Synthesis of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2-dione analogues and their inhibitory activities with reduced cytotoxicity in lipopolysaccharide-induced BV2 cells.

A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC50 = 4.71 ±â€¯0.11 µM) showed significantly higher inhibitory activity than rimonabant (IC50 = 16.17 ±â€¯0.56 µM), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases.

Synthesis of 1-(4-(dimethylamino)phenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione analogues and their anti-inflammatory activities in lipopolysaccharide-induced BV2 cells.

A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC50 = 7.1 µM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC50 > 50 µM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases.

Isolation, Structure Determination, and Semisynthesis of Diphenazine Compounds from a Deep-Sea-Derived Strain of the Fungus Cystobasidium laryngis and Their Biological Activities.

Phenazostatins E-J (1-6), six new diphenazine derivatives, were isolated from the EtOAc extract of the culture broth of a strain of Cystobasidium laryngis derived from deep-sea sediments of the Indian Ocean Ridge. The structures of 1-6 were elucidated based on the HRESIMS and 1D and 2D NMR spectra. The absolute configurations of 1-6, except for 3 and 6, were determined by modified Mosher's method, ECD data analysis, and calculations of optical rotation values. The absolute configurations of 3 and 6 were identified by chemical derivatization and comparing the specific rotation values with those of semisynthetic 3 obtained by the oxidation of 1 and saphenic acid (7). Phenazostatin J (6) was semisynthesized using saphenic acid (7) to prepare additional material for biological testing. During the purification of semisynthetic 6, a side product 9 was obtained from the reaction mixture along with 6. Compounds 1-6, along with previously reported 7 and 8, were assessed for anti-neuroinflammatory activity in LPS-induced BV-2 microglia cells. Compound 6 exhibited the highest anti-neuroinflammatory effect with an IC50 value of 0.30 µM, but it showed cytotoxicity at higher concentrations than 1.0 µM. Accordingly, cytotoxicities of 1-9 were evaluated against six human cancer cell lines. Among tested compounds, 6 and 9 showed potent cytotoxicity (IC50 values: 7.7-72 nM). Especially, 6 exhibited the strongest cytotoxicity with an IC50 value of 7.7 nM against the NUGC-3 (stomach) cell line, displaying 19-fold stronger activity than the positive control, adriamycin.

Dioscin-Mediated Autophagy Alleviates MPP+-Induced Neuronal Degeneration: An In Vitro Parkinson's Disease Model.

Autophagy is a cellular homeostatic process by which cells degrade and recycle their malfunctioned contents, and impairment in this process could lead to Parkinson's disease (PD) pathogenesis. Dioscin, a steroidal saponin, has induced autophagy in several cell lines and animal models. The role of dioscin-mediated autophagy in PD remains to be investigated. Therefore, this study aims to investigate the hypothesis that dioscin-regulated autophagy and autophagy-related (ATG) proteins could protect neuronal cells in PD via reducing apoptosis and enhancing neurogenesis. In this study, the 1-methyl-4-phenylpyridinium ion (MPP+) was used to induce neurotoxicity and impair autophagic flux in a human neuroblastoma cell line (SH-SY5Y). The result showed that dioscin pre-treatment counters MPP+-mediated autophagic flux impairment and alleviates MPP+-induced apoptosis by downregulating activated caspase-3 and BCL2 associated X, apoptosis regulator (Bax) expression while increasing B-cell lymphoma 2 (Bcl-2) expression. In addition, dioscin pre-treatment was found to increase neurotrophic factors and tyrosine hydroxylase expression, suggesting that dioscin could ameliorate MPP+-induced degeneration in dopaminergic neurons and benefit the PD model. To conclude, we showed dioscin's neuroprotective activity in neuronal SH-SY5Y cells might be partly related to its autophagy induction and suppression of the mitochondrial apoptosis pathway.

The GCN5: its biological functions and therapeutic potentials.

General control non-depressible 5 (GCN5) or lysine acetyltransferase 2A (KAT2A) is one of the most highly studied histone acetyltransferases. It acts as both histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). As an HAT it plays a pivotal role in the epigenetic landscape and chromatin modification. Besides, GCN5 regulates a wide range of biological events such as gene regulation, cellular proliferation, metabolism and inflammation. Imbalance in the GCN5 activity has been reported in many disorders such as cancer, metabolic disorders, autoimmune disorders and neurological disorders. Therefore, unravelling the role of GCN5 in different diseases progression is a prerequisite for both understanding and developing novel therapeutic agents of these diseases. In this review, we have discussed the structural features, the biological function of GCN5 and the mechanical link with the diseases associated with its imbalance. Moreover, the present GCN5 modulators and their limitations will be presented in a medicinal chemistry perspective.

Synthesis of 4-(3-oxo-3-phenylpropyl)morpholin-4-ium chloride analogues and their inhibitory activities of nitric oxide production in lipopolysaccharide-induced BV2 cells.

Based on our previous report that 3-morpholino-1-phenylpropan-1-one 2, one of the fluoxetine's simplified morpholino analogue, inhibited nitric oxide (NO) production, in this paper, various substituted benzene analogues with morpholine hydrochloride of 2 were synthesized and their inhibitory effects on NO production in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 2-trifluoromethyl analogue 16n (IC50 = 8.6 µM) showed a significantly higher inhibitory activity than that of the parent compound 2a (IC50 > 50 µM) and suppressed NO production dose-dependently without cytotoxicity. Compound 16n also inhibited iNOS expression in LPS-induced BV2 cells at 2, 10 and 20 µM concentrations. These results suggest that compound 16n inhibited NO production by suppressing the expression of iNOS and can be used as a lead structure for developing new inhibitor of NO production.

Synthesis and Biological Evaluation of Salicylic Acid Analogues of Celecoxib as a New Class of Selective Cyclooxygenase-1 Inhibitor.

A series of salicylic acid analogues of celecoxib where the phenylsulfonamide moiety in the structure of celecoxib is replaced by salicylic acid moiety was synthesized and tested for in vitro cyclooxygenase (COX)-1 and COX-2 enzyme inhibition. Among the series, 5-substituted-2-hydroxy-benzoic acid analogues (7a-7h) generally showed better inhibitory activities on both enzymes than 4-substituted-2-hydroxy-benzoic acid analogues (12a-12h). In particular, the chloro analogue 7f which had the highest inhibitory effect (IC50 = 0.0057 µM) to COX-1 with excellent COX-1 selectivity (SI = 768) can be classified as a new potent and selective COX-1 inhibitor. The high inhibitory potency of 7f was rationalized through the docking simulation of this analogue in the active site of COX-1 enzyme.

Two New Phomaligols from the Marine-Derived Fungus Aspergillus flocculosus and Their Anti-Neuroinflammatory Activity in BV-2 Microglial Cells.

Two new phomaligols, deketo-phomaligol A (1) and phomaligol E (2), together with six known compounds (3-8) were isolated from the culture broth of the marine-derived fungus Aspergillus flocculosus. Compound 1 was first isolated as a phomaligol derivative possessing a five-membered ring. The structures and absolute configurations of the new phomaligols were determined by detailed analyses of mass spectrometry (MS), nuclear magnetic resonance (NMR) data, optical rotation values and electronic circular dichroism (ECD). In addition, the absolute configurations of the known compounds 3 and 4 were confirmed by chemical oxidation and comparison of optical rotation values. Isolated compounds at a concentration of 100 µM were screened for inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Among the compounds, 4 showed moderate anti-neuroinflammatory effects with an IC50 value of 56.6 µM by suppressing the production of pro-inflammatory mediators in activated microglial cells without cytotoxicity.

The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson's Disease.

The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test-assessed motor performance and improved Y-maze test-assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.

Mitigating Effect of Lindera obtusiloba Blume Extract on Neuroinflammation in Microglial Cells and Scopolamine-Induced Amnesia in Mice.

Lindera obtusiloba Blume (family, Lauraceae), native to Northeast Asia, has been used traditionally in the treatment of trauma and neuralgia. In this study, we investigated the neuroinflammatory effect of methanol extract of L. obtusiloba stem (LOS-ME) in a scopolamine-induced amnesia model and lipopolysaccharide (LPS)-stimulated BV2 microglia cells. LOS-ME downregulated the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, inflammatory cytokines, and inhibited the phosphorylation of nuclear factor kappa-B (NF-ĸB) and extracellular signal-regulated kinase (ERK) in LPS-stimulated BV2 cells. Male C57/BL6 mice were orally administered 20 and 200 mg/kg of LOS-ME for one week, and 2 mg/kg of scopolamine was administered intraperitoneally on the 8th day. In vivo behavioral experiments (Y-maze and Morris water maze test) confirmed that LOS-ME alleviated cognitive impairments induced by scopolamine and the amount of iNOS expression decreased in the hippocampus of the mouse brain. Microglial hyper-activation was also reduced by LOS-ME pretreatment. These findings suggest that LOS-ME might have potential in the treatment for cognitive improvement by regulating neuroinflammation.

New Polyenes from the Marine-Derived Fungus Talaromyces cyanescens with Anti-Neuroinflammatory and Cytotoxic Activities.

Three new polyene compounds, talacyanols A-C (1-3), along with two known compounds, ramulosin (4) and eurothiocin A (5), were isolated from the marine fungus Talaromyces cyanescens derived from a seaweed Caulerpa sp. Structures of 1-5 were established by one-dimensional and two-dimensional (1D/2D) NMR, HR-ESIMS, and the modified Mosher's methods, as well as comparison with previously reported literature data. All the compounds (1-5) were tested for their in vitro cytotoxic and anti-neuroinflammatory activities. Among them, 1 showed moderate cytotoxic activity against a panel of cancer cell lines (HCT-15, NUGC-3, NCI-H23, ACHN, PC-3, and MDA-MB-231) with GI50 values ranging from 44.4 to 91.6 µM, whereas compounds 2 and 5 exhibited anti-neuroinflammatory effect without cytotoxicity against all the tested cell lines.

Comparative Studies on Behavioral, Cognitive and Biomolecular Profiling of ICR, C57BL/6 and Its Sub-Strains Suitable for Scopolamine-Induced Amnesic Models.

Cognitive impairment and behavioral disparities are the distinctive baseline features to investigate in most animal models of neurodegenerative disease. However, neuronal complications are multifactorial and demand a suitable animal model to investigate their underlying basal mechanisms. By contrast, the numerous existing neurodegenerative studies have utilized various animal strains, leading to factual disparity. Choosing an optimal mouse strain for preliminary assessment of neuronal complications is therefore imperative. In this study, we systematically compared the behavioral, cognitive, cholinergic, and inflammatory impairments of outbred ICR and inbred C57BL/6 mice strains subject to scopolamine-induced amnesia. We then extended this study to the sub-strains C57BL/6N and C57BL/6J, where in addition to the above-mentioned parameters, their endogenous antioxidant levels and cAMP response-element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) protein expression were also evaluated. Compared with the ICR strain, the scopolamine-inflicted C57BL/6 strains exhibited a substantial reduction of spontaneous alternation and an approximately two-fold increase in inflammatory protein expression, compared to the control group. Among the sub-strains, scopolamine-treated C57BL/6N strains exhibited declined step-through latency, elevated acetylcholinesterase (AChE) activity and inflammatory protein expression, associated with reduced endogenous antioxidant levels and p-CREB/BDNF expression, compared to the control and tacrine-treated groups. This indicates that the C57BL/6N strains exhibit significantly enhanced scopolamine-induced neuronal impairment compared to the other evaluated strains.

Toxin-Induced Experimental Models of Learning and Memory Impairment.

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-ß are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson's disease dementia and Alzheimer's disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.

Scoparone Inhibits LPS-Simulated Inflammatory Response by Suppressing IRF3 and ERK in BV-2 Microglial Cells.

Microglia activation and the release of various inflammatory cytokines are largely related to neurological diseases, including Parkinson's, Alzheimer's, and other brain diseases. The suppression of microglial cells using natural bioactive compounds has become increasingly important for brain therapy owing to the expected beneficial effect of lower toxicity. Scoparone (6,7-dimethoxycoumarin), a major bioactive compound found in various plant parts, including the inner shell of chestnut (Castanea crenata), was evaluated on lipopolysaccharide (LPS)-activated BV-2 microglia cells. The results indicated that scoparone suppresses the LPS-stimulated increase of neuroinflammatory responses and inhibited the pro-inflammatory cytokine production in the BV-2 microglial cells. A mechanistic study showed that scoparone specifically inhibited the LPS-stimulated activation via a major regulation of IRF-3 and a regulation of ERK, whereby the phosphorylation in the BV-2 microglial cells is blocked. These data suggest that scoparone has anti-neuroinflammatory effects in LPS-activated BV-2 microglial cells, and could possibly be used in the development of novel drugs for the prevention and treatment of neuroinflammatory diseases.

AD-1 Small Molecule Improves Learning and Memory Function in Scopolamine-Induced Amnesic Mice Model through Regulation of CREB/BDNF and NF-κB/MAPK Signaling Pathway.

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of AD-1 small molecule, we here explored the possible underlying mechanisms of the protective effect of AD-1 small molecule against scopolamine-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, scopolamine administration resulted in increased AChE activity, MDA levels, and decreased antioxidant enzymes, as well as the downregulation of the antioxidant response proteins of Nrf2 and HO-1 expression; however, treatment with AD-1 small molecule mitigated the generation of oxidant factors while restoring the antioxidant enzymes status, in addition to improving antioxidant protein levels. Similarly, AD-1 small molecule significantly increased the protein expression of neuroprotective markers such as BDNF and CREB and promoted memory processes in scopolamine-induced mice. Western blot analysis showed that AD-1 small molecule reduced activated microglia and astrocytes via the attenuation of iba-1 and GFAP protein expression. We also found that scopolamine enhanced the phosphorylation of NF-κB/MAPK signaling and, conversely, that AD-1 small molecule significantly inhibited the phosphorylation of NF-κB/MAPK signaling in the brain regions of hippocampus and cortex. We further found that scopolamine promoted neuronal loss by inducing Bax and caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, AD-1 small molecule significantly decreased the levels of apoptotic markers and increased neuronal survival. Furthermore, AD-1 small molecule ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. These findings revealed that AD-1 small molecule attenuated scopolamine-induced cognitive and memory dysfunction by ameliorating AChE activity, oxidative brain damage, neuroinflammation, and neuronal apoptosis.

Molecular Mechanisms and Therapeutic Potential of α- and ß-Asarone in the Treatment of Neurological Disorders.

Neurological disorders are important causes of morbidity and mortality around the world. The increasing prevalence of neurological disorders, associated with an aging population, has intensified the societal burden associated with these diseases, for which no effective treatment strategies currently exist. Therefore, the identification and development of novel therapeutic approaches, able to halt or reverse neuronal loss by targeting the underlying causal factors that lead to neurodegeneration and neuronal cell death, are urgently necessary. Plants and other natural products have been explored as sources of safe, naturally occurring secondary metabolites with potential neuroprotective properties. The secondary metabolites α- and ß-asarone can be found in high levels in the rhizomes of the medicinal plant Acorus calamus (L.). α- and ß-asarone exhibit multiple pharmacological properties including antioxidant, anti-inflammatory, antiapoptotic, anticancer, and neuroprotective effects. This paper aims to provide an overview of the current research on the therapeutic potential of α- and ß-asarone in the treatment of neurological disorders, particularly neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), as well as cerebral ischemic disease, and epilepsy. Current research indicates that α- and ß-asarone exert neuroprotective effects by mitigating oxidative stress, abnormal protein accumulation, neuroinflammation, neurotrophic factor deficit, and promoting neuronal cell survival, as well as activating various neuroprotective signalling pathways. Although the beneficial effects exerted by α- and ß-asarone have been demonstrated through in vitro and in vivo animal studies, additional research is required to translate laboratory results into safe and effective therapies for patients with AD, PD, and other neurological and neurodegenerative diseases.

Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson's Disease: Current Knowledge and Future Perspectives.

Parkinson's disease (PD) is the second-most common neurodegenerative chronic disease affecting both cognitive performance and motor functions in aged people. Yet despite the prevalence of this disease, the current therapeutic options for the management of PD can only alleviate motor symptoms. Research has explored novel substances for naturally derived antioxidant phytochemicals with potential therapeutic benefits for PD patients through their neuroprotective mechanism, targeting oxidative stress, neuroinflammation, abnormal protein accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, neurotrophic factor deficit, and apoptosis. The aim of the present study is to perform a comprehensive evaluation of naturally derived antioxidant phytochemicals with neuroprotective or therapeutic activities in PD, focusing on their neuropharmacological mechanisms, including modulation of antioxidant and anti-inflammatory activity, growth factor induction, neurotransmitter activity, direct regulation of mitochondrial apoptotic machinery, prevention of protein aggregation via modulation of protein folding, modification of cell signaling pathways, enhanced systemic immunity, autophagy, and proteasome activity. In addition, we provide data showing the relationship between nuclear factor E2-related factor 2 (Nrf2) and PD is supported by studies demonstrating that antiparkinsonian phytochemicals can activate the Nrf2/antioxidant response element (ARE) signaling pathway and Nrf2-dependent protein expression, preventing cellular oxidative damage and PD. Furthermore, we explore several experimental models that evaluated the potential neuroprotective efficacy of antioxidant phytochemical derivatives for their inhibitory effects on oxidative stress and neuroinflammation in the brain. Finally, we highlight recent developments in the nanodelivery of antioxidant phytochemicals and its neuroprotective application against pathological conditions associated with oxidative stress. In conclusion, naturally derived antioxidant phytochemicals can be considered as future pharmaceutical drug candidates to potentially alleviate symptoms or slow the progression of PD. However, further well-designed clinical studies are required to evaluate the protective and therapeutic benefits of phytochemicals as promising drugs in the management of PD.

Dendropanax Morbiferus and Other Species from the Genus Dendropanax: Therapeutic Potential of Its Traditional Uses, Phytochemistry, and Pharmacology.

The Dendropanax genus is a kind of flowering plant in the family of Araliaceae that encompasses approximately 91 to 95 species. Several Dendropanax species are used as traditional medicinal plants, extensively used Korea and South America and other parts of the world. Almost every part of the plant, including the leaves, bark, roots, and stems, can be used as traditional medicine for the prevention and management of a broad spectrum of health disorders. This paper sought to summarizes the ethnopharmacological benefits, biological activities, and phytochemical investigations of plants from the genus Dendropanax, and perhaps to subsequently elucidate potential new perspectives for future pharmacological research to consider. Modern scientific literature suggests that plants of the Dendropanax genus, together with active compounds isolated from it, possess a wide range of therapeutic and pharmacological applications, including antifungal, anti-complement, antioxidant, antibacterial, insect antifeedant, cytotoxic, anti-inflammatory, neuroprotective, anti-diabetic, anti-cancer, and anti-hypouricemic properties. The botanical descriptions of approximately six to 10 species are provided by different scientific web sources. However, only six species, namely, D. morbiferus, D. gonatopodus, D. dentiger, D. capillaris, D. chevalieri, and D. arboreus, were included in the present investigation to undergo phytochemical evaluation, due to the unavailability of data for the remaining species. Among these plant species, a high concentration of variable bioactive ingredients was identified. In particular, D. morbifera is a traditional medicinal plant used for the multiple treatment purposes and management of several human diseases or health conditions. Previous experimental evidence supports that the D. morbifera species could be used to treat various inflammatory disorders, diarrhea, diabetes, cancer, and some microbial infections. It has recently been reported, by our group and other researchers, that D. morbifera possesses a neuroprotective and memory-enhancing agent. A total of 259 compounds have been identified among six species, with 78 sourced from five of these species reported to be bioactive. However, there is no up-to-date information concerning the D. morbifera, its different biological properties, or its prospective benefits in the enhancement of human health. In the present study, we set out to conduct a comprehensive analysis of the botany, traditional medicinal history, and medicinal resources of species of the Dendropanax genus. In addition, we explore several phytochemical constituents identified in different species of the Dendropanax genus and their biological properties. Finally, we offer comprehensive analysis findings of the phytochemistry, medicinal uses, pharmacological actions, and a toxicity and safety evaluation of the D. morbifera species and its main bioactive ingredients for future consideration.

2-(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-N-(2-hydroxyethyl)-2-oxoacetamide (CDMPO) has anti-inflammatory properties in microglial cells and prevents neuronal and behavioral deficits in MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by the selective loss of nigrostriatal dopamine neurons associated with microglial activation. Inhibition of the inflammatory response elicited by activated microglia could be an effective strategy to alleviate the progression of PD. Here, we synthesized 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-N-(2-hydroxyethyl)-2-oxoacetamide (CDMPO) and studied its protective anti-inflammatory mechanisms following lipopolysaccharide (LPS)-induced neuroinflammation in vitro and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo. CDMPO and its parent compound, rimonabant, significantly attenuated nitric oxide (NO) production in LPS-stimulated primary microglia and BV2 cells. Furthermore, CDMPO significantly inhibited the release of proinflammatory cytokines and prostaglandin E2 (PGE2) by activated BV2 cells, also suppressed expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Mechanistically, CDMPO attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB), inhibitor of kappa B alpha (IκBα), and p38 phosphorylation in BV2 cells. MPTP intoxication of mice results in glial activation, tyrosine hydroxylase (TH) depletion, and significant behavioral deficits. Prophylactic treatment with CDMPO decreased proinflammatory molecules via NF-κB and p38 mitogen-activated protein kinase signaling, resulting in protection of dopaminergic neurons and improved behavioral impairments. These results suggest that CDMPO is a promising neuroprotective agent for the prevention and treatment of microglia-mediated neuroinflammatory conditions and may be useful for behavioral improvement in PD phenotype.

The Methanol Extract of Allium cepa L. Protects Inflammatory Markers in LPS-Induced BV-2 Microglial Cells and Upregulates the Antiapoptotic Gene and Antioxidant Enzymes in N27-A Cells.

Neuroinflammation, apoptosis, and oxidative stress are connected to the pathogenesis of neurodegenerative diseases (NDDs). Targeting these three factors, the intervention of neuroprotective agents may have great potential in the treatment of NDDs. In the current study, the anti-inflammatory effects of the methanol extract of Allium cepa (MEAC) in lipopolysaccharide (LPS)-induced BV-2 microglial cells were investigated. MEAC has been studied in regard to the regulation of the antiapoptotic gene (Bcl-2) and various antioxidant enzyme (HO-1, NQO-1, and catalase) expressions in N27-A cells. Additionally, the protective action of MEAC has also been studied against MPP+-induced death in N27-A cells. The results suggest that MEAC is significantly protected from NO release and increase iNOS expression at the mRNA and protein levels in LPS-stimulated BV-2 microglial cells. MEAC treatment also protects COX-2 expression at the mRNA and protein levels. Furthermore, MEAC treatment prevents LPS-stimulated increases of proinflammatory cytokines, including TNF-α, IL-6, and IL-1ß. In N27-A cells, MEAC treatment significantly upregulates antiapoptotic gene (Bcl-2) and antioxidant enzyme (HO-1, NQO1, and catalase) expressions. Moreover, MEAC treatment protects against MPP+-induced death in N27-A cells. To conclude, A cepa extract takes protective action against LPS and MPP+, and upregulates the antioxidant enzymes that could potentially be used in the therapy of NDDs.