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Background The interest in the plant-derived healthy foods, nutraceuticals, functional foods and food supplements is increasing in recent times as potential agents in maintenance of health and the prevention and treatment of diseases. Matcha tea powder is obtained from the leaves of tea plant (Camellia sinensis (L.) Kuntze) grown under specific condition using about 90% shade. As compared to green tea, a hot water extract of tea leaves, matcha is consumed as a powder of whole leaves. Matcha powder is reported to have higher content of some bioactive components such as catechins, theanine and caffeine. In recent years, there is an increased market demand and consumption of matcha as a drink and as a component in various beverages, snacks and other food products. Scope and approach In this review, the available scientific information of the chemical constituents and their analysis and biological activities were critically analyzed. These results may help to understand current status of research on matcha and the gaps which help to guide future research related to evidence based product formulations. Key findings and conclusions Various studies have reported the difference in bioactive compounds in matcha as compared to green tea and other tea formulations. The content and composition were mostly affected by the cultivation and processing techniques. Analysis of marketed samples in various countries have shown the variable content of the bioactive compounds. Thus, there is a need for proper standardization for maintaining the quality. Matcha as a whole, its extract and compounds have shown promising biological activities in in vitro and animal studies. However, comparatively only a few clinical studies are performed, which need future attention. There should also be more detailed studies regarding matcha-containing food products' formulation, quality control and biological activities.

Moringa oleifera, popularly known as a miracle tree or tree of life, has been extensively used as a functional food and nutritional asset worldwide. Ethnomedicinal and traditional uses of M. oleifera indicate that this plant might have a pleiotropic therapeutic efficacy against most human ailments. In fact, M. oleifera is reported to have several pharmacological activities, including antioxidant, antibacterial, antifungal, antidiabetic, antipyretic, antiulcer, antispasmodic, antihypertensive, antitumor, hepatoprotective, and cardiac stimulant properties. Recently, a few experimental studies reported the neuroprotective effects of M. oleifera against Alzheimer's disease, dementia, Parkinson's disease, stroke, and neurotoxicity-related symptoms. In addition, several neuroprotective phytochemicals have been isolated from M. oleifera, which signifies that it can have promising neuroprotective effects. Therefore, this review aimed to explore the current updates and future prospective of neuroprotective efficacies of M. oleifera.

Despite being a major global health concern, cerebral ischemia/stroke has limited therapeutic options. Tissue plasminogen activator (tPA) is the only available medication to manage acute ischemic stroke, but this medication is associated with adverse effects and has a narrow therapeutic time window. Curcumin, a polyphenol that is abundantly present in the rhizome of the turmeric plant (Curcuma longa), has shown promising neuroprotective effects in animal models of neurodegenerative diseases, including cerebral ischemia. In the central nervous system (CNS), neuroprotective effects of curcumin have been experimentally validated in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia. Curcumin can exert pleiotropic effects in the postischemic brain including antioxidant, anti-inflammatory, antiapoptotic, vasculoprotective, and direct neuroprotective efficacies. Importantly, neuroprotective effects of curcumin has been reported in both ischemic and hemorrhagic stroke models. A broad-spectrum neuroprotective efficacy of curcumin suggested that curcumin can be an appealing therapeutic strategy to treat cerebral ischemia. In this review, we aimed to address the pharmacotherapeutic potential of curcumin in cerebral ischemia including its cellular and molecular mechanisms of neuroprotection revealing curcumin as an appealing therapeutic candidate for cerebral ischemia.

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P1) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P1 and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P1 is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P1 was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P1 activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P1 activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P1 in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P1 activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P1 could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P1 activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P1 activation. Overall, these results revealed S1P1-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

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Sphingosine 1-phosphate (S1P) signaling has emerged as a drug target in cerebral ischemia. Among S1P receptors, S1P2 was recently identified to mediate ischemic brain injury. But, pathogenic mechanisms are not fully identified, particularly in view of microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed whether microglial activation is the pathogenesis of S1P2-mediated brain injury in mice challenged with transient middle cerebral artery occlusion (tMCAO). To suppress S1P2 activity, its specific antagonist, JTE013 was given orally to mice immediately after reperfusion. JTE013 administration reduced the number of activated microglia and reversed their morphology from amoeboid to ramified microglia in post-ischemic brain after tMCAO challenge, along with attenuated microglial proliferation. Moreover, JTE013 administration attenuated M1 polarization in post-ischemic brain. This S1P2-directed M1 polarization appeared to occur in activated microglia, which was evidenced upon JTE013 exposure in vivo as suppressed M1-relevant NF-κB activation in activated microglia of post-ischemic brain. Moreover, JTE013 exposure or S1P2 knockdown reduced expression levels of M1 markers in vitro in lipopolysaccharide-driven M1 microglia. Additionally, suppressing S1P2 activity attenuated activation of M1-relevant ERK1/2 and JNK in post-ischemic brain or lipopolysaccharide-driven M1 microglia. Overall, our study demonstrated that S1P2 regulated microglial activation and M1 polarization in post-ischemic brain.

Microglial activation is considered as the critical pathogenic event in diverse central nervous system disorders including cerebral ischemia. Proinflammatory responses of activated microglia have been well reported in the ischemic brain and neuroinflammatory responses of activated microglia have been believed to be the potential therapeutic strategy. However, despite having proinflammatory roles, microglia can have significant anti-inflammatory roles and they are associated with the production of growth factors which are responsible for neuroprotection and recovery after ischemic injury. Microglia can directly promote neuroprotection by preventing ischemic infarct expansion and promoting functional outcomes. Indirectly, microglia are involved in promoting anti-inflammatory responses, neurogenesis, and angiogenesis in the ischemic brain which are crucial pathophysiological events for ischemic recovery. In fact, anti-inflammatory cytokines and growth factors produced by microglia can promote neuroprotection and attenuate neurobehavioral deficits. In addition, microglia regulate phagocytosis, axonal regeneration, blood–brain barrier protection, white matter integrity, and synaptic remodeling, which are essential for ischemic recovery. Microglia can also regulate crosstalk with neurons and other cell types to promote neuroprotection and ischemic recovery. This review mainly focuses on the roles of microglia in neuroprotection and recovery following ischemic injury. Furthermore, this review also sheds the light on the therapeutic potential of microglia in stroke patients.

Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.

Tanshinones, lipophilic diterpenes isolated from the rhizome of Salvia miltiorrhiza, have diverse pharmacological activities against human ailments including neurological diseases. In fact, tanshinones have been used to treat heart diseases, stroke, and vascular diseases in traditional Chinese medicine. During the last decade, tanshinones have been the most widely studied phytochemicals for their neuroprotective effects against experimental models of cerebral ischemia and Alzheimer’s diseases. Importantly, tanshinone IIA, mostly studied tanshinone for biological activities, is recently reported to attenuate blood-brain barrier permeability among stroke patients, suggesting tanshinone IIA as an appealing therapeutic candidate for neurological diseases. Tanshinone I and IIA are also effective in experimental models of Parkinson’s disease, Multiple sclerosis, and other neuroinflammatory diseases. In addition, several experimental studies suggested the pleiotropic neuroprotective effects of tanshinones such as anti-inflammatory, antioxidant, anti-apoptotic, and BBB protectant further value aiding to tanshinone as an appealing therapeutic strategy in neurological diseases. Therefore, in this review, we aimed to compile the recent updates and cellular and molecular mechanisms of neuroprotection of tanshinone IIA in diverse neurological diseases.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19), is a worldwide pandemic, as declared by the World Health Organization (WHO). It is a respiratory virus that infects people of all ages. Although it may present with mild to no symptoms in most patients, those who are older, immunocompromised, or with multiple comorbidities may present with severe and life-threatening infections. Throughout history, nutraceuticals, such as a variety of phytochemicals from medicinal plants and dietary supplements, have been used as adjunct therapies for many disease conditions, including viral infections. Appropriate use of these adjunct therapies with antiviral proprieties may be beneficial in the treatment and/or prophylaxis of COVID-19. In this review, we provide a comprehensive summary of nutraceuticals, such as vitamins C, D, E, zinc, melatonin, and other phytochemicals and function foods. These nutraceuticals may have potential therapeutic efficacies in fighting the threat of the SARS-CoV-2/COVID-19 pandemic.

Lysophosphatidic acid receptor 1 (LPA1) contributes to brain injury following transient focal cerebral ischemia. However, the mechanism remains unclear. Here, we investigated whether nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation might be an underlying mechanism involved in the pathogenesis of brain injury associated with LPA1 following ischemic challenge with transient middle cerebral artery occlusion (tMCAO). Suppressing LPA1 activity by its antagonist attenuated NLRP3 upregulation in the penumbra and ischemic core regions, particularly in ionized calcium-binding adapter molecule 1 (Iba1)-expressing cells like macrophages of mouse after tMCAO challenge. It also suppressed NLRP3 inflammasome activation, such as caspase-1 activation, interleukin 1&beta, (IL-1&beta, ) maturation, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, in a post-ischemic brain. The role of LPA1 in NLRP3 inflammasome activation was confirmed in vitro using lipopolysaccharide-primed bone marrow-derived macrophages, followed by LPA exposure. Suppressing LPA1 activity by either pharmacological antagonism or genetic knockdown attenuated NLRP3 upregulation, caspase-1 activation, IL-1&beta, maturation, and IL-1&beta, secretion in these cells. Furthermore, nuclear factor-&kappa, B (NF-&kappa, B), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 were found to be LPA1-dependent effector pathways in these cells. Collectively, results of the current study first demonstrate that LPA1 could contribute to ischemic brain injury by activating NLRP3 inflammasome with underlying effector mechanisms.

Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA1) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.

The search for novel therapeutic agents for the management of cerebral ischemia/stroke has become an appealing research interest in the recent past. Neuroprotective phytochemicals as novel stroke drug candidates have recently drawn significant interests from stroke scientists due to their strong brain protective effects in animal stroke models. The underlying mechanism of action is likely owing to their anti-inflammatory properties, even though other mechanisms such as anti-oxidation and vasculoprotection have also been proposed. It is generally held that the early proinflammatory responses after stroke can lead to a secondary brain injury, mainly due to the damaging effect exerted by over-activation of brain resident microglial cells and infiltration of circulating monocytes and macrophages. This review focuses on the anti-inflammatory properties of bioactive phytochemicals, including activation and polarization of microglia/macrophages in the post-ischemic brain. The latest studies in animal stroke models demonstrate that this group of bioactive phytochemicals exerts their anti-inflammatory effects via attenuation of brain proinflammatory microglia and macrophages M1 polarization while promoting anti-inflammatory microglial and macrophages M2 polarization. As a result, stroked animals treated with brain protective phytochemicals have significantly fewer brain active M1 microglia and macrophages, smaller brain infarct volume, better functional recovery, and better survival rate. Therefore, this review provides insights into a new category of drug candidates for stroke drug development by employing neuroprotective phytochemicals.

Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P1-5. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720's efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P1, S1P2, and S1P3, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia.

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1&beta, maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

Tumor necrosis factor-alpha (TNF-α) is a well-known pro-inflammatory cytokine responsible for the modulation of the immune system. TNF-α plays a critical role in almost every type of inflammatory disorder, including central nervous system (CNS) diseases. Although TNF-α is a well-studied component of inflammatory responses, its functioning in diverse cell types is still unclear. TNF-α functions through its two main receptors: tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), also known as p55 and p75, respectively. Normally, the functions of soluble TNF-α-induced TNFR1 activation are reported to be pro-inflammatory and apoptotic. While TNF-α mediated TNFR2 activation has a dual role. Several synthetic drugs used as inhibitors of TNF-α for diverse inflammatory diseases possess serious adverse effects, which make patients and researchers turn their focus toward natural medicines, phytochemicals in particular. Phytochemicals targeting TNF-α can significantly improve disease conditions involving TNF-α with fewer side effects. Here, we reviewed known TNF-α inhibitors, as well as lately studied phytochemicals, with a role in inhibiting TNF-α itself, and TNF-α-mediated signaling in inflammatory diseases focusing mainly on CNS disorders.

Background The pathogenic roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling in cerebral ischemia have been evidenced mainly through the efficacy of FTY720 that binds non-selectively to four of the five S1P receptors (S1P1,3,4,5). Recently, S1P1 and S1P2 were identified as specific receptor subtypes that contribute to brain injury in cerebral ischemia; however, the possible involvement of other S1P receptors remains unknown. S1P3 can be the candidate because of its upregulation in the ischemic brain, which was addressed in this study, along with underlying pathogenic mechanisms. Methods We used transient middle cerebral artery occlusion/reperfusion (tMCAO), a mouse model of transient focal cerebral ischemia. To identify S1P3 as a pathogenic factor in cerebral ischemia, we employed a specific S1P3 antagonist, CAY10444. Brain damages were assessed by brain infarction, neurological score, and neurodegeneration. Histological assessment was carried out to determine microglial activation, morphological transformation, and proliferation. M1/M2 polarization and relevant signaling pathways were determined by biochemical and immunohistochemical analysis. Results Inhibiting S1P3 immediately after reperfusion with CAY10444 significantly reduced tMCAO-induced brain infarction, neurological deficit, and neurodegeneration. When S1P3 activity was inhibited, the number of activated microglia was markedly decreased in both the periischemic and ischemic core regions in the ischemic brain 1 and 3 days following tMCAO. Moreover, inhibiting S1P3 significantly restored the microglial shape from amoeboid to ramified microglia in the ischemic core region 3 days after tMCAO, and it attenuated microglial proliferation in the ischemic brain. In addition to these changes, S1P3 signaling influenced the proinflammatory M1 polarization, but not M2. The S1P3-dependent regulation of M1 polarization was clearly shown in activated microglia, which was affirmed by determining the in vivo activation of microglial NF-κB signaling that is responsible for M1 and in vitro expression levels of proinflammatory cytokines in activated microglia. As downstream effector pathways in an ischemic brain, S1P3 influenced phosphorylation of ERK1/2, p38 MAPK, and Akt. Conclusions This study identified S1P3 as a pathogenic mediator in an ischemic brain along with underlying mechanisms, involving its modulation of microglial activation and M1 polarization, further suggesting that S1P3 can be a therapeutic target for cerebral ischemia.

Microglia regulate immune responses in the brain, and their activation is key to the pathogenesis of diverse neurological diseases. Receptor-mediated lysophosphatidic acid (LPA) signaling has been known to regulate microglial biology, but it is still unclear which receptor subtypes guide the biology, particularly, microglial activation. Here, we investigated the pathogenic aspects of LPA receptor subtype 1 (LPA1) in microglial activation using a systemic lipopolysaccharide (LPS) administration-induced septic mouse model in vivo and LPS-stimulated rat primary microglia in vitro. LPA1 knockdown in the brain with its specific shRNA lentivirus attenuated the sepsis-induced microglia activation, morphological transformation, and proliferation. LPA1 knockdown also resulted in the downregulation of TNF-α, at both mRNA and protein levels in septic brains, but not IL-1β or IL-6. In rat primary microglia, genetic or pharmacological blockade of LPA1 attenuated gene upregulation and secretion of TNF-α in LPS-stimulated cells. In particular, the latter was associated with the suppressed TNF-α converting enzyme (TACE) activity. We reaffirmed these biological aspects using a BV2 microglial cell line in which LPA1 expression was negligible. LPA1 overexpression in BV2 cells led to significant increments in TNF-α production upon stimulation with LPS, whereas inhibiting LPA1 reversed the production. We further identified ERK1/2, but not p38 MAPK or Akt, as the underlying effector pathway after LPA1 activation in both septic brains and stimulated microglia. The current findings of the novel role of LPA1 in microglial activation along with its mechanistic aspects could be applied to understanding the pathogenesis of diverse neurological diseases that involve microglial activation.

Herbal medicines, mainly of plant source, are invaluable source for the discovery of new therapeutic agents for all sorts of human ailments. The complex pathogenesis of stroke and multifactorial effect of herbal medicine and their active constituents may suggest the promising future of natural medicine for stroke treatment. Anti-oxidant, anti-inflammatory, anti-apoptotic, neuroprotective and vascular protective effect of herbal medicines are believed to be efficacious in stroke treatment. Herbs typically have fewer reported side effects than allopathic medicine, and may be safer to use over longer period of time. Herbal medicines are believed to be more effective for the longstanding health complaints, such as stroke. Several medicinal plants and their active constituents show the promising results in laboratory research. However failure in transformation of laboratory animal research to the clinical trials has created huge challenge for the use of herbal medicine in stroke. Until and unless scientifically comprehensive evidence of the efficacy and safety of herbal medicine in ischemic stroke patients is available, efforts should be made to continue implementing treatment strategies of proven effectiveness. More consideration should be paid to natural compounds that can have extensive therapeutic time windows, perfect pharmacological targets with few side effects. Herbal medicine has excellent prospective for the treatment of ischemic stroke, but a lot of effort should be invested to transform the success of animal research to human use.

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.

Matrix metalloproteinases (MMPs) play a pivotal role in neuroinflammation that is associated with neurodegenerative diseases. Our group recently reported that MMP-8 mediates inflammatory reactions by modulating the processing of TNF-α. To improve the efficacy of the currently available MMP-8 inhibitor (M8I), we have synthesized structurally modified M8I derivatives (comp 2, 3, 4, 5) and compared their efficacy with original compound (comp 1). Among M8I derivatives, comp 2, 3, and 5 inhibited the production of NO, ROS, and IL-6 more efficiently than the original compound in lipopolysaccharide (LPS)-stimulated microglia. When we compared the anti-inflammatory mechanisms of the most effective derivative, comp 3, with comp 1, comp 3 suppressed the mRNA expression of iNOS and cytokines more efficiently than comp 1. Although comp 1 inhibits only TNF-α processing, comp 3 additionally inhibits the expression of TNF-α. Both compounds inhibited LPS-induced activity of MAP kinases, NF-κB, and AP-1, while they increased heme oxygenase-1 expression by upregulating AMPK-Nrf2 signaling. Overall, the effect of comp 3 on anti-inflammatory signaling was much stronger than comp 1. We verified the anti-inflammatory effects of comp 1 and 3 in the LPS-injected mouse brain and primary cultured astrocytes. Comp 1 and 3 suppressed microglial activation, astrogliosis, and proinflammatory gene expression in the brain. Moreover, the compounds inhibited proinflammatory gene expression in the cultured astrocytes. Collectively, our data suggest that the MMP-8 inhibitor may be a promising therapeutic agent for neuroinflammatory disorders.

Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P1. In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P1 is pathogenic or neuroprotective. Here, we investigated the involvement of S1P1 along with its role in cerebral ischemia using a transient middle cerebral artery occlusion ("tMCAO") model. Brain damage following tMCAO, as assessed by brain infarction, neurological deficit score, and neural cell death, was reduced by oral administration of AUY954, a selective S1P1 modulator as a functional antagonist, in a therapeutic paradigm, indicating that S1P1 is a pathogenic mediator rather than a neuroprotective mediator. This pathogenic role of S1P1 in cerebral ischemia was reaffirmed because tMCAO-induced brain damage was reduced by genetic knockdown with an intracerebroventricular microinjection of S1P1 shRNA lentivirus into the brain. Genetic knockdown of S1P1 or AUY954 exposure reduced microglial activation, as assessed by reduction in the number of activated microglia and reversed morphology from amoeboid to ramified, and microglial proliferation in ischemic brain. Its role in microglial activation was recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which the mRNA expression level of TNF-α and IL-1β, well-known markers for microglial activation, was reduced in microglia transfected with S1P1 siRNA. These data suggest that the pathogenic role of S1P1 is associated with microglial activation in ischemic brain. Additionally, the pathogenic role of S1P1 in cerebral ischemia appears to be associated with the blood-brain barrier disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, findings from the current study clearly identify S1P1 signaling as a pathogenic factor in transient focal cerebral ischemia, further implicating S1P1 antagonists including functional antagonists as plausible therapeutic agents for human stroke.

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P1) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P1 and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P1 is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P1 was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P1 activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P1 activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P1 in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P1 activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P1 could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P1 activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P1 activation. Overall, these results revealed S1P1-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

Isorhapontigenin (ISO), a tetrahydroxylated stilbenoid, is an analog of resveratrol (Rsv). The various biological activities of Rsv and its derivatives have been previously reported in the context of both cancer and inflammation. However, the anti-cancer effect of ISO against breast cancer has not been well established, despite being an orally bioavailable dietary polyphenol. In this study, we determine the anti-cancer effects of ISO against breast cancer using MCF7, T47D, and MDA-MB-231 cell lines. We observed that ISO induces breast cancer cell death, cell cycle arrest, oxidative stress, and the inhibition of cell proliferation. Additionally, sphingosine kinase inhibition by ISO controlled tubulin polymerization and cancer cell growth by regulating MAPK/PI3K-mediated cell cycle arrest in MCF7 cells. Interestingly, SPHK1/2 gene silencing increased oxidative stress, cell death, and tubulin destabilization in MCF7 cells. This suggests that the anti-cancer effect of ISO can be regulated by SPHK/tubulin destabilization pathways. Overall, ISO successfully induced breast cancer cell death and cell growth arrest, suggesting this phytochemical is a better alternative for breast cancer treatment. Further studies in animal models could confirm the potency and usability of ISO over Rsv for targeting breast cancer, potentially posing an alternative candidate for improved therapy in the near future.

Microglia regulate immune responses in the brain, and their activation is key to the pathogenesis of diverse neurological diseases. Receptor-mediated lysophosphatidic acid (LPA) signaling has been known to regulate microglial biology, but it is still unclear which receptor subtypes guide the biology, particularly, microglial activation. Here, we investigated the pathogenic aspects of LPA receptor subtype 1 (LPA

Microglial activation and its-driven neuroinflammation are characteristic pathogenetic features of neurodiseases, including focal cerebral ischemia. The Artemisia asiatica (Asteraceae) extract and its active component, eupatilin, are well-known to reduce inflammatory responses. But the therapeutic potential of eupatilin against focal cerebral ischemia is not known, along with its anti-inflammatory activities on activated microglia. In this study, we investigated the neuroprotective effect of eupatilin on focal cerebral ischemia through its anti-inflammation, particularly on activated microglia, employing a transient middle cerebral artery occlusion/reperfusion (tMCAO), combined with lipopolysaccharide-stimulated BV2 microglia. Eupatilin exerted anti-inflammatory responses in activated BV2 microglia, in which it reduced secretion of well-known inflammatory markers, including nitrite, IL-6, TNF-α, and PGE2, in a concentration-dependent manner. These observed in vitro effects of eupatilin led to in vivo neuroprotection against focal cerebral ischemia. Oral administration of eupatilin (10 mg/kg) in a therapeutic paradigm significantly reduced brain infarction and improved neurological functions in tMCAO-challenged mice. The same benefit was also observed when eupatilin was given even within 5 hours after MCAO induction. In addition, the neuroprotective effects of a single administration of eupatilin (10 mg/kg) immediately after tMCAO challenge persisted up to 3 days after tMCAO. Eupatilin administration reduced the number of Iba1-immunopositive cells across ischemic brain and induced their morphological changes from amoeboid into ramified in the ischemic core, which was accompanied with reduced microglial proliferation in ischemic brain. Eupatilin suppressed NF-κB signaling activities in ischemic brain by reducing IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation. Overall, these data indicate that eupatilin is a neuroprotective agent against focal cerebral ischemia through the reduction of microglial activation.

Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P

Background Lindera neesiana Kurz (Lauraceae), popularly known as Siltimur in Nepal, is an aromatic and spicy plant with edible fruits. It is a traditional herbal medicine widely used for the treatment of diarrhea, tooth pain, headache, and gastric disorders and is also used as a stimulant. Purpose The aim of the present study was to examine in vitro cytoprotective, anti-neuroinflammatory and neuroprotective potential of an aqueous extract of L. neesiana (LNE) fruit using different central nervous system (CNS) cell lines. Methods In order to study the neuroprotective potential of LNE, we used three different types of CNS cell lines: murine microglia (BV2), rat glioma (C6), and mouse neuroblastoma (N2a). Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent, and prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and nerve growth factor (NGF) release in the culture media was determined using enzyme linked immunosorbent assay (ELISA) kits. Western blot analysis was performed to determine the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), mitogen activated protein kinase (MAPK) family proteins, Bax, B cell lymphoma (BCL)-2, and cleaved caspase 3. Neurite outgrowth was determined using the IncuCyte imaging system. Results LNE treatment not only reduced nitric oxide (NO) production in a dose-dependent manner, but also significantly reduced proinflammatory cytokines, iNOS and COX-2 production by lipopolysaccharide (LPS) stimulated BV-2 cells. LNE increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), whereas p-p38 and p- janus kinase (JNK) expression was significantly decreased in activated microglia. Furthermore, LNE increased cell viability of N2a cells, which was accompanied by decreased caspase-3 expression and the ratio of Bax/Bcl2 protein expression as well as increased NGF and neurite outgrowth, suggesting its neuroprotective potential against LPS-induced effects. Additionally, LNE substantially increased nuclear factor erythroid 2-related factor 2 (Nrf2) secretion in N2a cells and inhibited lipid dehydrogenase (LDH) release in H2O2-stimulated BV2 cells demonstrating the strong anti-inflammatory and antioxidant effects of LNE in CNS cell lines. Conclusion Here we found that water the soluble extract of LNE has promising anti-neuroinflammation and anti-apoptotic properties and identify LNE as a potential natural candidate for neuroprotection.