, inflammation, and apoptosis are responsible for the etiology of neuronal diseases, and play detrimental roles in neuronal cell death and neurodegenerative processes. The diverse pathophysiological pathways influencing NDDs necessitate the discovery of pivotal dysregulated signaling mediators. The current review describes essential functions of protein kinase B (Akt)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway as possible therapeutic targets in the pathogenesis of NDDs. Consequently, finding new multi-target agents in regulating Akt/CREB/BDNF and thus associated downstream pathways is a critical factor in combating NDDs. Because of their neuroprotective properties, dietary phytochemicals have shown to be popular nutritional therapy methods. Ginsenosides, the most active ingredient of ginseng, and a secondary metabolite of steroid glycosides and triterpene saponins have been found to have a number of protective effects on the central nervous system (CNS). The protective roles of ginsenosides in CNS are potentially passing through Akt/CREB/BDNF pathway towards neuroprotective responses. In the present study, Akt/CREB/BDNF pathway is targeted by ginsenosides and associated nanoformulations towards potential neuroprotective effects.

Targeting cellular senescence in cancer by plant secondary metabolites: A systematic review.

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.

Modulation of integrin receptor by polyphenols: Downstream Nrf2-Keap1/ARE and associated cross-talk mediators in cardiovascular diseases.

As a group of heterodimeric and transmembrane glycoproteins, integrin receptors are widely expressed in various cell types overall the body. During cardiovascular dysfunction, integrin receptors apply inhibitory effects on the antioxidative pathways, including nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch like ECH Associated Protein 1 (Keap1)/antioxidant response element (ARE) and interconnected mediators. As such, dysregulation in integrin signaling pathways influences several aspects of cardiovascular diseases (CVDs) such as heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. So, modulation of integrin pathway could trigger the downstream antioxidant pathways toward cardioprotection. Regarding the involvement of multiple aforementioned mediators in the pathogenesis of CVDs, as well as the side effects of conventional drugs, seeking for novel alternative drugs is of great importance. Accordingly, the plant kingdom could pave the road in the treatment of CVDs. Of natural entities, polyphenols are multi-target and accessible phytochemicals with promising potency and low levels of toxicity. The present study aims at providing the cardioprotective roles of integrin receptors and downstream antioxidant pathways in heart failure, arrhythmia, angina, hypertension, hyperlipidemia, platelet aggregation and coagulation. The potential role of polyphenols has been also revealed in targeting the aforementioned dysregulated signaling mediators in those CVDs.

Antioxidant and anticancer potentials of edible flowers: where do we stand?

Edible flowers are attracting special therapeutic attention and their administration is on the rise. Edible flowers play pivotal modulatory roles on oxidative stress and related interconnected apoptotic/inflammatory pathways toward the treatment of cancer. In this review, we highlighted the phytochemical content and therapeutic applications of edible flowers, as well as their modulatory potential on the oxidative stress pathways and apoptotic/inflammatory mediators, resulting in anticancer effects. Edible flowers are promising sources of phytochemicals (e.g., phenolic compounds, carotenoids, terpenoids) with several therapeutic effects. They possess anti-inflammatory, anti-diabetic, anti-microbial, anti-depressant, anxiolytic, anti-obesity, cardioprotective, and neuroprotective effects. Edible flowers potentially modulate oxidative stress by targeting erythroid nuclear transcription factor-2/extracellular signal-regulated kinase/mitogen-activated protein kinase (Nrf2/ERK/MAPK), reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA) and antioxidant response elements (AREs). As the interconnected pathways to oxidative stress, inflammatory mediators, including tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukins (ILs) as well as apoptotic pathways such as Bcl-2-associated X protein (Bax), Bcl-2, caspase and cytochrome C are critical targets of edible flowers in combating cancer. In this regard, edible flowers could play promising anticancer effects by targeting oxidative stress and downstream dysregulated pathways.

Astaxanthin ameliorates serum level and spinal expression of macrophage migration inhibitory factor following spinal cord injury.

Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P < 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P < 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.

Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus.

The marine environment is important yet generally underexplored. It contains new sources of functional constituents that can affect various pathways in food processing, storage, and fortification. Bioactive secondary metabolites produced by marine microorganisms may have significant potential applications for humans. Various components isolated from disparate marine microorganisms, including fungi, microalgae, bacteria, and myxomycetes, showed considerable biological effects, such as anticancer, antioxidant, antiviral, antibacterial, and neuroprotective activities. Growing studies are revealing that potential anticancer effects of marine agents could be achieved through the modulation of several organelles. Mitochondria are known organelles that influence growth, differentiation, and death of cells via influencing the biosynthetic, bioenergetic, and various signaling pathways related to oxidative stress and cellular metabolism. Consequently, mitochondria play an essential role in tumorigenesis and cancer treatments by adapting to alterations in environmental and cellular conditions. The growing interest in marine-derived anticancer agents, combined with the development and progression of novel technology in the extraction and cultures of marine life, led to revelations of new compounds with meaningful pharmacological applications. This is the first critical review on marine-derived anticancer agents that have the potential for targeting mitochondrial function during tumorigenesis. This study aims to provide promising strategies in cancer prevention and treatment.

Polydatin: Pharmacological Mechanisms, Therapeutic Targets, Biological Activities, and Health Benefits.

Polydatin is a natural potent stilbenoid polyphenol and a resveratrol derivative with improved bioavailability. Polydatin possesses potential biological activities predominantly through the modulation of pivotal signaling pathways involved in inflammation, oxidative stress, and apoptosis. Various imperative biological activities have been suggested for polydatin towards promising therapeutic effects, including anticancer, cardioprotective, anti-diabetic, gastroprotective, hepatoprotective, neuroprotective, anti-microbial, as well as health-promoting roles on the renal system, the respiratory system, rheumatoid diseases, the skeletal system, and women's health. In the present study, the therapeutic targets, biological activities, pharmacological mechanisms, and health benefits of polydatin are reviewed to provide new insights to researchers. The need to develop further clinical trials and novel delivery systems of polydatin is also considered to reveal new insights to researchers.

ACE2: Its potential role and regulation in severe acute respiratory syndrome and COVID-19.

COVID-19, a new disease caused by the 2019-novel coronavirus (SARS-CoV-2), has swept the world and challenged its culture, economy, and health infrastructure. Forced emergence to find an effective vaccine to immunize people has led scientists to design and examine vaccine candidates all over the world. Until a vaccine is developed, however, effective treatment is needed to combat this virus, which is resistant to all conventional antiviral drugs. Accordingly, more about the structure, entry mechanism, and pathogenesis of COVID-19 is required. Angiotensin-converting enzyme 2 (ACE2) is the gateway to SARS-CoV and SARS-CoV-2, so our knowledge of SARS-CoV-2 can help us to complete its mechanism of interaction with ACE2 and virus endocytosis, which can be interrupted by neutralizing small molecules or proteins. ACE2 also plays a crucial role in lung injury.

The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: a review study.

As a complicated process of forming new blood vessels from the present vasculature endothelium, angiogenesis plays a critical role in the progression of cancer, through developing new blood vessels in tumor cells. Angiogenesis is regulated by proteins known as inhibitor or activator molecules, affected by different medicinal herbs and small molecules. In the present review, the molecular mechanisms of tumor angiogenesis are outlined, focusing on the pharmacological aspects and molecular mechanisms of natural compounds used in chemotherapy and their effects on angiogenesis, focusing on vascular endothelial growth factor (VEGF).Our findings show that a significant number of drugs used in the treatment of cancer are antiangiogenic small molecules and phytochemicals which inhibit VEGF and angiogenesis. Besides, medicinal herbs are potential multi-target agents with more covering mechanisms, lower costs and lower toxicity to develop novel anticancer drugs through targeting the VEGF signaling pathway and receptor tyrosine kinases (RTKs) in the angiogenesis. For this reason, herbal anti-VEGF agents are considered as imperative targets to be used for cancer treatment in clinical applications.The findings reveal a promising perspective for medicinal herbs and natural compounds acting on VEGF and angiogenesis to find new targets and potential therapeutic use in the treatment of cancer.

The anti-nociceptive activity of naringenin passes through L-arginine/NO/cGMP/KATP channel pathway and opioid receptors.

As a promising flavonoid, naringenin has shown potential anti-inflammatory and antioxidant properties mainly in inflammatory pain models by oral administration. Therefore, we investigated the antinociceptive activity of this compound by intraperitoneally (i.p.) administration, as well as, associated mechanism of action considering the involvement of L-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) pathway and opioid receptors. The antinociceptive effect of naringenin was evaluated in male NMRI mice using formalin test at early and late phases. To assess the involvement of L-arginine/NO/cGMP/KATP pathway and opioid receptors, mice were pretreated i.p. with L-arginine (NO precursor), S-nitroso-N-acetylpenicillamine (SNAP, NO donor), N(gamma)-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), sildenafil (inhibitor of phosphodiesterase enzyme), glibenclamide (KATP channel blocker) and naloxone (an opioid receptor antagonist), respectively 20 min before administration of the most effective dose of naringenin. Naringenin showed a dose-dependent antinociceptive effect at both early and late phases of the formalin test. The dose of 100 mg/kg of naringenin was identified as the most effective dose and selected for further experiments. Our mechanistic evaluations showed that L-arginine, SNAP and sildenafil could enhance the antinociceptive effects of naringenin, revealing the critical role of NO and cGMP during its antinociceptive effect. On the other hand, glibenclamide and naloxone could mitigate the antinociceptive potential of naringenin at both phases of formalin test, which confirmed the associated role of KATP channels and opioid receptors. In conclusion, naringenin could be a promising antinociceptive agent acting through opioid receptors and L-arginine/NO/cGMP/KATP channel pathway.

Astaxanthin engages the l-arginine/NO/cGMP/KATP channel signaling pathway toward antinociceptive effects.

One of the main functions of the sensory system in our body is to maintain somatosensory homeostasis. Recent reports have led to a significant advance in our understanding of pain signaling mechanisms; however, the exact mechanisms of pain transmission have remained unclear. There is an urgent need to reveal the precise signaling mediators of pain to provide alternative therapeutic agents with more efficacy and fewer side effects. Accordingly, although the anti-inflammatory, antioxidative and anti-neuropathic effects of astaxanthin (AST) have been previously highlighted, its peripheral antinociceptive mechanisms are not fully understood. In this line, considering the engagement of l-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) signaling pathway in the antinociceptive responses, the present study evaluated its associated role in the antinociceptive activity of AST. Male mice were intraperitoneally (i.p.) injected with l-arginine (100 mg/kg), SNAP (1 mg/kg), L-NAME (30 mg/kg), sildenafil (5 mg/kg), and glibenclamide (10 mg/kg) alone and prior to the most effective dose of AST. Following AST administration, intraplantarly (i.pl) injection of formalin was done, and pain responses were evaluated in mice during the primary (acute) and secondary (inflammatory) phases of formalin test. The results highlighted that 10 mg/kg i.p. dose of AST showed the greatest antinociceptive effect. Besides, while L-NAME and glibenclamide reduced the antinociceptive effect of AST, it was significantly increased by l-arginine, SNAP and sildenafil during both the primary and secondary phases of formalin test. These data suggest that the antinociceptive activity of AST is passing through the l-arginine/NO/cGMP/KATP pathway.

Flavonoids modulate AMPK/PGC-1α and interconnected pathways toward potential neuroprotective activities.

As progressive, chronic, incurable and common reasons for disability and death, neurodegenerative diseases (NDDs) are significant threats to human health. Besides, the increasing prevalence of neuronal gradual degeneration and death during NDDs has made them a global concern. Since yet, no effective treatment has been developed to combat multiple dysregulated pathways/mediators and related complications in NDDs. Therefore, there is an urgent need to create influential and multi-target factors to combat neuronal damages. Accordingly, the plant kingdom has drawn a bright future. Among natural entities, flavonoids are considered a rich source of drug discovery and development with potential biological and medicinal activities. Growing studies have reported multiple dysregulated pathways in NDDs, which among those mediator AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) play critical roles. In this line, critical role of flavonoids in the upregulation of AMPK/PGC-1α pathway seems to pave the road in the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), aging, central nervous system (brain/spinal cord) damages, stroke, and other NDDs. In the present study, the regulatory role of flavonoids in managing various NDDs has been shown to pass through AMPK/PGC-1α signaling pathway.

Marine Natural Products: Promising Candidates in the Modulation of Gut-Brain Axis towards Neuroprotection.

In recent decades, several neuroprotective agents have been provided in combating neuronal dysfunctions; however, no effective treatment has been found towards the complete eradication of neurodegenerative diseases. From the pathophysiological point of view, growing studies are indicating a bidirectional relationship between gut and brain termed gut-brain axis in the context of health/disease. Revealing the gut-brain axis has survived new hopes in the prevention, management, and treatment of neurodegenerative diseases. Accordingly, introducing novel alternative therapies in regulating the gut-brain axis seems to be an emerging concept to pave the road in fighting neurodegenerative diseases. Growing studies have developed marine-derived natural products as hopeful candidates in a simultaneous targeting of gut-brain dysregulated mediators towards neuroprotection. Of marine natural products, carotenoids (e.g., fucoxanthin, and astaxanthin), phytosterols (e.g., fucosterol), polysaccharides (e.g., fucoidan, chitosan, alginate, and laminarin), macrolactins (e.g., macrolactin A), diterpenes (e.g., lobocrasol, excavatolide B, and crassumol E) and sesquiterpenes (e.g., zonarol) have shown to be promising candidates in modulating gut-brain axis. The aforementioned marine natural products are potential regulators of inflammatory, apoptotic, and oxidative stress mediators towards a bidirectional regulation of the gut-brain axis. The present study aims at describing the gut-brain axis, the importance of gut microbiota in neurological diseases, as well as the modulatory role of marine natural products towards neuroprotection.