Development of dietary small molecules as multi-targeting treatment strategies for Alzheimer's disease.

Cognitive dysfunction can occur both in normal aging and age-related neurological disorders, such as mild cognitive impairment and Alzheimer's disease (AD). These disorders have few treatment options due to side effects and limited efficacy. New approaches to slow cognitive decline are urgently needed. Dietary interventions (nutraceuticals) have received considerable attention because they exhibit strong neuroprotective properties and may help prevent or minimize AD symptoms. Biological aging is driven by a series of interrelated mechanisms, including oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy, which function through various signaling pathways. Recent clinical and preclinical studies have shown that dietary small molecules derived from natural sources, including flavonoids, carotenoids, and polyphenolic acids, can modulate oxidative damage, cognitive impairments, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, autophagy dysregulation, and gut microbiota dysbiosis. This paper reviews research on different dietary small molecules and their bioactive constituents in the treatment of AD. Additionally, the chemical structure, effective dose, and specific molecular mechanisms of action are comprehensively explored. This paper also discusses the advantages of using nanotechnology-based drug delivery, which significantly enhances oral bioavailability, safety, and therapeutic effect, and lowers the risk of adverse effects. These agents have considerable potential as novel and safe therapeutic agents that can prevent and combat age-related AD.

The Neuropharmacological Evaluation of Seaweed: A Potential Therapeutic Source.

The most common neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are the seventh leading cause of mortality and morbidity in developed countries. Clinical observations of NDD patients are characterized by a progressive loss of neurons in the brain along with memory decline. The common pathological hallmarks of NDDs include oxidative stress, the dysregulation of calcium, protein aggregation, a defective protein clearance system, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and damage to cholinergic neurons. Therefore, managing this pathology requires screening drugs with different pathological targets, and suitable drugs for slowing the progression or prevention of NDDs remain to be discovered. Among the pharmacological strategies used to manage NDDs, natural drugs represent a promising therapeutic strategy. This review discusses the neuroprotective potential of seaweed and its bioactive compounds, and safety issues, which may provide several beneficial insights that warrant further investigation.

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.

Standardized extract of Glehnia Littoralis abrogates memory impairment and neuroinflammation by regulation of CREB/BDNF and NF-κB/MAPK signaling in scopolamine-induced amnesic mice model.

Mild cognitive impairment is a typical symptom of early Alzheimer's disease (AD). Glehnia littoralis (G. littoralis), a medicinal halophyte plant commonly used to treat strokes, has been shown to possess some therapeutic qualities. In this study, we investigated the neuroprotective and anti-neuroinflammatory effects of a 50% ethanol extract of G. littoralis (GLE) on lipopolysccharide (LPS)-stimulated BV-2 cells and scopolamine-induced amnesic mice. In the in vitro study, GLE treatment (100, 200, and 400 µg/mL) markedly attenuated the translocation of NF-κB to the nucleus concomitantly with the significant mitigation of the LPS-induced production of inflammatory mediators, including NO, iNOS, COX-2, IL-6, and TNF-α. In addition, the GLE treatment suppressed the phosphorylation of MAPK signaling in the LPS-stimulated BV-2 cells. In the in vivo study, mice were orally administered with the GLE (50, 100, and 200 mg/kg) for 14 days, and cognitive loss was induced via the intraperitoneal injection of scopolamine (1 mg/kg) from 8 to 14 days. We found that GLE treatment ameliorated memory impairment and simultaneously improved memory function in the scopolamine-induced amnesic mice. Correspondingly, GLE treatment significantly decreased the AChE level and upregulated the protein expression of neuroprotective markers, such as BDNF and CREB, as well as Nrf2/HO-1 and decreased the levels of iNOS and COX-2 in the hippocampus and cortex. Furthermore, GLE treatment attenuated the increased phosphorylation of NF-κB/MAPK signaling in the hippocampus and cortex. These results suggest that GLE has a potential neuroprotective activity that may ameliorate learning and memory impairment by regulating AChE activity, promoting CREB/BDNF signaling, and inhibiting NF-κB/MAPK signaling and neuroinflammation.

Neuroprotective Effects of Black Pepper and Its Bioactive Compounds in Age-Related Neurological Disorders.

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders whose risk increases with age. The main pathological hallmarks of ANDs include behavioral changes, excessive oxidative stress, progressive functional declines, impaired mitochondrial function, protein misfolding, neuroinflammation, and neuronal cell death. Recently, efforts have been made to overcome ANDs because of their increased age-dependent prevalence. Black pepper, the fruit of Piper nigrum L. in the family Piperaceae, is an important food spice that has long been used in traditional medicine to treat various human diseases. Consumption of black pepper and black pepper-enriched products is associated with numerous health benefits due to its antioxidant, antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective properties. This review shows that black pepper's major bioactive neuroprotective compounds, such as piperine, effectively prevent AND symptoms and pathological conditions by modulating cell survival signaling and death. Relevant molecular mechanisms are also discussed. In addition, we highlight how recently developed novel nanodelivery systems are vital for improving the efficacy, solubility, bioavailability, and neuroprotective properties of black pepper (and thus piperine) in different experimental AND models, including clinical trials. This extensive review shows that black pepper and its active ingredients have therapeutic potential for ANDs.

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.

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.

Ethyl Acetate Fraction from a Catalpa ovata G. Don Extract Inhibits ɑ-MSH-Induced Melanogenesis through the cAMP/CREB Pathway.

The whitening effect of reducing skin pigmentation is one of the most important goals of cosmetics. The purpose of this study was to determine whether Catalpa ovata extract and its fractions have potential as natural skin-lightening agents. Initially, we screened various fractions of Catalpa ovata extract using an in vitro antioxidant assay. Then, the inhibitory effects of C. ovata extract and its fraction on melanogenesis and the related mechanisms were investigated in B16F1 melanoma cells. The results showed that the ethyl acetate fraction (EF) from C. ovata extract markedly inhibited melanin synthesis in a dose-dependent manner at non-toxic concentrations. Furthermore, EF downregulated both the protein and mRNA levels of tyrosinase, which is a specific enzyme that catalyzes the conversion of tyrosine into melanin. We also found that EF decreased the microphthalmia-associated transcription factor (MITF) at the protein and mRNA levels. EF increased the phosphorylation of ERK and suppressed the phosphorylation of JNK and p38 in ɑ-MSH-induced B16F1 cells. These results indicate that EF can regulate the MAPK pathway. In addition, EF has an anti-melanogenic effect via the downregulation of intracellular cyclic-AMP (cAMP). Nineteen major compounds of EF were identified using LC-MS/MS. Taken together, these results suggest that EF may be a potential anti-melanogenic agent for use in skin-whitening cosmetics and in topical treatments for hyperpigmentation disorders.

α-Synuclein upregulates bim-mediated apoptosis by negatively regulating endogenous GCN5.

α-synuclein (αS) is a ß-sheet intracellular protein that has been implicated as a major pathological hallmark of Parkinson's disease (PD). Several studies have shown that overexpression of αS causes dopaminergic cell loss; however, the role of αS in apoptosis remains not fully known. Therefore, this study aims to address the mechanisms of the αS overexpression model in apoptosis and to its correlation with PD pathogenesis. Here, we used a human αS (hαS) plasmid to characterize the role of ectopic αS in neuronal apoptosis in sporadic PD in vitro. We found that overexpression of αS transcriptionally upregulated Bim-mediated apoptosis in neuronal SH-SY5Y cells. Interestingly, αS overexpression inhibited general control non-depressible 5 (GCN5), a histone acetyltransferase (HAT), and promoted transcriptional upregulation of Bim. Consequently, co-overexpression of GCN5 in the αS overexpressed model showed a reversal of αS toxicity in neuronal cells. These in vitro findings support the hypothesis of αS-mediated histone deacetylation and dopaminergic neuronal loss in PD. Moreover, our study indicates that therapeutic activation/homeostasis of GCN5 may benefit PD and other α-synucleinopathies.

Dioscorea nipponica Makino Rhizome Extract and Its Active Compound Dioscin Protect against Neuroinflammation and Scopolamine-Induced Memory Deficits.

Activation of microglial cells by intrinsic or extrinsic insult causes neuroinflammation, a common phenomenon in neurodegenerative diseases. Prevention of neuroinflammation may ameliorate many neurodegenerative disease progressions. Dioscorea nipponica Makino (DN) extract can alleviate muscular atrophy and inflammatory diseases; however, the efficacy and mechanism of action in microglial cells remain unknown. The current study investigates the possible anti-inflammatory effects and mechanisms of Dioscorea nipponica Makino ethanol extract and its steroidal saponin dioscin. Our in vitro study shows that Dioscorea nipponica rhizome ethanol extract (DNRE) and dioscin protect against lipopolysaccharide (LPS)-activated inflammatory responses in BV-2 microglial cells by inhibiting phosphorylation and the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), resulting in the downregulation of pro-inflammatory cytokines and enzymes. Consistent with our previous report of dioscin-mediated enhancement of neurotrophic factors in dopaminergic cells, here we found that dioscin upregulates brain-derived neurotrophic factor (BDNF) and cAMP-response element binding protein (CREB) phosphorylation (pCREB) in the cerebral cortex and hippocampus regions of the mouse brain. Scopolamine treatment increased pro-inflammatory enzyme levels and reduced the expression of BDNF and pCREB in the hippocampus and cortex regions, which led to impaired learning and referencing memory in mice. Pre-treatment of dioscin for 7 days substantially enhanced mice performances in maze studies, indicating amelioration in cognitive deficits. In conclusion, DNRE and its active compound dioscin protect against neurotoxicity most likely by suppressing NF-κB phosphorylation and upregulating neurotrophic factor BDNF.

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.

Group I mGluRs in Therapy and Diagnosis of Parkinson's Disease: Focus on mGluR5 Subtype.

Metabotropic glutamate receptors (mGluRs; members of class C G-protein-coupled receptors) have been shown to modulate excitatory neurotransmission, regulate presynaptic extracellular glutamate levels, and modulate postsynaptic ion channels on dendritic spines. mGluRs were found to activate myriad signalling pathways to regulate synapse formation, long-term potentiation, autophagy, apoptosis, necroptosis, and pro-inflammatory cytokines release. A notorious expression pattern of mGluRs has been evident in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia. Among the several mGluRs, mGluR5 is one of the most investigated types of considered prospective therapeutic targets and potential diagnostic tools in neurodegenerative diseases and neuropsychiatric disorders. Recent research showed mGluR5 radioligands could be a potential tool to assess neurodegenerative disease progression and trace respective drugs' kinetic properties. This article provides insight into the group I mGluRs, specifically mGluR5, in the progression and possible therapy for PD.

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.

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.

Piperine and Its Metabolite's Pharmacology in Neurodegenerative and Neurological Diseases.

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood-brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP's limitations, including bioavailability and blood-brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

Targeting α-synuclein aggregation and its role in mitochondrial dysfunction in Parkinson's disease.

Lewy bodies that contain aggregated α-synuclein in dopamine neurons are the main culprit for neurodegeneration in Parkinson's disease. However, mitochondrial dysfunction has a well-established and prominent role in the pathogenesis of Parkinson's disease. The exact mechanism by which α-synuclein causes dopamine neuronal loss is unclear. Recent evidence suggests that aggregated α-synuclein localises in the mitochondria contributes to oxidative stress-mediated apoptosis in neurons. Therefore, the involvement of aggregated α-synuclein in mitochondrial dysfunction-mediated neuronal loss has made it an emerging drug target for the treatment of Parkinson's disease. However, the exact mechanism by which α-synuclein permeabilises through the mitochondrial membrane and affects the electron transport chain remains under investigation. In the present study, we describe mitochondria-α-synuclein interactions and how α-synuclein aggregation modulates mitochondrial homeostasis in Parkinson's disease pathogenesis. We also discuss recent therapeutic interventions targeting α-synuclein aggregation that may help researchers to design novel therapeutic treatments for Parkinson's disease.

Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.

BACKGROUND: Nanoparticles have been utilized in brain research and therapeutics, including imaging, diagnosis, and drug delivery, owing to their versatile properties compared to bulk materials. However, exposure to nanoparticles leads to their accumulation in the brain, but drug development to counteract this nanotoxicity remains challenging. To date, concerns have risen about the potential toxicity to the brain associated with nanoparticles exposure via penetration of the brain blood barrier to address this issue. METHODS: Here the effect of silica-coated-magnetic nanoparticles containing the rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO2(RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO2(RITC) using transmission electron microscopy, and glucose uptake efficiency, were analyzed in BV2 murine microglial cells. Each omics data was collected via RNA-sequencing-based transcriptome analysis, liquid chromatography-tandem mass spectrometry-based proteome analysis, and gas chromatography- tandem mass spectrometry-based metabolome analysis. The three omics datasets were integrated and generated as a single network using a machine learning algorithm. Nineteen compounds were screened and predicted their effects on nanotoxicity within the triple-omics network. RESULTS: Intracellular reactive oxygen species production, an inflammatory response, and morphological activation of cells were greater, but glucose uptake was lower in MNPs@SiO2(RITC)-treated BV2 microglia and primary rat microglia in a dose-dependent manner. Expression of 121 genes (from 41,214 identified genes), and levels of 45 proteins (from 5918 identified proteins) and 17 metabolites (from 47 identified metabolites) related to the above phenomena changed in MNPs@SiO2(RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO2(RITC) and ten other nanoparticles in vitro and in the murine brain, protecting mostly the hippocampus and thalamus. CONCLUSIONS: Combination of glutathione and citrate can be one of the candidates for nanotoxicity alleviating drug against MNPs@SiO2(RITC) induced detrimental effect, including elevation of intracellular reactive oxygen species level, activation of microglia, and reduction in glucose uptake efficiency. In addition, our findings indicate that an integrated triple omics approach provides useful and sensitive toxicological assessment for nanoparticles and screening of drug for nanotoxicity.

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.

The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration.

Ageing is an inevitable event in the lifecycle of all organisms, characterized by progressive physiological deterioration and increased vulnerability to death. Ageing has also been described as the primary risk factor of most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and frontotemporal lobar dementia (FTD). These neurodegenerative diseases occur more prevalently in the aged populations. Few effective treatments have been identified to treat these epidemic neurological crises. Neurodegenerative diseases are associated with enormous socioeconomic and personal costs. Here, the pathogenesis of AD, PD, and other neurodegenerative diseases has been presented, including a summary of their known associations with the biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communications. Understanding the central biological mechanisms that underlie ageing is important for identifying novel therapeutic targets for neurodegenerative diseases. Potential therapeutic strategies, including the use of NAD+ precursors, mitophagy inducers, and inhibitors of cellular senescence, has also been discussed.

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.