Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell ...migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.
Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell ...migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only
-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.
The coronavirus disease 2019 (COVID-19) pandemic has increased the already high levels of stress that higher education students experience. Stress influences health behaviors, including those related ...to dietary behaviors, alcohol, and sleep; yet the effects of stress can be mitigated by resilience. To date, past research studying the connections between dietary behaviors, alcohol misuse, sleep, and resilience commonly investigated singular relationships between two of the constructs. The aim of the current study was to explore the relationships between these constructs in a more holistic manner using mediation and moderation analyses.
Higher education students from China, Ireland, Malaysia, South Korea, Taiwan, the Netherlands, and the United States were enrolled in a cross-sectional study from April to May 2020, which was during the beginning of the COVID-19 pandemic for most participants. An online survey, using validated tools, was distributed to assess perceived stress, dietary behaviors, alcohol misuse, sleep quality and duration, and resilience.
2254 students completed the study. Results indicated that sleep quality mediated the relationship between perceived stress and dietary behaviors as well as the relationship between perceived stress and alcohol misuse. Further, increased resilience reduced the strength of the relationship between perceived stress and dietary behaviors but not alcohol misuse.
Based on these results, higher education students are likely to benefit from sleep education and resilience training, especially during stressful events.
Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer's disease (AD). In the present study, we investigated the effect of
...-((3,4-dihydro-2H-benzohchromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive
-methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or
-methyl-d-aspartate (NMDA)-induced excitotoxic cell damage. The IC
value of BL-M against NMDA toxicity was comparable to that of memantine. BL-M potently inhibited intracellular reactive oxygen species generated by glutamate or NMDA. Additionally, it inhibited the formation of 1,1-diphenyl-2-picryl-hydrazyl radicals in vitro and lipid peroxidation in rat brain homogenates. In contrast, memantine showed minimal or negligible antioxidant activity. Western blotting and immunocytochemical analyses showed that BL-M, not memantine, increased the ERK1/2 phosphorylation and subsequent phosphorylation of cAMP response element-binding protein (CREB). The inhibition of NMDA toxicity by BL-M was dramatically reversed by U0126, a well-known MEK inhibitor, suggesting that ERK1/2-mediated CREB phosphorylation is required for the neuroprotective action. Collectively, in this study, we demonstrated the neuroprotective effect of a newly synthesized chromene derivative BL-M and its underlying action mechanism(s). In contrast to memantine, BL-M exhibited marked antioxidant activity. Furthermore, it enhanced the ERK-mediated phosphorylation of CREB, which plays a crucial neuroprotective role. Our findings suggest that BL-M may be beneficial for AD and other neurodegenerative disorders associated with excitotoxicity as well as oxidative stress.
Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing ...interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo3,4-
quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.
Microglial activation is known to cause inflammation resulting in neurotoxicity in several neurological diseases. N-((3,4-Dihydro-2H-benzohchromene-2-yl)methyl)-4-methoxyaniline (BL-M), a chromene ...derivative, was originally synthesized with the perspective of inhibiting nuclear factor-kappa B (NF-κB), a key regulator of inflammation. The present study evaluated the antioxidant and anti-inflammatory potential of BL-M in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Our results demonstrated that BL-M significantly inhibited the formation of 1,1-diphenyl-2-picrylhydrazyl radicals, as well as lipid peroxidation in rat brain homogenate in a concentration-dependent manner. In addition, it suppressed the generation of intracellular reactive oxygen species, and the levels of pro-inflammatory mediators including nitric oxide, tumor necrosis factor-α, and interleukin-6 in LPS-induced BV2 cells. Western blotting analyses revealed the inhibition of inhibitor of kappa B alpha (IκBα) phosphorylation and NF-κB translocation by BL-M in LPS-activated cells. Therefore, our study highlights marked antioxidant and anti-inflammatory activities of BL-M, and suggests that this compound may have a beneficial impact on various neurodegenerative diseases associated with inflammation.
Organocatalysts are abundantly used for various transformations, particularly to obtain highly enantio- and diastereomeric pure products by controlling the stereochemistry. These applications of ...organocatalysts have been the topic of several reviews. Organocatalysts have emerged as one of the very essential areas of research due to their mild reaction conditions, cost-effective nature, non-toxicity, and environmentally benign approach that obviates the need for transition metal catalysts and other toxic reagents. Various types of organocatalysts including amine catalysts, Brønsted acids, and Lewis bases such as N-heterocyclic carbene (NHC) catalysts, cinchona alkaloids, 4-dimethylaminopyridine (DMAP), and hydrogen bond-donating catalysts, have gained renewed interest because of their regioselectivity. In this review, we present recent advances in regiodivergent reactions that are governed by organocatalysts. Additionally, we briefly discuss the reaction pathways of achieving regiodivergent products by changes in conditions such as solvents, additives, or the temperature.
Although death is inevitable as a human being, talking about or planning for it may be an uncomfortable topic. Recently, due to the COVID-19 pandemic, we are witnessing an increase in deaths around ...us as well as globally, and health and social services professionals are more engaged in the death, dying, and bereavement services than ever. Dr. Eyetsemitan's book, Death, Dying, and Bereavement Around the World: Theories, Varied Views and Customs, would be a great textbook assisting health and social service professionals and students at both undergraduate and graduate levels to understand the concepts of death, dying, and bereavement across cultures. Additional relevant grief theories/models, diverse views, and customs/rituals in losses and grief provide useful supporting information.
A metal‐free, one‐pot synthesis of 1,2‐naphthoquinone was accomplished from 2‐naphthol by utilizing economically cheap NBS under open air conditions. Initial formation of 1,1‐dibromonaphthalen‐2‐one ...and subsequent transformation afforded the 1,2‐naphthoquinone. This oxidation was completed within 30 min and had broad substrate scope. Moreover, this system tolerated heterocyclic systems and was also applicable to 1,3‐dicarbonyl systems. This practical approach with short reaction times, a simple workup, and insensitivity to moisture could override the usage of expensive and hazardous oxidizing and metal reagents.
Obesity is a growing epidemic among university students, and the high levels of stress reported by this population could contribute to this issue. Singular relationships between perceived stress; ...engagement in restrained, uncontrolled, and emotional eating; sleep; dietary risk; and body mass index (BMI) have been reported in the current body of literature; however, these constructs interact with each other, and the complex relationships among them are infrequently examined. Therefore, the aim of the present study was to explore the complex relationships between these constructs using mediation and moderation analyses stratified by gender.
A cross-sectional study, enrolling university students from the United States (U.S.), the Netherlands, South Korea, Malaysia, Ireland, Ghana, and China, was conducted between October 2020 and January 2021 during the COVID-19 pandemic. Perceived stress; maladaptive eating behaviors including restrained, uncontrolled, and emotional eating; sleep duration and quality; dietary risk; and BMI were assessed using validated questionnaires, which were distributed through an online platform.
A total of 1392 students completed the online survey (379 male, 973 female, and 40 who self-identified as "other"). Uncontrolled and emotional eating mediated the relationship between perceived stress and dietary risk for both males and females; higher sleep quality weakened this relationship among female students but not males. Emotional eating mediated the relationship between perceived stress and BMI for both males and females, but higher sleep quality weakened this relationship only among females.
Our findings suggest that students in higher education are likely to benefit from interventions to reduce uncontrolled and emotional eating. Programs that improve sleep quality, especially during highly stressful periods, may be helpful.
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